A-Amino-/3-ketoadipate

Severe hypochromic microcytic anemia, responding only to vitamin B6 and not to iron, a typical symptom of B6 deficiency in many species of animals, is related to the dependence of porphyrin biosynthesis on vitamin Be, preceding the 8-aminolevulinic acid stage, at the condensation of glycine with succinate to yield a-amino- 3-ketoadipate, the immediate precursor of 8-aminolevulinic acid. 

Early isotope tracer experiments by David Shemin permitted the elucidation of the formation of the immediate precursor of the porphyrin needed for the cytochromes and for hemoglobin. These studies indicated that the glycine methylene carbon and nitrogen were incorporated along with both carbons of acetate. Subsequent enzymatic studies in both bacteria and animals revealed a condensation reaction between succinyl-CoA and glycine to yield 5-amino-levulinate and C02 (presumably by way of an enzyme-bound /3-keto acid, a-amino-/3-ketoadipate) (fig. 22.13). 

It has been demonstrated that succinate is first converted to succinyl-CoA in the synthesis of a-amino-/3-ketoadipic acid and that this condenses with the pyridoxal phosphate aldimine derivative of glycine to form 2-aminolevulinic acid and CO2 S9). 

The condensation of succinate with glycine was postulated by Shemin and Russell (29) to form a-amino-/3-ketoadipic acid. This compoimd de-carboxylates spontaneously to form 3-AL (SO). 5-AL when, supplied to duck erythrocytes was shown to be incorporated into heme more readily than succinate or glycine. With labeled 8-AL the tagged C atoms were found in the predicted positions in the porphyrins by the methods described above (SI). 

The outlines of the biosynthetic pathway of the complicated porphyrin structure have been established through elegant use of isotopic methods and biochemical genetics and several of the intermediates have been established, but the details of the enzymatic reactions are only now being investigated. The atoms of porphyrins are all derived from active succinate and glycine.These condense to form a-amino-j8-ketoadipic acid. The decarboxylation of this /3-keto acid results in the formation of... 

The catabolism of lysine merges with that of tryptophan at the level of (3-ketoadipic acid. Both metabolic pathways are identical from this point on and lead to the formation of acetoacetyl-CoA (Figure 20.21). Lysine is thus ketogenic. It does not transaminate in the classic way. Lysine is a precursor of carnitine the initial reaction involves the methylation of e-amino groups of protein-bound lysine with SAM. The N-methylated lysine is then released proteolytically and the reaction sequence to carnitine completed. See Equation (19.6) for the structure of carnitine. 

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