Download MBBS Biochemistry PPT 49 Chemistry and Functions of Hemoproteins Chemistry Lecture Notes

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Chemistry And Functions Of

Hemoglobin and Myoglobin

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Synopsis

What are Hemoproteins?
What is Hemoglobin?
Structure of Hemoglobin

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Functions of Hemoglobin
ODC and Factors affecting it
Normal Hb Variants
Hemoglobin Derivatives

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INTRODUCTION
Hemoproteins

What Are Hemoproteins?

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Hemoproteins are

Conjugated Proteins

With Heme as a

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Prosthetic group in

their structures.
Hemoproteins are

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Globular Proteins

(Whose Axial ratio less than 10)

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Examples Of

HEME CONTAINING

PROTEINS AND ENZYMES

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Of Human Body


Human Body Hemoproteins

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Compounds with Heme group

Heme Containing Proteins
1. Hemoglobin (Hb)

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2. Myoglobin (Mb)
3. Cytochromes (ETC Components)

Heme Containing Enzymes
1. Catalase

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2. Peroxidase
3. Tryptophan Dioxygenase/

Tryptophan Pyrrolase

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Hemoproteins are

vital for human body
Study Of Hemoglobin

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What Is Hemoglobin?

Hemoglobin(Hb)

is a major

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Hemoprotein of

Human body.

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Hemoglobin Chemically is:

Conjugated Protein

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In Hemoglobin

Heme is a Prosthetic group
Globin is a Protein part

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(Hemoglobin = Heme + Globin)



Hemoglobin(Hb) is Red color

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pigment

Location Of Hemoglobin-
Inside Red blood cells/Erythrocytes

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of blood.


Amount Of Hemoglobin-

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oEach RBC has approx

250-300 million Hb

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molecules

oIn 25 x 1012 Erythrocytes

-750 gm of Hb

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Hemoglobin In RBCs

Occupies:

33% of the RBC volume (1/3)

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90-95% of the dry weight of

RBC is by Hb.

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Normal concentration of

Hemoglobin in the Human Blood:

Adult Males-

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13.5?17.5 gm/dL

Adult Females-

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12.5?16.5 gm/dL
Hemoglobin Biosynthesis-

6.25 gm/day is the amount of Hb

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biosynthesized during stages of

Erythropoiesis in bone marrow.

Synthesis of Hb begins in

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Proerythroblast:

65% at Erythroblast stage

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35% at Reticulocyte stage



Hemoglobin Function

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Hb is associated to Respiration

Mechanism

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Hb is a characteristic of Aerobic

life very important for survival.

Hb brings exchange of Gases-:

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O2 and CO2

Terminologies of Hemoglobin

Hemoprotein -Heme is a prosthetic group

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Chromoprotein - Red in color
Metalloprotein - Metal Iron (Fe) present
Respiratory Protein- Connected to

Respiration process and Respiratory

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Chain(Electron Transport Chain)

Oxygen Binding Protein-Binds with

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molecular Oxygen and transports it.
HISTORICAL ASPECTS

Of

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Hemoglobin

Hemoglobin due to its

red color, has been of

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interest since antiquity.
? Hemoglobin was a :

? First Protein to be crystallized -

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1849.

? First Protein whose Mass

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accurately measured.

? Mol weight of Hb-67,000

Daltons.

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?First proteins to have X-ray

Diffraction structure

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determined.

?First protein to be studied by

Ultracentrifugation.

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?First protein to show that a

point mutation can cause

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problems.
STRUCTURE OF HEMOGLOBIN

Two parts of Hemoglobin

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Heme-Prosthetic group

Globin-Protein part
Hemoglobin Structural y

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Tetrameric-contain 4 subunits.
Quaternary level of structural

organization.

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Allosteric, Complex, Compact
Spheroidal= 64 x 55 x 50
Globular Protein

vHb of adults (Hb A) is a

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Tetramer with

v4 Polypeptide subunits /4

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Globin subunits

vConsisting of 2 - and 2 -

Globin chains

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Each Subunit of Hemoglobin

contains:

1 Globin Chain and 1 Heme

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group with a central Fe2+ ion

(Ferrous ion)

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Hemoglobin Structure



Heme

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One Hemoglobin molecule- 4 Subunits

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One Subunit- 1 Polypeptide

Globin chain and 1 Heme moiety

Four Subunits- 4 Globin

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Polypeptide chains+ 4 Heme

moieties.

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1 Heme binds with 1 Oxygen molecule

4 Heme binds with 4 Oxygen molecule

1 OxyHb = 4 Globin+4Heme+4Oxygen

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In Hb 4 polypeptide

chains are visualized as

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two identical dimers,

()1 and ()2.

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Two dimers are linked to

each other by weak polar

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bonds- movement at the

interface of these two occurs

more freely.

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Two polypeptide chains within a

dimer are held together tightly

by:

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Ionic bonds and Hydrophobic

interactions, which prevent their

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movement relative to each other.

v Thus Hb with

Quartenary structure is

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in native conformation.


Significance of 4 Hb Subunits

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11 and 2 2:

confirms stability of the

molecule.

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1 2 and 2 1 :

confirms solubility of the

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molecule.

1 2 and 1 2:
permit oxygenation and

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deoxygenation.

v a2-b2 or a1-b1 interface has

35 amino acid residues

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contact.

v a1-b2 and a2-b1 have 19

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amino acid residue

contact.
Hemoglobin has

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Outer relatively Hydrophillic

surface (Composed of polar a.a

/Provides Solubility)

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Interior Hydrophobic (Made of

non polar a.a /insoluble a .a- Influences

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Folding)

STRUCTURE /CHEMISTRY

OF HEME

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Chem icWha

ally t

He I

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m se H

is e

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a me?

Ferroprotoporphyrin.

Prosthetic group of Hemoproteins

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Red color pigment
Located interiorly in hydrophobic

Heme pocket present in Globin

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subunit of Hb.

Metalloporphyrin

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Chemically Heme is a

Ferroprotoporphyrin.
Heme Is- Ferroprotophoryin-IX

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Protoporphyrin IX ring + Ferrous (Fe++)

Structure Of Heme
Structure Of Protoporphyrin IX-

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Cyclic substituted Tetrapyrrole ring

structure (I,II,III and IV Tetrapyrrole ).

Tetrapyrrole rings has substituted

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groups in systematic manner-

MV,MV,MP,PM

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(M=Methyl ,V=Vinyl, P=Propionyl)

In Protoporphyrin ring ,Four

substituted Pyrrole rings are linked

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by- 4 Methenyl bridges

Planar network of conjugated

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double bonds of Heme absorbs

visible light and give red color

to Heme.

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Structure of Heme
Iron in Heme

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Functional form Iron in

Heme is-

Ferrous form(Fe++)

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Reduced state

Fe++ located centrally

in Protoporphyrin ring

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system.
Fe of Heme is

Hexavalent.

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Fe of Heme forms 6 coordinated

bonds to satisfy its six valencies:

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4 bonds linked with each Nitrogen

of 4 Pyrrole rings.

5th bond linked with Proximal

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Histidine (F8) of Globin chain

( Globin=87, Globin=92).
6th bond is with Oxygen.

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Binding of Iron in Hemoglobin-

Fe ++ is bound to :

4 Nitrogen of

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Protoporphyrin ring

Globin chain ( Nitrogen of

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Proximal His)

Oxygen

Iron content of Hb -

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3.4 mg / gm of Hb


Role Of Iron in Hemoglobin

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The Mineral, Iron, plays

indirectly an important

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role in the body's

Delivery and use of

Oxygen by working

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Muscles.

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Iron helps in binding

Oxygen to Hemoglobin,

Oxygen get bound to Hb

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then travels in the blood

stream to reach each and

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every cell of the body.
Required amount of

Oxygen, delivery to

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cells

Increases the body's

ability to perform

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work.

Iron supports Aerobic Exercise

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It has been postulated that a lack

of Iron in the body :

Reduces Aerobic capacity

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Impair endurance

performance of exercise.

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Iron of Heme gives red color

The visible absorption

spectra for Hemoglobin

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The red color arises

from the differences

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between the energy

levels of the d

orbitals around the

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Ferrous atom.


Dietary Iron Deficiency

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Features of Iron

deficient red blood

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cells

Low number of

red blood cells

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Hollow and

blanched red

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cells

Iron deficiency is related to

Iron Deficiency Anemia

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Low dietary Iron
Low Heme and Hb formation
Low Oxygen transport and release at

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tissues and cells

Low cellular respiration
Low ETC operation in cells
Low ATP production in cells

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Low cellular activity
Structure of Globin

Globin Subunits

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Adult Hemoglobin has 4

Polypeptide chains

2 and 2 (identical pair).

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Alpha Globin chains-

Composition- 141 amino acids

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Molecular. Wt = 15,126 Daltons
Biosynthesis-Expression of

Globin gene on 16th Chromosome.

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Beta Globin chains-

Composition- 146 amino acids
Molecular. Wt =15,866 Daltons
Biosynthesis- Expression of

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Globin gene on 11th chromosome.


