Haemoglobin synthesis & catabolism Dr. Suhair Abbas Ahmed Haemoglobin synthesis The haemoglobins 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 haemoglobin is composed of haem and globin. Haemoglobin synthesis The main function of red cells is to carry O2 to the tissues and to return carbon dioxide (CO2) from tissues to the lungs. In order to achieve this gaseous exchange the red cells contain the specialized protein haemoglobin. Each red cell contains approximately 640 million Hb molecules. Haemoglobin synthesis 65% of the Hb is synthesized in the erythroblasts, and 35% at the reticulocyte stage. Haem synthesis occurs largely in the mitochondria. Globin synthesis occurs in the polyribosomes. Although haem and globin synthesis occur separately within developing red cell precursors, their rates of synthesis are carefully coordinated to ensure optimal efficiency of Hb assembly. Globin synthesis The various globins that combine with haem 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 b-like cluster (b, g, d and e globin genes) on the short arm of chromosome 11 and the a-like cluster (a and z globin genes) on the short arm of chromosome 16. Ontogeny of globin synthesis Globin synthesis is first detected in the primitive erythroid precursors of the yolk sac at about 3 weeks’ gestation. Embyonic : Haemoglobin Gower I ( z2e2) Haemoglobin Portland ( z2g2) Haemoglobin Gower II (a2e2) Fetal : HbF (a2g2), HbA (a2b2) Adult : HbA, HbA2 ( a2d2), HbF. Haemoglobin Each molecule of normal adult haemoglobin (Hb-A) consists of four polypeptide chains a2b2, each with its own haem group. Haemoglobin Normal adult blood also contains small quantities of two other haemoglobins, Hb-F and Hb-A2. These also contain a chains but with g and d chains respectively instead of b. The major switch from fetal to adult haemoglobin occurs 3-6 months after birth. Normal Hb in adult blood Hb A Hb A2 Hb F structure a2b2 a2d2 a2g2 Normal % 96-98 % 1.5-3.2 % 0.5-0.8 % Haemoglobin synthesis Haem synthesis starts with the condensation of glycine and succinyl coenzyme A under the action of a rate limiting enzyme d-aminolaevulinic acid synthase. d-ALA will be formed. Pyridoxal phosphate (vit. B6) is a coenzyme for this reaction. Haemoglobin synthesis A series of biochemical reactions will follow. Two molecules of d-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. Haemoglobin synthesis CPG then changes to protoporphyrin which ultimately combines with iron in the ferrous state (Fe2+) to form haem. 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 back to circulation. Haemoglobin synthesis Each molecule of haem combines with a globin chain. A tetramer of four globin chains each with its own haem group in a pocket is formed to make up a haemoglobin molecule. Haemoglobin structure Haem consists of a protoporphyrin ring with an iron atom at its centre. The protoporphyrin ring consists of four pyrrole groups which 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 acid (-CH2-CH2COOH) groups. Haemoglobin 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), specially in the bone marrow but also in the liver and spleen. Red cell metabolism gradually deteriorates as enzymes are degraded and not replaced, until the cells become non viable, but the exact reason why the red cells die is obscure. Haemoglobin catabolism *normal red cell destruction* The breakdown of red cells liberates 1- iron for recirculation via 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 faeces). - Stercobilinogen and stercobilin are partly reabsorbed and excreted in urine as urobilinogen and urobilin. Normal red cell destruction A small fraction of protoporphyrin is converted to carbon monoxide (CO) and excreted via the lungs. Globin chains are broken down to amino acids which are reutilized for general protein synthesis in the body. Normal red cell breakdown haemoglobin haem iron transferrin globin protoporphyrin CO Expired air Amino acids Bilirubin (free) Liver conjugation erythroblast Bilirubin glucuronides Urobilin(ogen) Urine Stercobilin(ogen) faeces Haemoglobin abnormalities There are mainly two types of abnormalities, these are : Quantitative abnormalities: where there is reduction in the production of certain types of globins e.g. a thalassaemia b thalassaemia Qualitative abnormalities: where there is production of abnormal haemoglobin e.g. sickle cell anaemia.