Biological Chemistry - Berezov, T. T., & Korovkin, B. F. 1998

Metabolism of Complex Proteins
Chromoprotein Metabolism
Biosynthesis of Hemoglobin

Since the protein moiety of the Hemoglobin molecule (globin) is synthesized just like all other Proteins, The Biosynthesis of its prosthetic group—namely, the Synthesis of the tetrapyrrole compound heme—is discussed in detail below (see Chapter 2).

To date, the major pathways for The formation of Porphyrins and protoporphyrins, which serve as direct precursors of heme and chlorophyll, have been almost completely elucidated. Pioneering studies by D. Shemin and colleagues revealed the primary pathways of heme synthesis. Using labeled precursors in Cell-free extracts of avian erythrocytes, it was demonstrated that Glycine, acetic acid, and succinic acid take specific part in heme synthesis. Glycine was shown to be the source of all 4 nitrogen atoms and 8 carbon atoms of the tetrapyrrole ring, whereas succinic acid (succinate)—more precisely, its derivative succinyl-CoA—serves as the source of the remaining 26 of the 34 carbon atoms. The sequence of Chemical Reactions involved in tetrapyrrole synthesis in animal organisms can be conventionally divided into several stages.

In Stage I, which proceeds in 2 steps, succinyl-CoA reacts with glycine to form δ-aminolevulinic acid (δ-ALA).

Class="center">

This stage is catalyzed by a specific Pyridoxal phosphate-dependent enzyme, δ-aminolevulinate synthase, which is the key allosteric enzyme regulating tetrapyrrole synthesis.

This synthase was first discovered in The Endoplasmic reticulum of Liver Cells. The enzyme is induced by Steroids and other factors and is subject to feedback inhibition by the end product of biosynthesis, heme.

In Stage II, two molecules of δ-aminolevulinic acid condense to form the first monopyrrole compound, porphobilinogen (PBG).

The enzyme catalyzing this stage, porphobilinogen synthase, is also a regulatory enzyme subject to end-product inhibition. It is hypothesized that The Mechanism of this complex dehydration reaction involves the formation of a ketimine bond (Schiff base) between the keto group of one δ-aminolevulinic acid molecule and the ε-amino group of a Lysine residue in the enzyme. In the subsequent multi-step stage catalyzed by appropriate Enzymes, four monopyrrole molecules of porphobilinogen are assembled into the tetrapyrrole complex protoporphyrin IX, the direct precursor of heme. Certain steps of this complex pathway remain to be fully elucidated.

In The final stage, protoporphyrin IX incorporates an iron atom with the participation of ferrochelatase (heme synthase) to yield heme. The newly formed heme is then utilized for the biosynthesis of all heme-containing Chromoproteins.

The source of iron for this reaction is ferritin, which Functions as a reserve iron-protein complex stored within the Cells of the Bone Marrow, liver, and Spleen.

There is evidence that, alongside iron, certain Cofactors—specifically vitamin B₁₂ and copper ions—are also involved in heme synthesis, although their exact role remains to be fully clarified.

Thus, the complete pathway of heme synthesis can be represented as a schematic diagram detailing both the full and abbreviated designations of the intermediate metabolites and enzymes.