In Hemoglobin ?

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2 (282 amino acid residues)
2 (292 amino acid residues)

Total 574 amino acids are

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present in 1 Hemoglobin

molecule.
Each linear Globin

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Polypeptide chain folds

To form 3 dimensional

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Tertiary structure subunit.

Polypeptide chain has 8

Helices named as A, B, C, ...H.

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Heme Pocket

Heme Pocket is a crevice/

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hollow hydrophobic area

Formed in the interior of

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Globin subunits

To locate the Heme moiety

in it.

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The Heme pocket is surrounded

by E , F and H helices but not

with A , B, C ,D and G.

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Heme group is tucked between
E and F helices of Globin subunit.

Amino acids in Globin chain are

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identified by

The helix name and position

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of a.a in that helix.

E7 His ( Distal His)
F8 His ( Proximal His)
Distal Histidine-E7 ( 58 , 63)

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Proximal Histidine -F8 ( 87 , 92)

Fe++ of Heme is linked to

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Proximal Histidine (F8)

O2 is linked to Distal

Histidine(E7).

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Proximal and Distal His are

present in Heme pocket

In which Heme residue lies

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and facilitates Oxygen binding.

Linking of Divalent O2 :

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1.

Fe++ of Heme

2.

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Nitrogen of Imidazole

group of Distal Histidine

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of Globin chain( 58, 63)


Thus to attain stability

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Oxygen is bound to

both Heme and Globin .

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FUNCTIONS OF HEMOGLOBIN

Hemoglobin has important role in

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Respiration mechanism-

v Hb Majorly Transports-

Oxygen (97% -100%)

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v Hb Minorly Transports ?

Carbon dioxide (15% -25 %)
vDeoxy Hemoglobin

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Transports-Protons(H+)

vThis is also termed as

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Haldane effect

Hemoglobin Plays Role as Buffer-
(Hb/Hb-H+) in the Erythrocytes
Resists change in pH

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Imidazole group of amino acid

Histidine of Hb molecule ?

Participates in buffering

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mechanism of Hb.

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Role Of Hemoglobin in Respiration

Since Hemoglobin has important role

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in respiration mechanism, it is termed

as Respiratory Protein.

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Respiratory Protein Hb serves in

transport and exchange of gases (O2

and CO2) between lungs and tissues.

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How Significant Is

The Presence of Hemoglobin

To Human Body?

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Why Natural y

There Is Presence

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Of Hemoglobin

In the Living Bodies?
Presence of Hb in

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blood

Gives less load to

Heart

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Body cells requires approx. 500

gm/day of molecular Oxygen.

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Molecular Oxygen is sparingly

soluble in body fluids.

This limits the Oxygen

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transport in blood < 30 gm /day.


In fact if the body had to

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depend upon dissolved

Oxygen in the plasma to

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supply Oxygen to the cells.



The Heart would have to

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pump 140 liters per minute.

Instead of normally 4 liters

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per minute.

Hemoglobin a Polar, Oxygen

binding Protein/Oxygen

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carrying Protein of blood.

Increases the binding and

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effective transportation of

Oxygen through blood.
Presence of Hb in blood

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facilitates the blood

To dissolve approx 70 times

more Oxygen than the plasma

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without Hb can do.

oTotal Hb present in

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each RBC

oCarry approx. More

than 1 billion Oxygen

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molecules.
Thus to accomplish the following functions

Red blood cells has Hemoglobin (Hb):

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Transfer of O2 from lungs to tissue

Transfer of CO2 from tissue to lungs

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Hemoglobin serve as a

vehicle for transporting

the Oxygen

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Through blood to reach

each and every cell.
Oxygen transported by Hb and

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reached to every cell is used up in

Mitochondrial ETC

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(Respiratory Chain/Cellular

respiration)

To generate ATP

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(Oxidative Phosphorylation)

SALIENT FEATURES

OF

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OXYGENATION

AND

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DEOXYGENATION

OF HEMOGLOBIN
Oxygenation/Loading of

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Oxygen

Hemoglobin gets Oxygenated

At Lungs

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At increased pO2 concentration

(100-120 mm Hg)

At decreased pCO2

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Saturation Of Oxygen By Hb
Normal ranges of pO2

100-120 mm Hg in arterial

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blood at Lungs

35-40 mm Hg in venous

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blood at tissues.

Hemoglobin is 97 % saturated

with Oxygen when it leaves the

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Lungs-(Arterial Blood-Oxy Hb).

Under resting conditions Hb is

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about 75% saturated with

Oxygen when it returns-(Venous

blood- Deoxy Hb).

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Pulse Oximeter Is An

Instrument

That Measures The Percentage Hb

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Ful y Saturated With Oxygen In

Arterial Blood

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Thus the degree of

saturation with Oxygen is

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related to:

Oxygen tension (pO2)
Oxygen requirement for

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metabolic use at cellular

level

Features of Oxygenation of Hb

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Oxygen binds with Hb to form HbO2

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Oxygen links to Ferrous form

of Iron, of Heme

Non enzymatically, loosely

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and reversibly.

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During oxygenation One Hb

molecule with 4 Heme can

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bind to four O2 molecules.

Binding of Oxygen to Heme of

Hb subunits:

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Is weakly at low pO2

Is tightly at high pO2

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Rate Of Hb Oxygenation:

? Less than 0.01 sec is required

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for Hb Oxygenation.

?During Oxygenation

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Ferrous of Heme is not

oxidized to Ferric.

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v Oxygenation of

Hemoglobin causes

vConsiderable structural

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conformational change

in Globin subunits.

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Binding of Oxygen to Hb

rearranges the electronic

distribution and alters the d

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orbital energy.
This causes a difference in

the absorption spectra.

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Bluish for Deoxy Hb
Reddish for Oxy Hb
Measuring the absorption

at 578 nm allows an easy

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method to determine the

percent of Oxygen bound to

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Hemoglobin.

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Ferric form of Iron is

non functional form

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and cant bind with

Oxygen.

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Deoxygenation/Unloading or

Offloading of Oxygen

Hemoglobin gets Deoxygenated

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At Tissues
With Increased pCO2
Decreased pO2 levels (40 mm Hg)

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? Deoxy Hb has 2,3-Bis Phospho

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Glycerate (23BPG) within it located

central y

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? 2,3-BPG is pushed out of the Deoxy Hb

molecule during oxygenation

? Globin chains move closer when Hb

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is Oxygenated.

Globin chains are pulled apart

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when Hb is deoxygenated

This permits entry of 2,3-BPG

resulting in unloading of Oxygen

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When Hb is fully

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saturated with Oxygen

Each gram of

Hemoglobin is bound

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with 1.34 ml of Oxygen.

COOPERATIVE BINDING

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MECHANISM OF OXYGEN WITH

HEMOGLOBIN
Oxygen Binds To Hemoglobin

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with

Cooperative Mechanism

Positive Al osteric Effect

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Of Hemoglobin
Hb is an Allosteric Oxygen

binder with cooperative

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mechanism.

Cooperative binding mechanism

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is due to Tetrameric structure of

Hb.

Oxygen binding at the

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four sites to the Heme

of Hemoglobin does not

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happen simultaneously.
The binding of the first O2

to one subunit of Hb.

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Enhances the binding of

futher O2 molecules to

remaining subunits of Hb

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with greater affinities.

When Oxygen binds effectively

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with one subunit

There increases the Oxygen

affinities for remaining

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adjacent subunits, this is called

positive cooperativity.
Fourth Oxygen

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molecule binds to fourth

subunit of Hb

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300 times rapidly and

tightly as that of first

Oxygen bound to first

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subunit.

Thus Hemoglobin is a

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remarkable molecular

machine

That uses motion and

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small structural changes

to regulate this action.
When a First Oxygen binds to Fe

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in Heme of Hb,

The Heme Fe is drawn into the

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plane of the Porphyrin ring.

This initiates a series of small

conformational changes that are

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transmitted to adjacent Globin

subunits.

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Oxygen ligand binding

information is

transmitted from one

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subunit of Hb to another.
During Deoxygenation

Hemoglobin releases its bound

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Oxygen.

As soon as the first Oxygen

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molecule drops off, the

Hemoglobin starts changing its

shape.

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This prompts the

remaining three Oxygen

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molecules to be quickly

released.

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In this positive

cooperative way

Hemoglobin picks up the

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largest possible load of

Oxygen in the lungs,

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And delivers the Oxygen

where and when needed.

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T AND R FORMS

OF Hemoglobin
During loading and unloading

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of Oxygen by Hb there occurs

considerable amount of

Allosteric movement.

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This is due to the Oligomeric

/Tetrameric Structure of the

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Hb molecule.

Models for Al osteric Behavior

Monod, Wyman, Changeux (MWC)

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Model:

Allosteric Proteins can exist in two

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states:

v R (Relaxed) State ? Oxy Hb
v T (Taut/Tensed) ? Deoxy Hb

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Oxy & Deoxyhemoglobin


Quaternary structure of

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Deoxy and Oxy Hemoglobin

T-state

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R-state

The conformation of the Deoxy

state of Hb is called the T state

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The conformation of the Oxy

state of Hb is called the R

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state
T form of Hb

Deoxygenated Hemoglobin

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is T form or Tensed/Taut

form of Hemoglobin

conformation.

