Lecture 6 – Haemoglobin structure and function

Question 1

Haemoglobin structure (3)

Answer 1

• Haemoproteins are a group of specialized proteins that contain haem as a tightly bound prosthetic group.
o Haem is a complex of protoporphyrin IX and ferrous iron (Fe2+).
o Iron held in the centre of haem molecule by bonds to the 4 nitrogens of the porphyrin ring.

Question 2

Haemoglobin synthesis (4)

Answer 2

•	65% of the Hb is synthesized in the erythroblasts.
•	35% at the reticulocyte stage.
•	Normal conc. of Hb in blood:
o	Adult male	13.5 – 16.5 g/dl
o	Adult female	12.5 – 15.0 g/dl

Question 3

Haemoglobin synthesis - Regulation (2)

Answer 3

• Stimulated by tissue hypoxia.

* Hypoxia causes the kidneys to increase production of EPO, which increases RBC and Hb production.

Question 4

Haem synthesis (4)

Answer 4

• Haem synthesis occurs largely in the mitochondria.
• Chain of Events
o Iron delivery & supply
 Iron is delivered to the reticulocyte by transferrin.
o Synthesis of protoporphyrins
 Occurs in the mitochondria of RBC precursors.
 Mediated by EPO and vitamin B6.
o Protoporphyrin + Iron = haem

Question 5

Globin synthesis (9)

Answer 5

• Globin synthesis occurs in the polyribosomes.
• Rates of haem and globin synthesis are carefully coordinated to ensure optimal efficiency of Hb assembly.
• Proper globin synthesis depends on genes.
o Precise order of amino acids in the globin chains is critical to the structure and function of haemoglobin.
• Various types of globin combine with haem to form different haemoglobin.
• Eight functional globin chains, arranged in two cluster.
o Β-cluster (β, γ, δ and ε globin genes) short arm of chromosome 11.
o Α-cluster (α and ζ globin genes) short arm of chromosome 16.
• Globin gene clusters
• Globin synthesis starts from 3rd
week of gestation.

Question 6

Adult haemoglobin (3)

Answer 6

• Expression of α and β closely balanced.
• Mutations or deletions may lead to:
o Abnormal synthesis of globin chain as in Sickle Cell Diseases.
o Reduced rate of synthesis of normal α- or -globin chains as in Thalassaemias.

Question 7

Functions of haemoglobin (7)

Answer 7

• Remove CO2.
• Carry oxygen from the lungs to the tissues.
• Buffering action, maintains blood pH as it changes from oxyhaemoglobin (carrying O2) to deoxyhaemoglobin (without O2).
• Oxygen delivery to the tissues:
o One Hb can bind to four O2 molecules
o Less than .01 sec required for oxygenation.
o When oxygenated 2,3-DPG is pushed out; the ß-chains move closer.
o ß-chains are pulled apart when O2 is unloaded, permitting entry of 2,3-DPG resulting in lower affinity of O2.
• Oxygen binding and unloading.
• The amount of O2 bound to haemoglobin and released to tissues depends on:
o PO2
o PCO2, but also the
o affinity of haemoglobin for O2.
• Oxygen affinity is the ease with which haemoglobin binds and releases oxygen.

Question 8

Oxygen affinity (3)

Answer 8

• Determines the proportion of O2 released to the tissues or loaded onto the cell at a given oxygen pressure.
• Increases in oxygen affinity means haemoglobin has an increased affinity for O2, so it binds more & strongly.
• Decreases in oxygen affinity, cause O2 to be released.

Question 9

Bohr effect (2)

Answer 9

• Alterations in blood pH, shifts oxygen dissociation curve.
• In acidic pH, the curve shifts to the right  results in an enhanced capacity to release O2 where it is needed.

Question 10

Hb - Oxygen dissociation curve - right shift (5)

Answer 10

• Increased P50.
• Decreased affinity O2.
• Hb willing to release O2 to tissue.
• Examples: anemia, acidosis.
• Even though there may be less RBC’s, they act more efficiently to deliver O2 to target.

Question 11

Hb - Oxygen dissociation curve - left shift (4)

Answer 11

• Decreased P50.
• Increased affinity O2.
• Hb less willing to release O2 to tissue.
• Examples: presence of abnormal Hb’s, alkalosis.

Question 12

CO2 transport (3)

Answer 12

• Three mechanisms of transport:
o Dissolution in the plasma.
o Formation of Carbonic acid.
o Binding to carbaminohaemoglobin.

Question 13

Mutation in globin (3)

Answer 13

• Target cells occur in disproportional increase in SA: V; i.e. abnormally high SA (increased SA), or else decreased intracellular Hb conc.
• It is seen in diseases that affect lipid conc in RBC or decrease Hb; e.g. Thal, IDA, LCAT deficiency.
• Deficiency of lecithin-cholesterol acyltransferase (LCAT). LCAT is an enzyme that coverts free cholesterol into cholesteryl ester. In the absence of LCAT, the cholesterol: phospholipid ratio increases, causing cholesterol build up in the RBC and increasing the size of the membrane of the RBC. Eventually, the surface area rises to abnormally high levels.