Glycine porphyrin synthesis from

ALA and PBG are the precursors of porphyrin synthesis (Fig. 7.3.1). ALA is synthesized from glycine and succinyl-coenzyme A by ALAS. Two molecules of ALA are converted to PBG by the enzyme ALAD. 

Synthesis of haem is readily accomplished from simple precursors. In the first step of porphyrin synthesis succinyl-CoA, which is produced in the citrate cycle and during the metabolism of various amino acids, is condensed with glycine to give d-aminolaevulinic acid, and it is this reaction which is rate-controlling. Subsequently two molecules of d-aminolaevulinic acid condense to form porphobilinogen and four molecules of porphobilinogen undergo a series of reactions to produce protoporphyrin which combines with ferrous ions to form haem. 

It was proposed by Shemin and Russell ( 9) that 5-AL not only gave rise to porphyrins but could be oxidized back to succinic acid. This would provide an alternate path for glycine oxidation. It is difficult to obtain a quantitative idea of the amount of 5-AL that is decomposed via this cycle. Experiments from Neuberger s laboratory (391) suggested that perhaps 30 % of the 5-AL formed may undergo oxidation. The complex relation of glycine metabolism and porphyrin synthesis has recently been carefully analyzed by Neuberger (55). 

The growth, porphyrin excretion, and the activity of the first three enzymes involved in the synthesis of tetrapyrrole skeleton from glycine and succinyl-CoA, ALA synthase, PBG synthase, and PBG deminase, were measured under excretion (ethanol/malate/glutamate, 40°C) and non-excretion (ethanol/NaHC03/NH4Cl, 40°C) conditions (Figures 2 and 3). 

Hgb consists of a protein component with two a and two p chains each chain is linked to a heme group consisting of a porphyrin ring structure with an iron atom chelated at its center, which is capable of binding oxygen. The initial step in the synthesis of heme from the substrate succinyl CoA and glycine requires the presence of pyridox-ine phosphate (vitamin Be) as a catalyst. Following its synthesis in the cytoplasmic mitochondria of the RBC, heme diffuses into the extra-mitochondrial space, combines with the completed a and p chains, and forms Hgb. 

Synthesis of the amino acids Eleven of the twenty common amino acids can be synthesized in the body (Fig. 39.1). The other nine are considered essential and must be obtained from the diet. Almost all of the amino acids that can be synthesized by humans are amino acids used for the synthesis of additional nitrogen-containing compounds. Examples include glycine, which is used for porphyrin and purine synthesis glutamate, which is required for neurotransmitter and purine synthesis and aspartate, which is required for both purine and pyrimidine biosynthesis. 

Subsequently it was shown using [ N]glycine that all 4 nitrogen atoms in protoporphyrin were derived from that amino acid [372]. It is now known that one molecule of glycine and one molecule of succinyl-CoA condense to form one molecule of a-aminolaevulinic acid (ALA). Two molecules of ALA are then linked by the action of cytoplasmic ALA dehydrase to form porphobilinogen (PBG). Four molecules of PBG form a tetrapyrrole, uroporphyrinogen, and subsequently by decarboxylation and oxidation of the side chains, protoporphyrin IX is formed which combines with iron to form haem. Use has been made of both and precursors to elucidate the intermediate steps involved in haem synthesis [373—378]. Much of the early work covering the biosynthesis of porphyrin has been reviewed in detail [379]. 

Inasmuch as cytochrome c is a relatively small protein easily extractable and easily recognized by spectro-photometric methods, it is quite natural that its biosynthesis was investigated in vivo in a variety of tissues. Much of the in vivo work comes from Drabkin s laboratory [116]. These workers used labeled glycine as a precursor and followed its incorporation in both the heme and the protein moiety of cytochrome c. The following is a summary of their findings (1) the isotope is incorporated in both the porphyrin and the protein portion of the molecule (2) the incorporation is more rapid in the heme than in the protein fraction (3) practically all tissues are capable of independent cytochrome c synthesis (4) studies in regenerating liver also demonstrate that the rate of cytochrome c synthesis outweighs the active increase in the cellular population and (5) new cytochrome c is made in the endoplasmic reticulum and transferred by an unknown mechanism to mitochondria. 

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