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T form /Tensed/Taut form of Hb has:

Centrally 2,3 BPG
Hydrogen instead of Oxygen

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CO2

(Illustration Man with Three Tasks)

These moieties are held together by:

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Eight salt bridges/ non covalent

interactions.

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Thus T form is more constrained

form.
T form

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predominates in

the absence of O2.

T form has lower

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affinity for

Oxygen in low

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pO2 environment.
At the center in T form of

Hb there occupies 2,3BPG

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molecule which stabilizes

the Deoxy state of Hb.

Hb has more affinity for 2,3

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BPG when pO2 is low.
Hence R form(OxyHb) at

low pO2

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Gets attracted towards 2,3

BPG

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Binds with it and looses its

Oxygen at Tissues.

R form of Hb

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Oxygenated Hemoglobin

is a R form or relaxed

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form of Hemoglobin

conformation.
During Oxygenation salt

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bridges of T form are broken

T conformation is transformed

to R form.

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R form is less constrained.

R form has

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higher affinity for

Oxygen in high

pO2 environment.

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At the Lungs where pO2 is

high

T form(Deoxy Hb) has now

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higher affinity for O2, than 2,3

BPG

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Hence T form binds with

Oxygen, extruding 2,3BPG

and get transformed to R

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Form.

In R form of Hb

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Only Oxygen is bound

R form has No linkage of

2,3BPG molecule

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Protons
CO2
T R

Hb + pO2 HbO2

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Deoxy-Hb Lungs Oxy-Hb

Increase of partial

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pressure of Oxygen (pO2)

Causes the conversion of

T-form to R-form of Hb.

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Transformation Of

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T to R form of Hb is at Lungs
R to T form of Hb is at Tissues

Directly depends upon pO2

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concentrations in the

environment of body and cells.
The conformational

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changes of Hb from T to R

form and vice a versa are

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known as "Respiratory

movement".

O2 binds much tighter to R

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than to T.

R form of Hb(OxyHb) is more

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negatively charged.


T-form (Tense/Taut)

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has a much lower

oxygen affinity than

the R-form.

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Oxy versus Deoxy Hemoglobin

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Oxygenation

rotates the a1b1

dimer in

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relation to a2b2

dimer about 15?

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T Form of Hb

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R Form Of Hb

Deoxy Hb is in T form

Oxy Hb is in R form binds

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binds with CO2,H+ and

only with Oxygen

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2,3BPG
T form has 8 salt bridges

Salt bridges are broken in

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linked in between the dimer between the dimer subunits

subunits

during oxygenation of Hb.

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More constrained form

Less constrained form

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2,3 BPG is centrally located 2,3 BPG is extruded out from

in T form of Hb

R form of Hb

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T form has low affinity for R form has higher affinity

Oxygen

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for Oxygen

T form of Hb predominates R form of Hb predominates

in low pO2

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at high pO2

Il ustration

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Lungs ? Class Room
Tissues/Cells? House Environment
Oxygen- Study/Knowledge
Hemoglobin- Student
pO2 ?Teacher

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Increased pO2- Knowledgeable and Skilled Teacher
Decreased pO2-Poor knowledge and Skill
T form of Hb- Student at House with

Dance,Sport,Internet

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R form of Hb- Student at Class Room with Study
Oxygenation- Grasping of Knowledge
Deoxygenation- Revision /practice of Knowledge
Metabolic Condition-Examination

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Significance of Tetrameric

Al osteric Structure

Hb being Tetrameric,

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Allosteric protein facilitates

Cooperative binding

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mechanism of Oxygen.

Enhances the efficiency of

Hb as an Oxygen transporter

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Hb rapidly bind with oxygen

in lungs where pO2 is high (100

mm Hg)

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Hb liberate Oxygen at tissue

capillaries where pO2 is low

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(40mm Hg)

4 Factors Affecting

(Al osteric Effectors)

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Loading and Unloading of Oxygen

At Lungs and Tissues
1. pO2 Concentration

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2. pCO2 Concentration
3. pH (H+ Ion Concentration)
4. 2,3

BisPhosphoGlycerate

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(2,3BPG/2,3DPG)

5. Glucose Concentration
6. Metabolic Condition

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pO2 Concentration

At lungs pO2 concentration is

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high pO2 =100-120 mmHg /torr

This favors oxygenation and

loading of oxygen by DeoxyHb.

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DeoxyHb (T form) transformed to

form OxyHb (R form).
At Tissues pO2 concentration is low

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35-40 mmHg /torr

This favors deoxygenation and

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unloading of oxygen by OxyHb

OxyHb(R form) transformed to form

Deoxyhb (T form).

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pCO2 And pH

At tissues due to active

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metabolism

There is high

concentration of pCO2

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and H+ ion concentration

(Low pH values).
Increased pCO2 and low pH at

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tissues

Favors the OxyHb to loose

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affinity for Oxygen,

Which in turn help in

unloading/off loading of oxygen

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at tissues

(R form changes to T form).

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The Bohr's Effect

Relation of Hemoglobin between

pCO2, pO2 and pH

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Described by Danish Physiologist

Christian Bohr In 1904
The Bohr effect is a

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physiological phenomenon

which states that:

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Hemoglobin's Oxygen binding

affinity is inversely related for

both acidity and

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concentration of Carbon

dioxide.

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Thus The effect of

pCO2 and pH on

OxyHb is known as

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Bohr's effect.
Bohr effect facilitates release of

Oxygen/Unloading Of Oxygen.

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Since the tissues are relatively rich

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in Carbon dioxide, the pH is

lower than in arterial blood;

Bohr effect is a

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manifestation of

The acid-base equilibrium

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of Hemoglobin.
CO2 + H2O CA H2CO3 CA H+ + HCO3-

Hydration of CO2 in tissues and

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extremities leads to Proton production.

These Protons are taken up by Hb after

Oxygen released at tissues to Lungs.

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The Protons transported by Hb are

released at the lungs.

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Binding of protons to

Hb diminishes Oxygen

binding to Hb.

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Binding of Oxygen to

Hb diminishes Proton

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binding to Hb.
As the Proton(H+)

concentration increases

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Affinity of Hemoglobin

towards Oxygen is

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reduced.

At acidic pH (More H+ ion

concentration)-Favors unloading

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of Oxygen from OxyHb

At alkaline pH(Less H+ ion

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concentration)-Favors loading of

oxygen to Deoxyhb.
At lungs low pCO2 and low H+.
Favors oxygenation or loading of Hb

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by O2.

Deoxyhb transports H+(protons)

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from tissues to lungs.

On oxygenation of Deoxyhb, the

protons are liberated at lungs.

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Effect Of 2,3BPG

on Loading and Offloading

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Of Oxygen by Hb


2,3 Bis Phospho Glycerate

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2,3 Bis Phospho Glycerate

(2,3BPG/2,3DPG) is an

intermediate of Rapaport

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Leubering cycle

Related to Glycolysis inside

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mature Erythrocytes.
2,3BPG is impermeable

to RBC membrane.

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Glucose metabolism in

Erythrocytes increases the

concentration of 2,3BPG.

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The "Inside" Story......

Where does 2,3-BPG bind ?

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"Inside"
In the central cavity of Hb molecule.

What is special about 2,3-BPG ?

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Negative charges interact with 2 Lys, 4

His, 2 N-termini of Globin.
At low pO2, 2,3BPG has high

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affinity for adult Hb.

Increased 2,3BPG levels ?favors

Oxygen unloading by Hb.

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Decreased 2,3BPG levels -favors

Oxygen loading by Hb.

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The T form of Hb has 2,3

BPG centrally located

Which lowers the affinity

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for Oxygen.
As the partial pressure of Oxygen

increases(pO2),

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The 2,3, BPG is extruded out, and the

Hemoglobin resumes its original

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state, known as the "Relaxed" or "R"

form,

R form has a high affinity for

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Oxygen.

Conditions Of

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High levels of 2,3BPG

During conditions of

cellular deprivation of

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Oxygen.

2,3BPG levels in

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Erythrocytes are increased
Conditions Of

High levels of 2,3BPG

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Hypoxia
At high Altitudes
Severe Anemia
Lung Diseases
Cardiac disease -Anoxia

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Blood loss

2,3 BPG levels in Hypoxia

2,3BPG levels increases in

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hypoxia and at high altitudes.

Changes in 2,3-BPG levels

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play an important role in

adaptation to hypoxia.
In hypoxic conditions pO2 is low

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and

2,3 BPG levels are high

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Due to affected metabolism of

Glucose in RBC's.

Increased 2,3-BPG levels

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in red cells

Decreases Oxygen affinity
Facilitates unloading of

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Oxygen to tissues.
Increased 2,3-BPG

also plays a role in

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adaptation to

exercise.

