2- Methylacyl-CoA racemase

Alkyl PAT, alkyl-dihydroxy phosphate synthase Bif, bifunctional enzyme DHAPAT, dihydroxyphosphate acyltransferase deficiency DHCA, dihydroxycholestanoic acid N, normal nd, not determined Ox, acyl-CoA oxidase Rac, 2-methylacyl-CoA racemase RCDP, rhizomelic chondrodysplasia punctata Ref, Refsum s disease THCA, trihydroxycholestanoic acid VLCFA, very-long-chain fatty acid. 

The synthesis of optically pure 2-methylacyl-CoA allowed us to investigate the stereospecificity of the acyl-CoA oxidases. Rat pristanoyl-CoA oxidase and THCCox (and most likely BRCACox) desaturate only the 2S-forms. Naturally occurring pristanic acid is racemic at position 2. To degrade the 2R-isomer, it needs to be transformed to the 2S-isomer and this happens at the level of the CoA ester. The responsible enzyme is 2-methylacyl-CoA racemase. It is present in mitochondria and in peroxisomes, both in rat and man. Presumably, the mitochondrial racemase activity is required for the racemisation of the shortened pristanic acid metabolites formed by peroxisomal P-oxidation and that contain 2R-methyl branches. Mitochondrial oxidation of branched fatty acids, like the peroxisomal one, is stereospecific for the 2S-isomers. ... 

Peroxisomal fatty acid y9-oxidation deficiencies Acyl-CoA oxidase deficiency and D-bifunctional protein deficiency have both been resolved at the molecular level [10] and many often private mutations have been identified. The same is true for Refsum disease and 2-methylacyl-CoA racemase deficiency [16]. 

Also other members of the profen-family, among them naproxen, flurbiprofen, ketoprofen and tiaprofenic acid, are of great importance today. In general, these are 2-aryl- or 2-heteroaryl-propionic acids, of which in vitro only the (S)-(+)-enantiomer inhibits cyclooxygenase-1 (Fig. 5.84). In vivo, depending on the particular animal species, and also in humans, the (U)-(-)-enantiomer is converted to various degrees into its (S)-enantiomer with the aid of -methylacyl-CoA-racemase, via the Coenzyme A-thioester. In addition, more recent investigations could show that (R)-ibuprofen and (R)-flurbiprofen themselves have also anti-inflammatory properties. Many of the profens, with the exception of naproxen, are therefore marketed as racemates. 

Ferdinandusse S, Denis S, Clayton PT, Graham A, Rees JE, Allen JT et al. Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy. Nat Genet 2000 24(2) 188-191. 

Van Veldhoven, P.P., Croes, K., Casteels, M. Mannaerts, G.P. (1997) Biochim. Biophys. Ada. 1347, 62-68. 2-Methylacyl racemase a coupled assay based on the use of pristanoyl-CoA oxidase/peroxidase and reinvestigation of its subcellular istribution in rat and human liver. 

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