Tetrapyrrole synthesis enzymes

The pyrrole monomer porphobilinogen arises from the condensation of two molecules of S-aminolevulinate with the ions of two water molecules. This reaction is catalyzed by S-aminolevulinate dehydrase. Condensation of four porphobilinogen molecules yields the branchpoint compound in tetrapyrrole synthesis, uroporphyrinogen III. This is a complex reaction requiring two enzymes Uroporphyrinogen I synthase, which catalyzes a head-to-tail condensation... 

A number of ALA analogues are known as competitive inhibitors of ALA dehydratase (Figure 5.7). These contain the succinyl residue of ALA and are believed to form Schiff bases with the enzyme, causing ALA to accumulate in treated tissues. Potentially, such a target for herbicides should be effective, resulting in inhibition of all tetrapyrrole synthesis. However, toxicological problems may be associated with the use of such compounds as herbicides owing to the universal occurrence of ALA dehydratase. 

Perhaps the best-characterized example of this mechanism involves the synthesis of heme cofactors and their subsequent incorporation into various hemoproteins (see Iron Heme Proteins Electron Transport). Succinctly, enzyme-catalyzed reactions convert either succinyl-CoA or glutamate into 5-ammolevulinic acid. This molecule is further converted through a series of intermediates to form protoporphyrin IX, the metal-ffee cofactor, into which Fe is inserted by ferrochelatase. Analogous reactions are required for the synthesis of other tetrapyrrole macrocycles such as the cobalamins (see Cobalt Bu Enzymes Coenzymes), various types of chlorophylls, and the methanogen coenzyme F430 (containing Co, Mg, or Ni, respectively). Co- and Mg-chelatases have been described for insertion of these metals into the appropriate tetrapyrrolic ring structures. ... 

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). 

The a-oxoamine synthases family is a small group of fold-type I enzymes that catalyze Claisen condensations between amino acids and acyl-CoA thioesters (Figure 16). Members of this family are (1) 8-amino-7-oxononanoate (AON) synthase (AONS), which catalyzes the first committed step in the biosynthesis of biotine, (2) 5-aminolevulinate synthase (ALAS), responsible for the condensation between glycine and succinyl-CoA, which yields aminolevulinate, the universal precursor of tetrapyrrolic compounds, (3) serine palmitoyltransferase (SPT), which catalyzes the first reaction in sphingolipids synthesis, and (4) 2-amino-3-ketobutyrate CoA ligase (KBL), involved in the threonine degradation pathway. With the exception of the reaction catalyzed by KLB, all condensation reactions involve a decarboxylase step. 

The aerobic pathway is initiated by the addition of a methyl group to C20 of the tetrapyrrole template resulting in the synthesis of precorrin-3A (Figure 20). This reaction is catalyzed by an enzyme called SAM precorrin-2 methyltransferase (SP2MT), an enzyme that is encoded by coZ /within P. denitrificans The enzyme generates a trimethylated dipyrrocorphin called precorrin-3A as well as It has an of 26 k but in its native... 

For example, incorporation of nickel into carbon monoxide dehydrogenase of Rhodospirillum rubrum requires the prior reduction of an Fe-S cluster. Structural studies of this protein reveal that the added Ni completes a unique [lNi-4Fe-4S] center that is required for activity.Another example of a reductive activation step occurs during NiFe-hydrogenase biosynthesis, perhaps involving participation of the Fe-S cluster in HypD. Yet a third example from the Ni-enzyme literature involves the synthesis of methyl-X-coenzyme M reductase, a methanogen enzyme that contains the Ni-tetrapyrrole cofactor F43q. Formation of active enzyme requires both the reduction of Ni + to NF+ and reduction of a C=N bond in the organic macrocycle. 

To summarize, corrinoids in propionic acid bacteria are involved not onh in fermentation, but also in such important anabolic processes as protein and DNA synthesis and DNA methylation. In this respect, corrinoids differ from other related tetrapyrrole compounds by their polyfunctionalit. The involvement of corrinoid-dependent enzymes in different metabolic processes in propionibacteria explains the propensity of anaerobic strains of the classical propionic acid bacteria to synthesize large amounts of corrinoids under suitable conditions. 

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