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Conditions of

Low 2,3BPG levels

Prolonged starvation

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Erythrocyte disorders reduces

the levels of 2.3BPG.

Low 2,3 BPG reduces low

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unloading of oxygen at tissue

level.
However formation of 2,3-BPG is

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not very essential to life.

An individual who lacked the

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enzymes necessary for 2,3-BPG

synthesis (Rapaport Leubering )

was perfectly well except for mild

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Polycythemia.

The increased Oxygen

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affinity of stored blood is

accounted (Blood Banks)

Due to reduced levels of

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2,3-BPG.


Inosine addition to

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stored blood in blood

bank

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Increases the 2,3BPG

levels in it

This favors unloading

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Oxygen on blood

transfusion.

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OXYGEN DISSOCIATION CURVE

OF HEMOGLOBIN

(ODC)

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Oxygen Dissociation Curve

(ODC) of Hemoglobin

ODC describes the relation

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between

Partial pressure of Oxygen

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(pO2) and percent saturation

of Oxygen by Hb.

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ODC for Tetrameric ,Al osteric

Hb molecule is sigmoid shaped

(S shaped)

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Sigmoid Shaped ODC Curve

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Due To

Positive Allosteric Effect

Cooperative Binding Mechanism

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Of Oxygen With Hb
p50 Of ODC

P5o is that pO2 value

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Where the Hb is 50

percent saturated

with Oxygen.

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P50 is 50% saturation

of Hb at pO2 of 27

mm Hg.

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In ODC of Hb

P50 for Adult Hb

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is 27 mm.Hg/torr
ODC depicts

O2 carrying

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capacity of Hb

at different pO2

Salient Features Of ODC of Hb

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Oxygen Dissociation

Curve Depicts:

Oxygen uptake and

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release by Hemoglobin.

ODC Describes

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The fractional saturation

of Heme groups of

Hemoglobin with Oxygen

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at various Oxygen partial

pressures.
Normally the partial O2 pressure in the

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Lungs is 100 mm.Hg and the Hb is

100 % saturated with O2.

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In Tissues the partial oxygen pressure is

40mm.Hg and the Hb is 75% saturated

with O2.

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100 - 75 = 25% of the O2 is released by

OxyHb and delivered to the tissues.

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Percent Saturation Of Hb

At Different pO2

pO2 in torr

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Percent Saturation

Of Hb

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100 in Alveoli

97 %

40 in resting muscles

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64 ? 75 %

20 in working muscles

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20%

10 in vigorously exercising

10%

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muscles
The sigmoid shape of the ODC curve

shows that:

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With a small drop in partial O2

tension (pO2).

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A significant amount of O2

release/offloading by OxyHb will

occur.

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It is to be noted that the

OxyHb reaching to

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tissues

Does not releases its

Oxygen completely at

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one instance.
Instead the release of

Oxygen by OxyHb at

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tissues is

As per the cellular need

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for the Oxygen .

This regulated way of Oxygen

release by OxyHb at tissue level

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May prevent from generation of

oxygen derived free radicals

--- Content provided by⁠ FirstRanker.com ---

(Reactive Oxygen Species: ROS)
Which in turn protect the

peroxidation of cellular

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biomolecules by action of ROS.
FACTORS AFFECTING ODC

OR

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ALLOSTERIC MODULATORS of ODC

The characteristics of normal

ODC depends upon following

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factors:

Hemoglobin Structure

--- Content provided by⁠ FirstRanker.com ---

Environment within the

Erythrocyte
The environment Of

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RBCs depends upon:

pO2
pCO2

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pH(H+ concentration)
2,3-Bisphosphoglycerate
Glucose Concentration
Metabolic Condition
Temperature

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Increased

H+,pCO2, 2,3BPG,Temperature

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Causes unloading of Oxygen

from OxyHb.

They are Negative Allosteric

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effectors of ODC.


Types And Conditions

--- Content provided by FirstRanker.com ---

Of ODC Shifts


Right Shift of ODC

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With Its Conditions

If the Oxygen Dissociation

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Curve is shifted towards Right

v Oxygen is unloaded by OxyHb

--- Content provided by​ FirstRanker.com ---

Oxygen affinity is decreased by Hb

Oxygen is not linked and

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not retained in the Hb structure

--- Content provided by FirstRanker.com ---

--- Content provided by‌ FirstRanker.com ---

--- Content provided by​ FirstRanker.com ---

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Conditions Which Shift ODC

To

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Right Hand Side

Low Oxygen Affinity/Easy Oxygen Delivery/Easy

Unloading/ Prompt Offloading of Oxygen

--- Content provided by⁠ FirstRanker.com ---

? High pCO2 (Increased Metabolic States)

? High H+ (Acidosis)

--- Content provided by⁠ FirstRanker.com ---

? High 2,3-BPG: Hypoxic , Anoxic Conditions

? Exercise

? High body temperature : (Fever)

--- Content provided by FirstRanker.com ---

? Anemia : Hb S (low pO2)


Mnemonic for Factors causing

--- Content provided by FirstRanker.com ---

Right Shift of ODC :

CADET

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C ? CO2
A ? Acid (H+)
D? 2,3-BPG /2,3 DPG
E ? Exercise
T ? Temperature

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Left Shift of ODC

With Its Conditions
If the Oxygen Dissociation

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Curve is shifted towards Left

Oxygen is not unloaded by OxyHb

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Oxygen affinity is increased by Hb

Oxygen is linked and

retained in the Hb structure

--- Content provided by⁠ FirstRanker.com ---

Conditions Which Shift ODC

To

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Left Hand Side

--- Content provided by‍ FirstRanker.com ---

--- Content provided by‍ FirstRanker.com ---

--- Content provided by‌ FirstRanker.com ---

High affinity for Oxygen/ Low oxygen

Delivery/poor unloading of Oxygen

? High pO2

--- Content provided by‌ FirstRanker.com ---

? In Alkalosis ( Low H+ high HCO3-)

? Low 2,3-BPG

--- Content provided by‍ FirstRanker.com ---

? HbF

? Increased Methb and Carboxyhb

COMPARISON OF AN O2 DISSOCIATION CURVE AT NORMAL PH

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AND WITH ACIDOSIS OR ALKALOSIS

--- Content provided by‌ FirstRanker.com ---

Transport Of CO2 and H+

About 75 - 80% of tissue

--- Content provided by FirstRanker.com ---

Carbon dioxide is

processed and

transported in the form

--- Content provided by‍ FirstRanker.com ---

of HCO -3(Bicarbonate ions)
Carbon dioxide

formed during

--- Content provided by‍ FirstRanker.com ---

metabolism in tissues

is out in plasma

--- Content provided by‌ FirstRanker.com ---

Then it diffuses freely

into the Erythrocytes

In aqueous solutions,

--- Content provided by​ FirstRanker.com ---

carbon dioxide undergoes a

pair of reactions

--- Content provided by‍ FirstRanker.com ---

biocatalyzed by enzyme

Carbonic Anhydrase (CA).

--- Content provided by‍ FirstRanker.com ---

Reaction 1

CO + H O H CO (Carbonic Acid)

2

--- Content provided by‍ FirstRanker.com ---

2

2

--- Content provided by⁠ FirstRanker.com ---

3

Reaction 2

H CO H+ + HCO - (Bicarbonate ions)

--- Content provided by‍ FirstRanker.com ---

2

3

--- Content provided by‌ FirstRanker.com ---

3
Where the presence

of an enzyme

--- Content provided by⁠ FirstRanker.com ---

Carbonic

Anhydrase facilitates

reaction 1.

--- Content provided by‍ FirstRanker.com ---

The H+ liberated in

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reaction 2 are accepted by

deoxygenated

Hemoglobin, and

--- Content provided by​ FirstRanker.com ---

transported
The bicarbonate formed

in this sequence of reactions

--- Content provided by‍ FirstRanker.com ---

Diffuses freely across the

red cell membrane and a

--- Content provided by​ FirstRanker.com ---

portion is exchanged with

plasma Cl-,

A phenomenon called the

--- Content provided by​ FirstRanker.com ---

"Chloride shift."

The bicarbonate ions are

--- Content provided by FirstRanker.com ---

carried in plasma to the

lungs

--- Content provided by‍ FirstRanker.com ---

Where excretion of CO

2

occurs in the expired air.

--- Content provided by FirstRanker.com ---

Hb Minorly Transports CO2

15 ? 20% of CO2 is

Transported by Hb.

--- Content provided by‌ FirstRanker.com ---

Transport of Carbon

dioxide by Hb, is unlike

that of Oxygen

--- Content provided by‍ FirstRanker.com ---

CO2 does not bind to

Heme/Fe++ of Hb

--- Content provided by‍ FirstRanker.com ---

CO2 is linked to

Globin part of Hb

and transported.

--- Content provided by‍ FirstRanker.com ---

CO2 is bound to the

To Deoxygenated Hemoglobin
In Globin chains
At N-terminal Amino groups of

--- Content provided by‌ FirstRanker.com ---

Valine residue
To form Carbaminohemoglobin

2 molecules of CO2 are

--- Content provided by‌ FirstRanker.com ---

linked to 1 Hemoglobin

Transported through

blood from tissues to

--- Content provided by‍ FirstRanker.com ---

Lungs and expired out.


