Download MBBS Biochemistry PPT 13 Hemoglobin Structure And Function Lecture Notes

HEMOGLOBIN:

STRUCTURE AND

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FUNCTION

Case 1

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

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having been found unconscious in the bathroom by the elder

brother of the patient.

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There was no evidence of associated tonic-clonic

movements, tongue bite, frothing from mouth, vomiting,

bladder, and bowel incontinence or trauma. There was no

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

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

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

was extensor bilaterally and systemic examination was

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normal.

Patient was intubated, mechanically ventilated, and was

started on antiedema measures and other supportive

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treatment

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

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Patient improved and was extubated on the fourth day of

admission and was discharged in satisfactory condition after

seven days without any neurological sequelae.

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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

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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

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He had residual hypoxic damage in the form of persistent

vegetative state and was discharged to a domiciliary care on

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request.

Discussion

Gas geysers have emerged as a cost-effective efficient

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method for heating water at homes. Gas geysers run on

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

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hydrocarbons, and nitrogen oxides.

CO toxicity occurs by competitive binding of CO to the

hemoglobin heme groups shifting the oxygen-

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hemoglobin dissociation curve to the left.

The predilection for the globus pallidus may relate to

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hypotensive effect of CO poisoning in the watershed territory

of the arterial supply.
Treatment: ?

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Hints:

Competitive Inhibitor

Affects oxygen dissociation curve

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Learning objectives
Structure of Hemoglobin

Binding of oxygen to Hemoglobin

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Binding of CO to hemoglobin

Importance of Oxygen
Why these many symptoms by inhaling a

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

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efficiently to protect against anoxic episodes

What is the mechanism for this efficient transport?

What is the biomolecule responsible and its characteristics

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that supports this function?

Hemoglobin(Hb)

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Hemoglobin

Quaternary structure
Hemoglobin

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Heme(4)

Globin(4)

Heme : Prosthetic group

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Globin: Protein part

Protoporphyrin

ring

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HbA: 2, 2

Fe2+
Structure of Heme

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Iron containing pigment heme is attached to protein globin

Heme is iron porphyrin complex

called Iron protoporphyrin IX

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Conjugated double bonds

Red color to Heme.

Functional form Iron in Heme is-

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Ferrous form(Fe++)

Reduced state
Structure of Globin

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Adult Hemoglobin has 4 Polypeptide chains : 2 and 2

Heme Pocket

Heme Pocket is a crevice/

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hol ow hydrophobic area

Formed in the interior of

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Globin subunits

Heme group is tucked

between E and F helices

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of Globin subunit.

Amino acids in Globin chain are identified by Helix name

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and Position of a.a in that helix.

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

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Iron has 4 covalent bonds

with pyrrole rings, Fifth

coordination bond with

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proximal histidine(F8),

Sixth coordination bond

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with divalent oxygen

Divalent oxygen is linked to

Fe++ of Heme and

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imidazole group of Distal

histidine(E7)

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Where did CO bind in Case 1 and 2?

Hint :
Competitive binding

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

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(Oxidative Phosphorylation)
Treatment for CO Poisoning

Treatment includes immediate removal of the victim from the

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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

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locking the door from inside, ventilation should be kept open

Gas geyser unit should be placed outside the bathroom with

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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.

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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

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Why 2,3 BPG reduces in stored blood?
During storage of RBCs, large amounts of lactate are formed

and blood pH drops rapidly.

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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

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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?

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Was it 1,3 BPG or 2,3 BPG?

What do 2,3 BPG has to do with

Oxygenation and Oxygen transport?

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In Hb 4 polypeptide chains

are visualized as two

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identical dimers, ()1

and ()2 held by

Ionic bonds and

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Hydrophobic interactions,

Two dimers are linked to

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each other by weak polar

bonds.
Taut and Relaxed forms of Hb

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T Form of Hb

R Form Of Hb

Deoxy Hb is in T form

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Oxy Hb is in R form binds

binds with CO2,H+ and

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only with Oxygen

2,3BPG
T form has salt bridges

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Salt bridges are broken in

linked in between the dimer between the dimer subunits

subunits

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during oxygenation of Hb.

More constrained form

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Less constrained form

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

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in low pO2

at high pO2
How does these bonds break on

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Oxygenation?

Changes in Hb on oxygenation

Fe moves into plane of of heme

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22 moves 150 relative to 11

(0.3A0 to 0.1A0 )

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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

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molecules

Shows c operative binding like allosteric regulatio

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Fol ows Hil s equation

Due to tetrametric structure o Hb

Makes it efficient in oxygen transport

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How cooperative binding mechanism

makes Hb efficient in oxygen transport

Allows 100% saturation at pO2 much lower than

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what it actually requires

Hemoglobin picks up the largest possible load of

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Oxygen in the lungs, and delivers the Oxygen

where and when needed.

Role of 2,3 BPG in release of oxygen

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One molecule of 2,3-BPG binds

to a pocket, formed by the two -

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globin chains, in the center of

the deoxyhemoglobin tetramer
This pocket contains several

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positively charged amino

acids(lysine, valine) that form

ionic bonds with the

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negatively charged

phosphate groups of 2,3-

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BPG.

Stabilizes T form of deoxyHb

Consequence of Transfusing stored blood

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

"trap" rather than as an oxygen transport system.

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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

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

blood
The maximum storage time for red cells has been

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

by changes in H+, phosphate and hexose sugar

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concentration

Response of 2,3-BPG levels to chronic

hypoxia or anemia

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Al osteric effect of 2,3 BPG

on oxygen affinity

2,3 BPG concentration

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increases in RBC in

hypoxia/ anemia

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HbF: Low affinity for 2,3

BPG
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