Hb Synthesis

Question 1

Haemoglobin

Answer 1

•Haemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates.

Question 2

Functions of rbc

Answer 2

Transfer of O2 from lungs to tissue
•Transfer of CO2 from tissue to lungs
•Also carries NO bound to thiol group of globin chain

Question 3

Structure of hb

Answer 3

Adult Hb is made up of a tetramer of four globin chains (α1, β1, α2, β2) each with its own haem group (tetrapyrol ring with an Fe2+ molecule in the middle)

Question 4

Sites of hb synthesis

Answer 4

Haem- mitochondria
Globin- polyribosomes

Question 5

Heam synthesis

Answer 5

Precursors are succinyl CoA & glycine forming δ-aminolaevulinic acid (ALA)
•Enzyme is ALA synthase (ALA-S), Pyridoxal phosphate acts as a coenzyme
•Aminolaevulinic acid is converted to Porphobilinogen using a synthase (PBGS)
•Porphobilinogen condenses (deaminase, PBGD) to uroporphyrinogen (a tetrapyrrole ring)

Uroporpyhrinogen is converted to coproporphyrinogen by the action of decarboxylase.
•Coproporphyrinogen is then converted to protoporphyrin by the action of an oxidase enzyme.
•Fe2+ is incorporated into protoporphyrin, catalysed by ferrochelatase

Question 6

Induction of ALA-S and PBGD

Answer 6

IL-3 and erythropoietin induce the enzymes above

Question 7

Rate limiting enzyme for Haem synthesis

Answer 7

•ALA-S is a rate limiting enzyme for haem synthesis

Question 8

Globin synthesis genes

Answer 8

b- cluster (b, g, d and e globin genes) on the short arm of chromosome 11
•a- cluster (a and z globin genes) on the short arm of chromosome 16

Question 9

Regulation of globin synthesis

Answer 9

The locus control region (LCR) or locus activating region (LAR) for β-gene clusters
•HS40 (DNAse 1 hypersensitive site) for α-gene clusters

Question 10

Rxn of hb and oxygen

Answer 10

Oxygenation not oxidation
•One Hb can bind to four O2 molecules
•Less than 0.1 sec required for oxygenation
•b chain move closer when oxygenated
•When oxygenated 2,3-DPG is pushed out
•b chains are pulled apart when O2 is unloaded, permitting entry of 2,3-DPG resulting in lower affinity of O2

Question 11

Rxn of hb and oxygen

Answer 11

Oxygenation not oxidation
•One Hb can bind to four O2 molecules
•Less than 0.1 sec required for oxygenation
•b chain move closer when oxygenated
•When oxygenated 2,3-DPG is pushed out
•b chains are pulled apart when O2 is unloaded, permitting entry of 2,3-DPG resulting in lower affinity of O2

Question 12

Hb configuration

Answer 12

Hb can exist in 2 configurations, deoxy(R) & oxy(T) (T and R stand for tight & relaxed states respectively)
• At some point during the sequential addition of oxygen to the 4 haems, transition from the T to R configuration occurs and the oxygen affinity of the partially liganded molecule increases dramatically.

Question 13

Hb oxygen dissociation curve

Answer 13

Sigmoid shape
•Binding of one molecule facilitate the second molecule binding
•P 50 (partial pressure of O2 at which Hb is half saturated with O2) = 26.6mmHg
•It reflects the allosteric properties of haemoglobin (Hb conformation, & it’s O2 affinity changes as each successive molecule of O2 is bound)
•Ensures that oxygen is rapidly taken up at the high oxygen tensions found in the lungs

And is released readily at the low tensions encountered in the tissues.

Question 14

P50

Answer 14

partial pressure of O2 at which Hb is half saturated with O2) = 26.6mmHg

Question 15

Factors affecting normal position of the hb oxygen dissociation curve

Answer 15

Concentration of 2,3-DPG
◦H+ ion concentration (pH)
◦CO2 in red blood cells
◦Structure of Hb

Question 16

Right shift of the hb oxygen dissociation curve and it’s meaning

Answer 16

Easy oxygen delivery
◦High 2,3-DPG
◦High H+
◦High CO2
◦HbS

Question 17

Left shift of the hbo2 dissociation curve

Answer 17

Low 2,3-DPG
◦HbF

Question 18

Clinical correlates of hb synthesis

Answer 18

Anaemia
•Iron deficiency
•Methaemoglobinaemia
•Haemoglobinopathy
•Acid – base balance