? 5% of CO2 is

--- Content provided by⁠ FirstRanker.com ---

carried in free,

dissolved form

--- Content provided by‍ FirstRanker.com ---

through blood.
Thus Deoxy Hb

carries:

--- Content provided by‌ FirstRanker.com ---

CO2 and Protons

from Tissues to

Lungs.

--- Content provided by FirstRanker.com ---

At Lungs as Oxygen

gets bound to Deoxyhb

--- Content provided by FirstRanker.com ---

The CO2 and H+ comes

off of Deoxyhb and

expired out of Lungs.

--- Content provided by⁠ FirstRanker.com ---

At Lungs

At Tissue level

Respired air ?

--- Content provided by‌ FirstRanker.com ---

Metabolism

pO2 is high ?90-100 mm Hg

--- Content provided by⁠ FirstRanker.com ---

pO2 is low-40mm Hg

pCO2 is high.

pH low (H+ high),2,3BPG high.

--- Content provided by⁠ FirstRanker.com ---

Hb is oxygenated to OxyHb (R Form)

OxyHb is dissociated to release

--- Content provided by‌ FirstRanker.com ---

Cooperative binding mechanism of O2 to

oxygen at tissue level./O2 is

Hb

--- Content provided by‌ FirstRanker.com ---

unloaded. OxyHb is deoxygenated

`T' form is transformed to `R' form.

--- Content provided by‌ FirstRanker.com ---

R form is transformed to T form.

O2 binds to Fe ++ of Heme non

O2 released by Hb at tissue level is

--- Content provided by⁠ FirstRanker.com ---

enzymatically loosely and reversibly.

utilized for Biological Oxidation

--- Content provided by‍ FirstRanker.com ---

and process(ETC).

4 O2 to 1 Hb

15-25% of Co2 is transported to

--- Content provided by‍ FirstRanker.com ---

1.34 ml O2/gm of Hb transported

lungs by Hb forming

--- Content provided by‌ FirstRanker.com ---

Carbaminohemoglobin and expired

out through lungs.

O2 is directly linked to Fe ++ of Heme and

--- Content provided by⁠ FirstRanker.com ---

CO2 is not linked to Fe ++ of Heme

distal His of 58 a.a and 63 a.a of Globin. But linked to amino groups of Val

--- Content provided by‍ FirstRanker.com ---

residue.of Globin subunits

NORMAL HB VARIANTS
Normal Hb variants are

--- Content provided by⁠ FirstRanker.com ---

type of Hemoglobins

Present in different

physiological phases of

--- Content provided by‍ FirstRanker.com ---

human life.

Role of Normal Hb Variant

--- Content provided by⁠ FirstRanker.com ---

:

To rightly fit for that

particular physiological

--- Content provided by⁠ FirstRanker.com ---

phase of life

Transport and Deliver

--- Content provided by‍ FirstRanker.com ---

Oxygen as per need and

maintains normal cellular

activity.

--- Content provided by‍ FirstRanker.com ---

Examples of Normal Hb Variants

Of Human Body

Globin Chain Synthesis,

--- Content provided by FirstRanker.com ---

starts at 3rd week of gestation.

Embryonic Stage/Embryonic

--- Content provided by‌ FirstRanker.com ---

Hb -

vHemoglobin Gower I (z2e2)
vHemoglobin Gower II (a2e2)
vHemoglobin Portland (z2g2)

--- Content provided by​ FirstRanker.com ---

Fetal Stage:

v Major Hb : Hb F (a2g2)
v Minor Hb :HbA1(a2b2)

--- Content provided by FirstRanker.com ---

Adult Stage:

v Major Hb : Hb A1 (a2 b2)
v Minor Hb :

--- Content provided by‍ FirstRanker.com ---

vHb A2 ( a2 d2)
vHb A3 (In old RBC's)

vHb F (a2 g2)
vGlycosylated Hb/Hb A1c

--- Content provided by‌ FirstRanker.com ---

All Globin polypeptide chains are

homologous which arise from same

ancestral Genes.

--- Content provided by⁠ FirstRanker.com ---

Beta Polypeptide chain-146 a.a
Gamma chain-146 a.a
(differ in 39 a.a from chain )
Delta chain -146 a.a

--- Content provided by FirstRanker.com ---

(differ in 10 a.a from chain)

GLOBIN GENES

Of

--- Content provided by‌ FirstRanker.com ---

Normal Hb Variants


Globin Gene Clusters

--- Content provided by‍ FirstRanker.com ---

GLOBIN CHAINS In

Different Stages Of

--- Content provided by‍ FirstRanker.com ---

Human life
Globin chain switch

Fetal Hemoglobin

--- Content provided by⁠ FirstRanker.com ---

(HbF)
HbF is a normal Hb

variant of fetal life

--- Content provided by‌ FirstRanker.com ---

Hb F Predominates:

Fetus

--- Content provided by​ FirstRanker.com ---

New born infants

Fetal Hb (Hb F)

Globin part has : 2 and 2 subunits.

--- Content provided by‍ FirstRanker.com ---

Globin chain differs

from Globin chain

in 39 amino acid

--- Content provided by​ FirstRanker.com ---

residues

Histidine residue at 143

--- Content provided by‍ FirstRanker.com ---

position of Globin chain of

Hb A is replaced with

Serine a neutral amino

--- Content provided by​ FirstRanker.com ---

acid In Hb F .
Biosynthesis Of Hb F

Expression of following Globin genes

--- Content provided by​ FirstRanker.com ---

will produce and Globin chains

to form HbF:

--- Content provided by​ FirstRanker.com ---

Globin Gene located on 16 Chromosome
Globin Gene located on 11 Chromosome
Hb F biosynthesis starts by

7th week of gestation.

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In Fetus Hb F predominates

during

--- Content provided by​ FirstRanker.com ---

Second and Third trimester

of gestation

At birth in newborn infants.

--- Content provided by‌ FirstRanker.com ---

After birth there is rapid post

natal decline in HbF levels.

--- Content provided by⁠ FirstRanker.com ---

Within 4 months after birth

HbF is almost completely

replaced by Hb A.

--- Content provided by​ FirstRanker.com ---

Globin chain switch

Function and Features

--- Content provided by​ FirstRanker.com ---

Of HbF
HbF functions in

loading and unloading

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of Oxygen in Fetus and

new born infants.

--- Content provided by FirstRanker.com ---

Hb F has a high

affinity for O2 than

HbA1.

--- Content provided by‍ FirstRanker.com ---

Hb F has low

affinity for 2,3 BPG
HbF binds with O2 at

--- Content provided by​ FirstRanker.com ---

lower pO2 concentrations

than Hb A1.

--- Content provided by‍ FirstRanker.com ---

P 50 for Hb F is 20 torr.

HbF has low Oxygen

releasing/unloading

--- Content provided by FirstRanker.com ---

capacity.

Thus ODC for HbF is

--- Content provided by​ FirstRanker.com ---

shifted towards Left.
Significance Of Hb F in Fetal Stage

The fetus is circulated

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with maternal blood

Which has

comparative low pO2

--- Content provided by⁠ FirstRanker.com ---

as that of Lungs.
Hb F having high

Oxygen affinity

--- Content provided by FirstRanker.com ---

Gets oxygenated at low

pO2 of maternal blood.

--- Content provided by⁠ FirstRanker.com ---

This makes more

efficient trans placental

transfer of Oxygen from

--- Content provided by‍ FirstRanker.com ---

maternal blood to fetal

HbF.
Thus Hb F in fetal phase rightly

--- Content provided by⁠ FirstRanker.com ---

fits for this state:

Since there is a low metabolic

--- Content provided by⁠ FirstRanker.com ---

activities in fetal cells and

requirement of low Oxygen.

Thus low release of Oxygen by

--- Content provided by FirstRanker.com ---

HbF suffice in this condition.

High levels of Hb F

--- Content provided by⁠ FirstRanker.com ---

In Adults Is Abnormal

Normally HbF in adults is less

than 1 %

--- Content provided by FirstRanker.com ---

HbF more than 1% in adult

hood is abnormal.
15-20% of HbF is found in patients

--- Content provided by​ FirstRanker.com ---

of Sickle Cell disease.

(Defect in Globin Genes)

--- Content provided by‍ FirstRanker.com ---

More higher percent of HbF

is noted in individuals

suffering from

--- Content provided by​ FirstRanker.com ---

Thalassemia.

(Defect in Globin synthesis)
High levels of HbF in Adults will

--- Content provided by​ FirstRanker.com ---

have low release of Oxygen at

tissue levels:

--- Content provided by‌ FirstRanker.com ---

Where the metabolic state and

requirement of Oxygen is high.

Thus HbF does not fit in adult

--- Content provided by‍ FirstRanker.com ---

life.

