Porphyrins, biosynthesis

The tetramerization of suitable monopyrroles is one of the simplest and most effective approaches to prepare porphyrins (see Section 1.1.1.1.). This approach, which is best carried out with a-(hydroxymethyl)- or ot-(aminomethyl)pyrroles, can be designated as a biomimetic synthesis because nature also uses the x-(aminomethyl)pyrrole porphobilinogen to produce uroporphyrinogen III. the key intermediate in the biosynthesis of all kinds of naturally occurring porphyrins, hydroporphyrins and corrins. The only restriction of this tetramerization method is the fact that tnonopyrroles with different -substituents form a mixture of four constitutionally isomeric porphyrins named as porphyrins I, II, III, and IV. In the porphyrin biosynthesis starting from porphobilinogen, which has an acetic acid and a propionic acid side chain in the y6-positions, this tetramerization is enzymatically controlled so that only the type III constitutional isomer is formed. 

Pyridoxamine phosphate serves as a coenzyme of transaminases, e.g., lysyl oxidase (collagen biosynthesis), serine hydroxymethyl transferase (Cl-metabolism), S-aminolevulinate synthase (porphyrin biosynthesis), glycogen phosphoiylase (mobilization of glycogen), aspartate aminotransferase (transamination), alanine aminotransferase (transamination), kynureninase (biosynthesis of niacin), glutamate decarboxylase (biosynthesis of GABA), tyrosine decarboxylase (biosynthesis of tyramine), serine dehydratase ((3-elimination), cystathionine 3-synthase (metabolism of methionine), and cystathionine y-lyase (y-elimination). 

Certain strictly anaerobic bacteria and lactic acid bacteria apparently do not contain heme compounds. In the first named organisms this cannot be ascribed to a failure to perform the first step in porphyrin biosynthesis since Clostridia are notorious for production of the porphyrin-like nucleus (corrin) which occurs in vitamin B12 (7, 43). 

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. 

F. R. Murphy, V. Krupta, G. S. Marks, Drug-Induced Porphyrin Biosynthesis. XIII. Role of Lipophilicity in Determining Porphyrin-Inducing Activity of Aliphatic Amides after Blockade of Their Hydrolysis by Bis-(p-nitrophenyl)phosphate , Biochem. Pharmacol. 1975, 24, 883-889. 

Formation of S-aminolevulinic acid (ALA) All the carbon and nitrogen atoms of the porphyrin molecule are provided by two simple building blocks glycine (a nonessential amino acid) and succinyl CoA (an intermediate in the citric acid cycle). Glycine and succinyl CoA condense to form ALA in a reaction catalyzed by ALA synthase (Figure 21.3) This reaction requires pyridoxal phosphate as a coenzyme, and is the rate-controlling step in hepatic porphyrin biosynthesis. 

B. catalyzes a rate-limiting reaction in porphyrin biosynthesis. 

Porphyrin Biosynthesis Starts with the Condensation of Glycine and Succinyl-CoA Glutathione Is y-Glutamylcysteinylglycine... 

De Vemeuil H, Deybach JG, Phung N et al. (1983) Study of anaesthetic agents for their ability to elicit porphyrine biosynthesis in chick embryo liver. Biochem Pharmacol 32 1011-1018... 

S. F. MacDonald and K. H. Michl, Ciba Found. Symp. on Porphyrin Biosynthesis and Metabolism, pp. 285-291 (1955). 

This reaction has been used as an intermediate step in an attempt to synthesize 5-amino-2-fluorolcvLilinic acid (5). a potential inhibitor of porphyrin biosynthesis. ... 

Porphyrin-based photosynthesis has not yet been observed in any archaebac-teria, although the capacity for porphyrin biosynthesis is widely distributed in this group [112]. 

Propionyl-CoA is converted to succinyl-CoA, which is oxidized or converted to glucose by way of oxaloacetate and pyruvate (gluconeogenesis Chapter 15). Succinyl-CoA may also form. 5-aminolevulinate, a precursor of porphyrin biosynthesis (Chapter 29). Formation of succinyl-CoA from propionyl-CoA requires three mitochondrial enzymes and two vitamins (Figure 18-5). 

In vivo C-NMR can be used to study processes such as glycolysis [43-48], gluconeogenesis [49-51], glycogen metabolism [52], COj metaboli.sm [53,54] and porphyrin biosynthesis [13]. These studies have confirmed information obtained by more conventional biochemical methods. 

Physiol 48, 316 (1971). Use of labelled acid in porphyrin biosynthesis studies C. A. Rebciz et al. ibid. 46. 543 (1970). Enhancement of chlorophyll formation S. Ochiai, E. Hase, Plant Cell Physiol 11, 663 (1970), Proposed use as photodynamic herbicide C. A. Rebei2 et al. Enzyme Mt eroh. 

Porphyrinogens are a class of molecules in porphyrin biosynthesis that contain four porphobilinogen molecules. Examples of porphyrinogens include uroporphyrinogen III, coproporphyrinogen III, and protoporphyrinogen IX (Figure 21.30). 

Flolley, A., L.J. King, A.H. Gibbs, and F. De Matteis (1990). Strain and sex differences in the response of mice to drugs that induce protoporphyria Role of porphyrin biosynthesis and removal.,/ Biochem. Toxicol. 5, 175-182. 

V.M. Sardesai, J. Waldman, J.M. Orten (1964). A comparative study of porphyrin biosynthesis in different tissues. Blood, 24, 178-186. 

The synthesis of 5-aminolevulinate requires succinyl CoA, an intermediate in the citric acid cycle, which occurs in the mitochondrial matrix. Thus it makes sense to have the first step in porphyrin biosynthesis occur in the matrix. 

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