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Hemoglobin synthesis & catabolism

Hemoglobin synthesis & catabolism 

Hemoglobin synthesis 

The hemoglobin’s are red globular proteins, which have a molecular weight of about 68,000 and comprise almost one-third of the weight of a red cell. 
The hemoglobin is composed of heme and globin.
▪The main function of red cells is to carry O2 to the tissues and to return carbon dioxide (CO2) from tissues to the lungs.
▪To achieve this gaseous exchange the red cells contain the specialized protein hemoglobin.
▪Each red cell contains approximately 640 million Hb molecules.
▪65% of the Hb is synthesized in the erythroblasts, and 35% at the reticulocyte stage.
▪Heme synthesis occurs largely in the mitochondria. 

▪Globin synthesis occurs in the polyribosomes. 

▪While heme and globin synthesis occur individually inside developing red cell progenitors, their rates of synthesis are orderly coordinated to confirm the optimal efficiency of Hb assembly. 

Globin synthesis 

▪The various globins that combine with heme to form Hb are all single chain polypeptides. 

▪The synthesis of these globins is under genetic control. 

▪Humans normally carry eight functional globin chains, arranged in two, duplicated gene clusters: the β-like cluster (β, ϓ, δ, and ε α globin genes) on the short arm of chromosome 11 and the α-like collection (α and ζ globin genes) on the short arm of chromosome 16. 

Ontogeny of globin synthesis 

Globin synthesis is first noted in the primitive erythroid precursors of the yolk sac at about 3 weeks’ gestation. 


Hemoglobin Gower I (ζ2ε2) 

Hemoglobin Portland (ζ2ϓ2) 

Hemoglobin Gower II (α2ε2) 

Fetal: HbF (α2ϓ2), HbA (α2β2) 

Adult: HbA, HbA2 (α2δ2), HbF. 


Each molecule of normal adult hemoglobin (Hb-A) consists of four polypeptide chains α2β2, each with its heme group. 

▪Normal adult blood also contains small quantities of two other hemoglobins, Hb-F and Hb-A2. These also contain α chains but with ϓ and δ chains respectively instead of β. 

▪The major switch from fetal to adult hemoglobin occurs 3-6 months after birth. 

Normal Hb in adult blood 









Normal %

96-98 %

1.5-3.2 %

0.5-0.8 %

Hemoglobin synthesis 

▪Heme formation starts with the condensation of glycine and succinyl coenzyme A under the action of a rate-limiting enzyme δ -aminolaevulinic acid synthase. 

▪δ-ALA will be formed. 

▪Pyridoxal phosphate (Vit. B6) is a coenzyme for this reaction. 

▪A series of biochemical reactions will follow. 

▪Two molecules of δ -ALA condense to form a pyrrole called porphobilinogen (PBG) 

▪Four PBG condense to form a tetrapyrrole uroporphyrinogen III. 

▪UPG III is then converted to coproporphyrinogen. 

▪CPG then changes to protoporphyrin which ultimately combines with iron in the ferrous state (Fe2+) to form heme. 

▪Iron is brought to the developing red cells by a carrier protein (transferrin) which attaches to special binding sites on the surface of these cells. 

▪Transferrin releases iron and returns to circulation. 

▪Each molecule of heme combines with a globin chain. 

▪A tetramer of four globin chains each with its heme group in a pocket is formed to make up a hemoglobin molecule. 

▪Heme consists of a protoporphyrin ring with an iron atom at its Centre. 

▪The protoporphyrin ring consists of four pyrrole groups that are united by methane bridges (=C-). 

▪The hydrogen atoms in the pyrrole groups are replaced by four methylene (CH3-), two vinyl (-C=CH2), and two propionic acids (-CH2-CH2-COOH) groups.

Hemoglobin catabolism (normal red cell destruction) 

▪Red cell destruction usually occurs after a mean life span of 120 days. 

▪The cells are removed extravascularly by macrophages of the reticuloendothelial system (RES), especially in the bone marrow but also in the liver and spleen. 

▪Red cell metabolism slowly decays as enzymes are degraded and not replaced until the cells become non-viable, but the exact reason why the red cells die is obscure. 

▪The breakdown of red cells liberates: 

1- Iron for recirculation through plasma transferrin to marrow erythroblasts. 

2- Protoporphyrin which is broken down to bilirubin. 

3- Globins which are converted to amino acids. 

Normal red cell destruction 

- The bilirubin circulates to the liver where it is conjugated to glucuronides which are excreted into the gut via bile and converted to stercobilinogen and stercobilin(excreted in feces). 

- Stercobilinogen and stercobilin are partially reabsorbed and excreted in urine as urobilinogen and urobilin. 

▪A small fraction of protoporphyrin is converted to carbon monoxide (CO) and excreted via the lungs. 

▪Globin chains are broken down into amino acids which are reutilized for general protein synthesis in the body. 

Hemoglobin abnormalities
There are chiefly two types of abnormalities, these are: 

▪Quantitative abnormalities: where there is a reduction in the production of certain types of globins e.g. 

α thalassemia 

β thalassemia 

▪Qualitative abnormalities: where there is a production of abnormal hemoglobin e.g. sickle cell anemia.