P50 values for Hb A and HbF

--- Content provided by⁠ FirstRanker.com ---

P50 for Hb A= 27 mm.Hg
P50 for Hb F= 20 mm.Hg

--- Content provided by FirstRanker.com ---

--- Content provided by⁠ FirstRanker.com ---

--- Content provided by⁠ FirstRanker.com ---

Adult Hemoglobins

--- Content provided by⁠ FirstRanker.com ---

Adult Hemoglobin Forms

Hb A1

Hb A2

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Hb F

Globin chain a2b2

--- Content provided by‌ FirstRanker.com ---

a2d2

a2g2

combinations

--- Content provided by‌ FirstRanker.com ---

Normal %

96-98 %

--- Content provided by‍ FirstRanker.com ---

1.5-3.2 %

0.5-0.8 %
Globin chain synthesis in adults

--- Content provided by FirstRanker.com ---

25% 25%

0.5% 1.5%

48%

--- Content provided by‍ FirstRanker.com ---

--- Content provided by‍ FirstRanker.com ---

25% 25%

0.5% 1.5% 48%

--- Content provided by‌ FirstRanker.com ---

Chromosome 16

Chromosome 11

--- Content provided by‍ FirstRanker.com ---

Hb A1
HbA1 is the major form

of Hb in adults and in

--- Content provided by​ FirstRanker.com ---

children over 7 months.

Globin has 2 and 2

subunits.

--- Content provided by‍ FirstRanker.com ---

Hb A2
HbA2 has 2 and 2

Globin subunits.

--- Content provided by​ FirstRanker.com ---

Hb A2 is a minor form

of Hb in adults.

--- Content provided by⁠ FirstRanker.com ---

Hb A2 is 2 ? 3% of a total

adult Hb.

Hb A3

--- Content provided by FirstRanker.com ---

HbA3-altered form

of HbA1 found in

old RBC's.

--- Content provided by​ FirstRanker.com ---

Approx 3-10 %.

Hb A1

--- Content provided by⁠ FirstRanker.com ---

Hb F

P D

r iffe

--- Content provided by‍ FirstRanker.com ---

edo

r

--- Content provided by​ FirstRanker.com ---

min eannc

t af etser be

1 yea tr w ofe Predominant in fetus and

--- Content provided by⁠ FirstRanker.com ---

birth and adults.

enn A

--- Content provided by​ FirstRanker.com ---

ew dult

born in - HbA

fants.

--- Content provided by‍ FirstRanker.com ---

1

G and F

--- Content provided by FirstRanker.com ---

lobin ch e

a t

in al- HbF

--- Content provided by‍ FirstRanker.com ---

-2 2

Globin chain-2 2

--- Content provided by FirstRanker.com ---

Less affinity towards O2 and More affinity towards O2

more affinity towards 2.3

and less affinity towards 2.3

--- Content provided by FirstRanker.com ---

BPG at tissues

BPG at tissues.

--- Content provided by​ FirstRanker.com ---

P50 is 27 mm.Hg

P5o 20 mm.Hg

Unloading power of oxygen Unloading power of oxygen

--- Content provided by FirstRanker.com ---

at tissue level is high.

at tissue level is low.

--- Content provided by‍ FirstRanker.com ---

HbA1 denatured by alkali

Hb F resistant to alkali

denaturation.

--- Content provided by​ FirstRanker.com ---

ODC of Fetal Hb F vs. Adult Hb

GLYCOSYLATED

--- Content provided by​ FirstRanker.com ---

HEMOGLOBIN

(HbA1c)
Hb undergoes

--- Content provided by‍ FirstRanker.com ---

spontaneous

glycosylation with

--- Content provided by​ FirstRanker.com ---

Glucose present in

Blood/RBCs.

The extent of glycosylation

--- Content provided by⁠ FirstRanker.com ---

with Hb depends on the

plasma concentration of

--- Content provided by⁠ FirstRanker.com ---

Glucose.


Once Hb is glycated

--- Content provided by‌ FirstRanker.com ---

it remains till the

life span of RBC

(120 days).

--- Content provided by‌ FirstRanker.com ---

Site Of Linkage Of Glucose

To Hemoglobin

Glucose is linked to Globin

--- Content provided by​ FirstRanker.com ---

part of Hemoglobin to Amino

acids:

--- Content provided by FirstRanker.com ---

Valine (terminal a.a ) of
Globin chain and
Lysine amino group

--- Content provided by‌ FirstRanker.com ---

vLater the linked

Glucose is

transformed to

--- Content provided by⁠ FirstRanker.com ---

1-Deoxy Fructose.
Significance of Estimation

of

--- Content provided by‌ FirstRanker.com ---

Blood Glycosylated Hemoglobin

Glycosylated Hb (HbA1c)

--- Content provided by⁠ FirstRanker.com ---

in normal healthy adults

is less than 5%

In Diabetes mellitus the

--- Content provided by​ FirstRanker.com ---

HbA1c is more than 5%
WHO Criteria for Diabetes Mellitus

HbA1c > 6.5%

--- Content provided by‌ FirstRanker.com ---

Levels of Glycated Hb

gives idea of

--- Content provided by​ FirstRanker.com ---

Blood Glucose levels of a

person in last 3-4

months back.

--- Content provided by​ FirstRanker.com ---

Thus estimation of

Glycosylated Hb from blood

--- Content provided by⁠ FirstRanker.com ---

specimens in clinical

Biochemistry laboratory:

--- Content provided by‍ FirstRanker.com ---

Gives Index of Glucose

Control in patients of known

Diabetes mellitus.

--- Content provided by‌ FirstRanker.com ---

As the blood Glucose

levels increases

--- Content provided by FirstRanker.com ---

The percentage of

Glycosylated Hb increases
High Levels Of Glycosylated Hb

--- Content provided by FirstRanker.com ---

Decreases Oxygen Transport to

Tissues

--- Content provided by​ FirstRanker.com ---

Increased Glycosylated Hb

increases its affinity for

Oxygen.

--- Content provided by‌ FirstRanker.com ---

Prevent release/unloading of

Oxygen at tissues

--- Content provided by​ FirstRanker.com ---

Induces hypoxia in extreme

cases
Increased Glycosylated Hb

--- Content provided by FirstRanker.com ---

Decreases Oxygen saturation

with Hb.

Increased Glycosylated Hb

--- Content provided by​ FirstRanker.com ---

Decreases Oxygen release at

tissues

--- Content provided by⁠ FirstRanker.com ---

Risk Of High Levels Of

Glycosylated Hb

In Patients Of Diabetes Mellitus

--- Content provided by‍ FirstRanker.com ---

Diabetes mellitus Patients

Glycated hemoglobin of 6.5% -
Less risk for development of Diabetic

--- Content provided by⁠ FirstRanker.com ---

complications.

Glycated hemoglobin of 12 %-
High risk for development of Diabetic

--- Content provided by FirstRanker.com ---

complications.

HEMOGLOBIN DERIVATIVES
Hemoglobin interacts with chemical

--- Content provided by‍ FirstRanker.com ---

agents to form Hb derivatives.

During formation of Hb derivatives

mostly Fe+2 part of Hb is involved.

--- Content provided by FirstRanker.com ---

Hemoglobin

O2

--- Content provided by⁠ FirstRanker.com ---

NORMAL HB DERIVATIVES
Normal Hb derivatives are

physiological and functional

--- Content provided by FirstRanker.com ---

forms of Hb.

Examples of Normal Hb derivatives.

OxyHb- Hb Bound to O2

--- Content provided by FirstRanker.com ---

Reduced Hb- Hb Bound to H+

ABNORMAL HB DERIVATIVES

or

--- Content provided by⁠ FirstRanker.com ---

Dyshemoglobins
Abnormal Hb Derivatives are

Acquired ones:

--- Content provided by​ FirstRanker.com ---

Abnormal Hb derivatives are

formed:

--- Content provided by‍ FirstRanker.com ---

When blood interacts with

Chemical pollutants/Drugs

which has affinity for Hb.

--- Content provided by‌ FirstRanker.com ---

Abnormal Hb derivatives has

Heme Iron linked to other

--- Content provided by‍ FirstRanker.com ---

chemical compounds

instead of O2

OR

--- Content provided by FirstRanker.com ---

Hb is in a state where

Oxygen may not get linked

--- Content provided by‍ FirstRanker.com ---

to Heme.
Examples of Abnormal Hb

Derivatives

--- Content provided by FirstRanker.com ---

1. Carboxyhemoglobin- CO linked to Fe+2 of Hb
2. Methemoglobin-Fe+2 of Heme transformed to

Fe+3

--- Content provided by​ FirstRanker.com ---

3. Cyanmethemoglobin-CN linked to Methb
4. Sulfhemoglobin-H2S interacted with Hb,
5. Sulfur linked to Fe +2 of Hb
6. Hematin- Ferriprotoporphyrin.
7. Hemin- Hematin Chloride.

--- Content provided by FirstRanker.com ---

8. Hemochromogen - Heme with denatured

Globin.

