Flavin-dependent decarboxylases

Flavin-dependent decarboxylases catalyze the oxidative decarboxylation of the C-terminal peptidyl-cysteines to peptidylaminoenethils/aminoenethiolates during the biosynthesis of antibiotics. The key element of this conversion is an oxidation-reduction reaction. The CHjSH side chain of the C-terminal cysteine residue is oxidized to a thioaldehyde or to a tautomeric enethiol with the concomitant reduction of the flavin cofactor. Decarboxylation of the thioaldehyde/enethiolate intermediate occurs spontaneously, because this step is favored by the delocalization of the negative charge of the adjacent thioaldehyde group in a manner similar to the decarboxylation of p-keto acids (Figure 1.35). 

Phosphopantothenic acid reacts with cysteine, forming 4 -phosphopant-othenyl cysteine, which is decarboxylated to 4 -phosphopantetheine in a flavin-dependent reaction. In most bacteria, phosphopantetheinyl cysteine synthase and decarboxylase occur as a single bifunctional enzyme, but the human enzymes occur as two separate proteins (Daugherty et al., 2002). 

Three types of subunit proteins constitute such dehydrogenase complexes (1) a TPP-dependent decarboxylase, which converts the a-keto acid to an a-hydroxyalkyi-TPP complex (2) a transacylase core, which contains lipoyl residues that are acylated by the a-hydroxyalkyl-TPP and (3) a flavin adenine dinucleotide (FAD)-dependent dihy-drolipoyi dehydrogenase, which reoxidizes the reduced Hpoyl... 

Scheme 23.4 Production of methylketones from fatty acids by Penicillium roqueforti. 1 ATP-de-pendent acylcoenzyme A (acyl-CoA) synthase 2 flavin adenine dinucleotidedependent acyl-CoA dehydrogenase 3 enoyl-CoA hydratase 4 NAD-dependent 3-hydroxyacyl-CoA dehydrogenase 5 3-oxoacyl-CoA thiolase 6 3-oxoacyl-CoA thiolester hydrolase and 3-oxoacid decarboxylase. (Adapted from [46])...

One important subgroup of the lyases are the decarboxylases. The decarboxylation of amino acids is assisted by pyridoxal phosphate as a prosthetic group, whereas in the decarboxylation of pyruvate to acetaldehyde, thiamine pyrophosphate (TPP) plays that role. Oxidative decarboxylation, lastly, depends on the cooperation of no fewer than five cofactors thiamine pyrophosphate, lipoic acid, coenzyme A, flavin-adenine dinucleotide, and nicotinamide-adenine dinucleotide. 

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