Download MBBS Biochemistry PPT 13 Hemoglobin Structure And Function Lecture Notes

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HEMOGLOBIN:

STRUCTURE AND

FUNCTION

Case 1

A 11-year-old male child was admitted with a history of

having been found unconscious in the bathroom by the elder

brother of the patient.

There was no evidence of associated tonic-clonic

movements, tongue bite, frothing from mouth, vomiting,

bladder, and bowel incontinence or trauma. There was no

history of fever, seizures, headache, vomiting, and substance

abuse prior to this episode.
At the time of admission, patient was unresponsive. Pupils

were normal size and well reacting to light, and plantar reflex

was extensor bilaterally and systemic examination was

normal.

Patient was intubated, mechanically ventilated, and was

started on antiedema measures and other supportive

treatment

MRI: bilateral gyral swelling of the frontal and parietal lobes.

Patient improved and was extubated on the fourth day of

admission and was discharged in satisfactory condition after

seven days without any neurological sequelae.

Ref: Sharma S, Gupta R, Paul BS, et al: Accidental carbon monoxide poisoning in our homes.

Indian J Crit Care Med 2009;13:169-170.
Case 2
A 25-year-old male was found lying unconscious and brought

out after breaking open the bathroom door after one hour.

Similar Examination and MRI like Case 1

He had residual hypoxic damage in the form of persistent

vegetative state and was discharged to a domiciliary care on

request.

Discussion

Gas geysers have emerged as a cost-effective efficient

method for heating water at homes. Gas geysers run on

LPG, the combustion of which leads to generation of CO,

hydrocarbons, and nitrogen oxides.

CO toxicity occurs by competitive binding of CO to the

hemoglobin heme groups shifting the oxygen-

hemoglobin dissociation curve to the left.

The predilection for the globus pallidus may relate to

hypotensive effect of CO poisoning in the watershed territory

of the arterial supply.
Treatment: ??

Hints:

Competitive Inhibitor

Affects oxygen dissociation curve

Learning objectives
Structure of Hemoglobin

Binding of oxygen to Hemoglobin

Binding of CO to hemoglobin

Importance of Oxygen
Why these many symptoms by inhaling a

gas?
ANOXIA
Oxygen needs to be transported from lungs to tissues

efficiently to protect against anoxic episodes

What is the mechanism for this efficient transport?

What is the biomolecule responsible and its characteristics

that supports this function?

Hemoglobin(Hb)

Hemoglobin

Quaternary structure
Hemoglobin

Heme(4)

Globin(4)

Heme : Prosthetic group
Globin: Protein part

Protoporphyrin

ring

HbA: 2, 2

Fe2+
Structure of Heme
Iron containing pigment heme is attached to protein globin

Heme is iron porphyrin complex

called Iron protoporphyrin IX
Conjugated double bonds

Red color to Heme.

Functional form Iron in Heme is-

Ferrous form(Fe++)

Reduced state
Structure of Globin
Adult Hemoglobin has 4 Polypeptide chains : 2 and 2

Heme Pocket

Heme Pocket is a crevice/

hol ow hydrophobic area

Formed in the interior of

Globin subunits

Heme group is tucked

between E and F helices

of Globin subunit.

Amino acids in Globin chain are identified by Helix name

and Position of a.a in that helix.

E7 His ( Distal His), F8 His ( Proximal His)
Oxygen binding of Hemoglobin

Iron has 4 covalent bonds

with pyrrole rings, Fifth

coordination bond with

proximal histidine(F8),

Sixth coordination bond

with divalent oxygen

Divalent oxygen is linked to

Fe++ of Heme and

imidazole group of Distal

histidine(E7)

Where did CO bind in Case 1 and 2??

Hint :
Competitive binding

Affects Mitochondrial ETC
(Respiratory Chain/
Cellular respiration)
To generate AT P

(Oxidative Phosphorylation)
Treatment for CO Poisoning

Treatment includes immediate removal of the victim from the

exposure and administration of high-flow or 100% oxygen by

a non-rebreather reservoir oxygen mask

Prevention: The geyser should not be switched on after

locking the door from inside, ventilation should be kept open

Gas geyser unit should be placed outside the bathroom with

a hose of hot water going inside.