9. Cathemoglobin - Hematin with denatured

--- Content provided by‌ FirstRanker.com ---

Globin.
Consequences of

Abnormal Hb Derivatives/

--- Content provided by‌ FirstRanker.com ---

Dyshemoglobins

Dyshemoglobin Causes

--- Content provided by​ FirstRanker.com ---

Cyanosis

(Low Oxygen Saturation By Hb)
Dyshemoglobins in acquired states

--- Content provided by FirstRanker.com ---

affect normal structure and

function of Hb.

Dyshemoglobins are non

--- Content provided by​ FirstRanker.com ---

functional forms of Hb.

Dyshemoglobins affects Oxygen

--- Content provided by‌ FirstRanker.com ---

transportation from lungs to

tissues.

CARBOXYHEMOGLOBIN

--- Content provided by​ FirstRanker.com ---

or

Carbon Monoxide Poisoning
Carbon Monoxide (CO)

--- Content provided by⁠ FirstRanker.com ---

is a colorless ,odorless,

toxic gas

--- Content provided by FirstRanker.com ---

Present in atmosphere as

chemical pollutant.

Sources of CO

--- Content provided by‌ FirstRanker.com ---

Product of incomplete combustion of

fuel by vehicles.

--- Content provided by‌ FirstRanker.com ---

Byproduct of Coal mines.
Cigarette Smoking (more than 4%).
Endogenous normal metabolism-

Heme catabolism(Heme Oxygenase

--- Content provided by‍ FirstRanker.com ---

step)
CO has 200 times

more affinity for

--- Content provided by FirstRanker.com ---

Hb than O2.

CO readily links to Fe+2 of Hb and

--- Content provided by FirstRanker.com ---

form- Carboxyhb (Pink colour).

CarboxyHb has no place for binding

O2.

--- Content provided by‍ FirstRanker.com ---

CarboxyHb reduces transportation

and delivery of O2 by Hb.

--- Content provided by‍ FirstRanker.com ---

CarboxyHb delivers CO

at tissues instead of O2.

--- Content provided by FirstRanker.com ---

CO released in cells is

inhibitor of Cytochrome

oxidase in ETC.

--- Content provided by FirstRanker.com ---

CarboxyHb Toxicity

Toxicity due to CarboxyHb

is noted when concentration

--- Content provided by​ FirstRanker.com ---

is more than 20% in blood.

Concentration more than 40

--- Content provided by​ FirstRanker.com ---

-60% of Carboxyhb in body

may lead to death.
Symptoms of CarboxyHb Toxicity:

--- Content provided by⁠ FirstRanker.com ---

v Nausea

v Vomiting

v Headache

--- Content provided by FirstRanker.com ---

v Breathlessness

v Irritability

--- Content provided by​ FirstRanker.com ---

vFatigue

Investigation for CarboxyHb

Study of blood sample using

--- Content provided by FirstRanker.com ---

Hand Spectroscope.

Characteristic bands at 527

--- Content provided by‍ FirstRanker.com ---

and 580 nm in green region

of visible spectrum confirms

presence of CarboxyHb.

--- Content provided by FirstRanker.com ---

Management and Treatment

Of CO Poisoning

Carbon monoxide poisoning

--- Content provided by‍ FirstRanker.com ---

may be reverted

By increasing high

--- Content provided by FirstRanker.com ---

concentrations of O2
Cyanotic cases of Carboxyhb

treated by administration of

--- Content provided by‍ FirstRanker.com ---

oxygen mask/Oxygen

cylinder.

Oxygen under high pressure

--- Content provided by‌ FirstRanker.com ---

is helpful in managing

severe cases of CO toxicity.

--- Content provided by​ FirstRanker.com ---

Increased pO2 favors

replacement of CO by O2 to

form OxyHb transport and

--- Content provided by​ FirstRanker.com ---

deliver to tissues and support

the metabolic function.
METHEMOGLOBIN

--- Content provided by‌ FirstRanker.com ---

Methemoglobin (MetHb) is an

abnormal Hemoglobin

--- Content provided by‌ FirstRanker.com ---

derivative.

Methemoglobin has

Hematin/ Heme Iron in Ferric

--- Content provided by⁠ FirstRanker.com ---

(Fe+3) state.
Hematin is Ferriprotoporphyrin

Hematin +Globin = Methemoglobin

--- Content provided by‌ FirstRanker.com ---

MetHb has defect in Heme

with normal Globin part.

--- Content provided by‍ FirstRanker.com ---

MetHb has non functional

Iron- which cannot bind with

O2 and transport it.

--- Content provided by​ FirstRanker.com ---

Methemoglobin is non

functional oxidized

form of Hemoglobin.

--- Content provided by FirstRanker.com ---

Fe+3 of Hb gets

coordinated with water

--- Content provided by​ FirstRanker.com ---

instead of Oxygen at the

sixth position.
Formation of Methemoglobin

--- Content provided by‌ FirstRanker.com ---

OR

Causes Of Methemoglobinemia

Normally about 1% of

--- Content provided by‍ FirstRanker.com ---

Methemoglobin is

produced in blood

--- Content provided by FirstRanker.com ---

circulation.

Abnormal high levels of

blood Methemoglobin is-

--- Content provided by‍ FirstRanker.com ---

Methemoglobinemia
Causes for Methemoglobinemia:

Acquired Cause :

--- Content provided by⁠ FirstRanker.com ---

Increases above 2% can

occur with the ingestion of

--- Content provided by​ FirstRanker.com ---

strong oxidant drugs

When blood is exposed to Oxidant Drugs

,Hb interacts with it and Fe+2 of Heme

--- Content provided by FirstRanker.com ---

truly gets oxidized to Fe+3.

Potassium Ferricyanide

--- Content provided by‌ FirstRanker.com ---

Nitrites

Chlorates

Antipyrins

--- Content provided by⁠ FirstRanker.com ---

Sulfa Drugs (Sulfonamides)

Aniline Dyes
Conversion

--- Content provided by FirstRanker.com ---

Of

Methemoglobin

--- Content provided by‍ FirstRanker.com ---

To

Hemoglobin

Reducing agents converts

--- Content provided by‍ FirstRanker.com ---

Methemoglobin to functional Hb.

Glutathione

--- Content provided by‌ FirstRanker.com ---

Ascorbic acid
Enzymes converts Methemoglobin

back to

--- Content provided by​ FirstRanker.com ---

Hemoglobin:

Methemoglobin Reductase
Cytochrome b5 Reductase

--- Content provided by​ FirstRanker.com ---

Conversion Of Methemoglobin To

Hemoglobin is

NADPH+H+ Dependent

--- Content provided by‌ FirstRanker.com ---

H2O2 and Oxidant Drugs

Hemoglobin

--- Content provided by FirstRanker.com ---

Methemoglobin

(Fe+2)

--- Content provided by FirstRanker.com ---

(Fe+3)

Methemoglobin Reductase

--- Content provided by‍ FirstRanker.com ---

NADP+ NADPH+ H+
The source of

NADPH+H+ for the use

--- Content provided by⁠ FirstRanker.com ---

of Methemoglobin

reductase activity is

--- Content provided by‍ FirstRanker.com ---

Pentose Phosphate

Pathway(HMP Shunt).

Defect in HMP Shunt

--- Content provided by⁠ FirstRanker.com ---

affects the conversion of

Methemoglobin to

--- Content provided by⁠ FirstRanker.com ---

Hemoglobin due to devoid

of NADPH+H+

--- Content provided by​ FirstRanker.com ---

Congenital Causes of

Methemoglobinemia

As a result of deficiencies of

--- Content provided by‌ FirstRanker.com ---

Methemoglobin

Reductase

--- Content provided by⁠ FirstRanker.com ---

G6PD enzyme of HMP

shunt
Familial Methemoglobinemia

--- Content provided by⁠ FirstRanker.com ---

Inherited deficiency of

Enzyme Methemoglobin

Reductase in the body

--- Content provided by⁠ FirstRanker.com ---

Causes Familial

Methemoglobinemia.

--- Content provided by​ FirstRanker.com ---

G6PD deficiency of HMP shunt

reduces generation of NADPH+H+

Which in turn affects

--- Content provided by​ FirstRanker.com ---

Methemoglobin Reductase

activity also leads to

--- Content provided by‌ FirstRanker.com ---

Methemoglobinemia.
Methemoglobin Reductase in

absence of NADPH+H+

--- Content provided by‌ FirstRanker.com ---

Does not convert

Methemoglobin back to

Hemoglobin.

--- Content provided by​ FirstRanker.com ---

Methemoglobin levels in blood

gradually increases to

--- Content provided by FirstRanker.com ---

Methemoglobinemia.

Consequences

Of

--- Content provided by​ FirstRanker.com ---

Methemoglobinemia
Methemoglobin is brown

colored pigment.

--- Content provided by‌ FirstRanker.com ---

Hence

Methemoglobinemia ?

--- Content provided by FirstRanker.com ---

termed as :

Chocolate Cyanosis

--- Content provided by​ FirstRanker.com ---

Toxic Effects Of Methemoglobin

Methb has Fe+3 which is non

--- Content provided by⁠ FirstRanker.com ---

functional

Does not bind and transport

O2 to tissues.

