Porphyrins 5-amino levulinic acid

The precursor for vitamin B12 synthesis is uroporphyrinogen 111, the common precursor for aU porphyrins, including heme and chlorophyll. Uroporphyrinogen III is synthesized by condensation between succinyl coenzyme A (CoA) and glycine to yield 5-aminolevulinic acid. Two molecules of (5-amino-levulinic acid then condense to form the pyrrole phorphobilinogen, and four molecules of porphobilinogen condense to yield uroporphobilinogen III. 

Intoxication. This indicates that the absorbed lead is having adverse metabolic effects upon a body tissue. The toxicity is proportional to the concentration of lead at the site. Defining minimal manifestations of toxicity has extended with our increasing ability to develop sensitive indices of toxicity. Inhibition of delta-amino levulinic add dehydratase with an increase in urinary amino-levulinic acid is a relatively sensitive index of toxidty in intoxication, indicating that the lead is having an adverse effect on porphyrin metabolism... 

Experiments made on pyridoxal-deficient animals suggested that pyridoxal phosphate and iron are required for the biosynthesis of porphyrin. It was later established that pyridoxal phosphate is required for the formation of -amino levulinic acid, probably by participating in the formation of active glycine. The condensation of succinate and glycine leads to the formation of a very labile a-amino-j -keto adipic acid. The participation of a-amino-jS-keto adipic acid as an intermediate in the reaction was established in experiments proving the acid to be an efficient precursor of porphyrin biosynthesis in vitro. An enzyme system capable of catalyzing the succinyl CoA-glycine condensation and the decarboxylation of the intermediate to yield amino levulinic acid has also been obtained from a particular fraction of chicken erythrocyte. In liver, an enzyme has been found in the mitochondria [132]. 

The fate of 5-amino levulinic acid is dual. It may be converted to porphobilinogen by a pathway to be described below, or under the influence of a transaminase it may yield a-ketoglutaraldehyde, which in turn produces a-ketoglutarate or succinate (see Fig. 3-50). Thus, 5-amino levulinic acid occupies a key position between the citric acid cycle and the porphyrins biosynthetic pathway. The significance of 5-amino levulinic acid in metabolism is illustrated in Fig. 3-50 showing the metabolic conversions involved in the so-called Shemin succinate glycine cycle. 

The porphyrin content of stools is not increased, which suggests that porphobilinogen and a-amino levulinic acid, in contrast to uro- and coproporphyrins, are not excreted in the bile. 

The metabolic alterations are restricted to liver porphyrin metabolism. There are no changes in porphyrin biosynthesis in bone marrow and no hematological changes. The biochemical lesions in the intermittent type of porphyria are probably different from that responsible for erythropoietic porphyria, since in the intermittent type mainly a-amino levulinic acid and porphobilinogen accumulate, whereas mainly uroporphyrin I accumulates in erythropoietic porphyria. The lesions that develop in acute intermittent porphyria could result either from a lack of porphobilinogen use for further metabolic conversion or from an overproduction of a-amino levulinic acid or porphobilinogen. 

Strand, L. J., Felsher, B. F., Redeker, A. G., and Marver, H. S., 1970, Heme biosynthesis in intermittent acute porphyria Decreased hepatic conversion of porphobilinogen to porphyrins and increased delta-amino-levulinic acid synthetase activity, Proc. Natl. Acad. Sci. USA 67 1315. 

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). 

Synthesis of the porphyrin involves the integration between the mitochondrion and cytosol, as in a number of metabolic processes previously examined such as urea synthesis, gluconeogenesis, and some amino-acid catabolism. The first step is mitochondrial, where glycine and succinyl CoA combine, catalyzed by the pyridoxal phosphate-dependent enzyme, amino levulinate synthase (Fig. 20.10). 

The site of heme synthesis for leghemoglobin in nodules has been proposed as being in the bacteroids on the basis of studies examining the incorporation of 8-amino[4- C]levulinic acid into haem in different fractions from legume nodules (Cutting and Schulman, 1969 Godfrey and Dilworth, 1971). Support for this hypothesis has been obtained from studies showing that the level of 8-aminolevulinic acid synthase, a key enzyme in porphyrin biosynthesis, increases in bacteroids from soybean over the same time course as... 

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