References
1. Victor W. Rodwell, David A. Bender, Kathleen M. Botham, Peter J. Kennel y, P. Anthony Weil.

Harper's Illustrated Biochemistry, 30th Edition

2. Denise R. Ferrier; Lippincott Illustrated Reviews Biochemistry, 7th Edition

3. Kasper, Fauci, Hauser et al., Harrison's Principles of Internal Medicine, 19th Edition
Why 2,3 BPG reduces in stored blood?
During storage of RBCs, large amounts of lactate are formed

and blood pH drops rapidly.

When the pH falls below 7.2, the bisphosphoglycerate

phosphatase wil be activated and the normally high

concentration of 2,3-DPG is rapidly depleted

Duhm J, Gehrlach E. Metabolism and function of 2,3- diphosphoglycreate in red blood cells.

Greenwalt TJ, Jamieson GA, editors. The human red cell in vitro. New York: Grune & Stratton; 1974. p. 111-48.
Where was 2,3 BPG in Glycolysis?
Was it 1,3 BPG or 2,3 BPG?

What do 2,3 BPG has to do with

Oxygenation and Oxygen transport??

In Hb 4 polypeptide chains

are visualized as two

identical dimers, ()1

and ()2 held by

Ionic bonds and

Hydrophobic interactions,

Two dimers are linked to

each other by weak polar

bonds.
Taut and Relaxed forms of Hb

T Form of Hb

R Form Of Hb

Deoxy Hb is in T form

Oxy Hb is in R form binds

binds with CO2,H+ and

only with Oxygen

2,3BPG
T form has salt bridges

Salt bridges are broken in

linked in between the dimer between the dimer subunits

subunits

during oxygenation of Hb.

More constrained form

Less constrained form

T form has low affinity for R form has higher affinity

Oxygen

for Oxygen

T form of Hb predominates R form of Hb predominates

in low pO2

at high pO2
How does these bonds break on

Oxygenation?

Changes in Hb on oxygenation

Fe moves into plane of of heme

22 moves 150 relative to 11

(0.3A0 to 0.1A0 )

Features of oxygenation of Hb
Oxygen links to Ferrous form of Iron, of Heme ( Reversible,

non-enzymatic, no oxidation of Ferrous)
One Hb molecule with 4 Heme can bind to four O2

molecules

Shows c operative binding like allosteric regulatio

Fol ows Hil s equation

Due to tetrametric structure o Hb

Makes it efficient in oxygen transport
How cooperative binding mechanism

makes Hb efficient in oxygen transport

Allows 100% saturation at pO2 much lower than

what it actually requires

Hemoglobin picks up the largest possible load of

Oxygen in the lungs, and delivers the Oxygen

where and when needed.

Role of 2,3 BPG in release of oxygen

One molecule of 2,3-BPG binds

to a pocket, formed by the two -

globin chains, in the center of

the deoxyhemoglobin tetramer
This pocket contains several

positively charged amino

acids(lysine, valine) that form

ionic bonds with the

negatively charged

phosphate groups of 2,3-

BPG.

Stabilizes T form of deoxyHb

Consequence of Transfusing stored blood

Hemoglobin deficient in 2,3-BPG thus acts as an oxygen

"trap" rather than as an oxygen transport system.

Transfused RBCs are able to restore their depleted supplies

of 2,3-BPG in 6?24 hours.

However, severely il patients may be compromised if

transfused with large quantities of such 2,3-BPG?"stripped"

blood
The maximum storage time for red cells has been

doubled (21 to 42 days, with median time of 15 days)

by changes in H+, phosphate and hexose sugar

concentration

Response of 2,3-BPG levels to chronic

hypoxia or anemia
Al osteric effect of 2,3 BPG

on oxygen affinity

2,3 BPG concentration

increases in RBC in

hypoxia/ anemia

HbF: Low affinity for 2,3

BPG
Thank You!

This post was last modified on 05 April 2022