--- Content provided by‌ FirstRanker.com ---

Instead binds with water.
10-20% of Methemoglobin- Mild

Cyanosis.

--- Content provided by⁠ FirstRanker.com ---

50-60% of Methemoglobin- Severe

Cyanosis, Cardiopulmonary

--- Content provided by‍ FirstRanker.com ---

Symptoms-Tachycardia, Depression.

More than 60% of Methemoglobin-

Unconsciousness and death.

--- Content provided by⁠ FirstRanker.com ---

Investigation Of MetHb

Study of Blood Sample

--- Content provided by​ FirstRanker.com ---

using Hand

Spectroscope.

Performing Schumm's

--- Content provided by FirstRanker.com ---

Test (Spectroscopy)
Management Of

Methemoglobinemia

--- Content provided by‌ FirstRanker.com ---

Oral administration

of reducing agents

--- Content provided by‍ FirstRanker.com ---

Ascorbic acid

Methylene Blue

Dried blood and old meat

--- Content provided by​ FirstRanker.com ---

have brown color.

Butchers uses Ascorbic acid

--- Content provided by FirstRanker.com ---

to reduce Methemoglobin to

make the meat look fresh!!
Sulfhemoglobin

--- Content provided by⁠ FirstRanker.com ---

Sulfhemoglobin - occurs when the

sulfur content of the blood

increases due to

--- Content provided by⁠ FirstRanker.com ---

Ingestion of sulfur containing

drugs

--- Content provided by​ FirstRanker.com ---

In chronic constipation( Gut

bacteria acts on unexcreted

material produces H2S)

--- Content provided by FirstRanker.com ---

Sulfhemoglobin is greenish

compound where sulfur is

--- Content provided by​ FirstRanker.com ---

covalently attached to

Porphyrin ring (Not to Iron).

Sulfhemoglobin cannot bind

--- Content provided by FirstRanker.com ---

with Oxygen.
Unlike the formation of

Carboxyhb and Methb,

--- Content provided by‌ FirstRanker.com ---

The formation of Sulfhb is an

irreversible change of Hb.

--- Content provided by​ FirstRanker.com ---

Drugs producing Sulfhemoglobin:

Dapsone (Leprosy treating drug)
Phenacetin
Acetanilide

--- Content provided by‍ FirstRanker.com ---

Sulfanilamides
These drugs produce Methb too
MYOGLOBIN

Myoglobin (Mb)-

--- Content provided by​ FirstRanker.com ---

Mb is a Hemoprotein of red

skeletal muscles.

--- Content provided by​ FirstRanker.com ---

Primarily occur in Cardiac

muscles.

--- Content provided by​ FirstRanker.com ---

Structure Of Myoglobin

Myoglobin is a

Monomeric unit

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Mb is composed one

Globin chain and one

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Heme moiety.

Myoglobin (Mb)
Mb is Spheroidal ,globular

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molecule 44 x 44 x 25

Mb: Mol Wt 17,200 Daltons.

Myoglobin is rich in alpha

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helix.

Globin part of Myoglobin is

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composed of single

polypeptide chain

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Composed of 153 amino

acid residues.
Myoglobin contains 1 Heme

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group which binds with 1 O2 .

Iron in Mb is Fe2+ (Ferrous ion)

the functional form that binds

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Oxygen.

Oxygen binds as the sixth

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ligand to Fe (MbO2)

Myoglobin has very low

p50 value 2-3 torr/mm.Hg.

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ODC of Myoglobin is

simple hyperbolic curve.

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In comparison to Hemoglobin A and

HbF Myoglobin has high affinity for

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Oxygen.

Hb F and Mb has low p50 values as

compared to p50 value of Hb A1.

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With low p50 ,more Oxygen binds at

low pO2.
Function Of Myoglobin

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Myoglobin is found in

cytosol of skeletal and

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Heart muscles.
Myoglobin facilitates rapidly

Respiring muscle tissue

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The rate of O2 diffusion from capillaries to

tissue is slow because of the solubility of

Oxygen.

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Myoglobin increases the solubility of

Oxygen.

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Myoglobin facilitates Oxygen diffusion.

Myoglobin in Muscle

Cells is a:

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Oxygen storing

Hemoprotein

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Reservoir of Oxygen
Myoglobin does not allow

Oxygen to remain in free state:

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Oxygen diffused in muscle cells is

used up in Oxidative

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phosphorylation.

If Oxygen remained unused in the

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cells it immediately binds with Mb

to form MbO2

MbO2 releases/unloads

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O2 when required.

MbO2 unloads oxygen

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at extreme conditions

When pO2 of cellular

level reaches to 5 mm Hg.

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Myoglobin releases

Oxygen in rapidly

respiring cells.

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The released O2 is used

up in Oxidative

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Phosphorylation.

Mb present within muscle cells comes

out in blood after damage to muscle

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cells.

Mb is found abnormally in blood and

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urine of MI cases.

Thus elevated Myoglobin levels in

blood/urine is a marker of

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Myocardial damage.
Metmyoglobin does not

bind to Oxygen.

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Since oxidation of Fe+2 yields

Fe +3 -Ferric iron

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(non functional form)

Differentiate Between Hb and Mb
S.No Hemoglobin (Hb) Myoglobin (Mb)

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1. Diffe

Hb rise

O nc

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xyge e

n t s

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ra nsof

port

Mb is Oxygen storing protein in

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protein in RBCs of bloo Hb

d.

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A

mu nd

scles. Mb

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2.

Tetrameric has four Heme and Monomeric has one Heme and

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binds with 4O2

binds with 1 O2.

3.

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Oxygenated at Lungs

Oxygenated at Muscle Cell

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Cytosol.

4.

HbO2 unloads oxygen at

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MbO2 unloads oxygen at cell

tissues when pO2 is at 40

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cytosol when pO2 is at 5 mmHg. To

mmHg.

rapidly respiring cells

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P50 for HbA1 is 27 torr.

P50 for Mb is 2 torr.

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5.

ODC is sigmoid shaped

ODC is hyperbolic shaped.

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6.

Hb has 574 amino acids.

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Mb has 153 amino acids.

Mol .wt-67,000 Daltons.

Mol wt-17,200 Daltons.

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Cytochromes
Cytochromes ? Hemoprotein.

Cytochromes are components

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of ETC

Who bring Oxidative

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phosphorylation and

generates ATP .

Cytochrome P450-

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Involved in Drug

detoxification.
Catalase and Peroxidases

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Enzymes present richly in

Peroxisomes of cells.

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Catalase and Peroxidase are of

Enzyme Class- Hydroperoxidases.

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Glutathione

Peroxidase (R.B.C)

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Leucocytes

Peroxidase (W.B.C)
Catalase and Peroxidase

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Detoxify H2O2

Substrate for Catalase and

Peroxidase is H2O2 which detoxify

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it.

Catalase and Peroxidase decomposes

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2H2O2 to 2 H2O and O2.
Role of Catalase and Peroxidase

v Prevents accumulation of H2O2

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(Toxic free radical) in cells .

vPrevents Peroxidation of membrane

lipids and protect cellular lysis.

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Tryptophan Dioxygenase

Tryptophan Dioxygenase/Tryptophan

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Pyrrolase involved in Tryptophan

catabolism.

Deficiency of Tryptophan Dioxygenase

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Accumulates Tryptophan without its

breakdown to liberate Acetyl-CoA

(Ketogenic precursor) and Alanine

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(Glucogenic precursor).
Deficiency of Tryptophan

Dioxygenase

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Blocks Kynurenine

Pathway for the biosynthesis

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of Niacin from Tryptophan.

Effect Of Cyanide and Carbon

Monoxide on Hemoproteins

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CN and CO disrupts

physiological function of

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HemoProteins.

Thus CN inhibits the function

of Hb ,Mb, Cytochromes.

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Impaired activity of these

Hemoproteins

Badly affects Oxygen

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metabolism and ATP

generation.

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More affected cells are

Nervous system,

Erythrocytes.

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Questions Of Hb Chemistry
1. Structure Of Hemoglobin
2. Heme Structure
3. Globin Structure

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4. Functions of

Hemoglobin/Biomedical

Importance of Hemoglobin.

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5. Salient features of Hemoglobin

Oxygenation and Deoxygenation.

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6. Allosteric Effectors of Loading and

Unloading of Oxygen by Hemoglobin.

7. 2,3 BPG and its role in Hb.

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8. ODC of Hemoglobin and factors

affecting it

9. CO2 Transportation in human body

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10. Normal Hb Variants
11. Glycosylated Hb and its significance.
12. Hemoglobin Derivatives
13. Dyshemoglobins/Abnormal Hb

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derivatives

14. CarboxyHemoglobin
15 . Methemoglobin
16. Types of Hemoproteins

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Differentiate between following:
1. Hb A and Hb F
2. Hemoglobin and Myoglobin
3. T form and R form of Hb

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4. Hb at Lungs and Hb at Tissues/
Oxygenation of Hb and

Deoxygenation of Hb.
THANKYOU

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