Blood physiology 2

- Synthesis of heme (Ferroprotoporphyrin 1X):-

-Protoporphyrin synthesis begins in the mitochondria , in which succinyl COA combines with glycine to form delta aminolevulinic acid (?ALA) , which is the major rate – limiting step in heme biosynthesis .
-The mitochondrial enzyme ?ALA synthetase , which mediates this reaction, is influenced by erythropoietin & requires the presence of the cofactor pyridoxal phosphate ( vit B6 ) .
-In the cytoplasm , condensation of two molecules of ?ALA , catalyzed by ?ALA dehydrase , produces the mono pyrrole porphobilinogen ( PBG ) .
-Four molecules of porhobilinogen condense to form the tetrapyrrole uroporphyrinogen ? ( UPG ? ) , a reaction catalysed by PBG – deaminase & UPG – isomerase .
-Coproporphyrinogen ? is next formed through decarboxylation reactions from uroporphyrinogen ?.
-The final steps of heme synthesis are carried out in the mitochondria & involve the formation of protoporphyrinogen 1X from coproporphyrinogen ? ( CPG ? ) & subsequently to form protoporphyrin 1X is by aseries of decarboxylations .
-The insertion of iron into protoporyphyrin 1X to form heme which is catalysed by the enzyme heme synthetase .
























( Biosynthesis of Heme )

Glycine Succinyl COA
ALA – synthetase ?
?- aminolaevulinic acid
( ? - ALA ) Erythropoietin


? ALA dehydrase
Porphobilinogen
( PBG )
PBG deaminase
UPG isomerase
Uroporphyrinogen ?

UPG decarboxylase
Coproporphyrinogen ?

CPG decarboxylase
CPG oxidase
Protoporphyrinogen 1X

Protoporphyrin 1X

Fe+2 Heme synthetase

Heme



- The globin synthesis :-

-Globin chain synthesis occurs on RBC –specific cytoplasmic ribosomes, which are initiated from the inheritance of various structural genes . Each gene results in the formation of a specific polypeptide chain .
-The RBC contains four alpha (?) genes , two beta (?) genes , two delta (?) genes & four gamma (?)genes .
-The alpha genes are located on chromosome 16 & the beta , delta & gamma genes are located on chromosome 11.
-The resulting gene product formed have been called alpha , beta ,delta & gamma chains .
-All adult normal Hb are formed as tetramers consisting of two alpha chains Plus two ( non- alpha ) globin chains .

-Normal adult RBC contain the following types of hemoglobin :-

-92 - 95% of Hb is HbA which consist of ?2 B2 chains.
-2 -3% of the Hb is HbA2, which consist of ?2 ?2 chains .
-1-2% of the Hb is HbF ( fetal Hb ) which consist of ?2 ?2 chains .
-Each synthesized globin chain links with heme (Ferroprotoporphyrin 1X ) to form hemoglobin , which consist of two alpha chains , two beta chains & four heme groups .
-An adequate amount of globin chain synthesis is also important since decreased production of one of the polypeptide chains leads to a group of disorders known as thalassemia .
-Since Beta thalassemia , the more common form , refers to a decrease in beta chain production & alpha thalassemia refers to a decrease in alpha chain production .
-The rate of globin synthesis is directly related to the rate of porphyrin synthesis , since the proto porphyrin synthesis is reduced when globin synthesis is impaired .
- In the body of a 70 kg man , there is about 900 gm of Hb ,& 0.3 gm of Hb destroyed & 0.3 gm synthesized every hour.