Mutations in the gene encoding peroxisomal α-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy

Abstract

The rat liver carnitine palmitoyltransferase 1 (L-CPTl) is the key regulatory enzyme of fatty acid oxidation in the liver, with malonyl-CoA acting as a physiological inhibitor. L-CPT1 is anchored into the outer mitochondria1 membrane (OMM) with a Ncyto-Ccyto topology by two transmembrane domains located within the N-terminal domain (residues 1 to 148). We have previously shown that this domain contains all of the informations for targeting the protein to the mitochondria. Moreover, replacement of the N-terminal domain by a specific O M M signal anchor sequence led to the unfolding of the cytosolic C-terminal domain of L-CPTI which is less active and malonyl-CoA insensitive. This has indicated that the N-terminal domain of L-CPTI is essential for maintenance of an optimal conformation of the catalytic C-terminal domain. Other molecular biological studies have now confirmed that the N-terminus of the enzyme is essential for expression of malonyl-CoA sensitivity and full activity of the protein. However, its role in maintenance of the folding state of the catalytic C-terminal domain of L-CPT1 has not been further explored. This and other aspects will be discussed. 82Mitochondria1 carnitine acylcarnitine translocase (CACT) deficiency: identification of new cases using a novel assay followed by molecular analysis of the C A C T gene. L. Ijlst', J.P.N Ruiter', W. Oostheim', H.R. Waterham', V.83 Peroxisomal beta-oxidation in yeast: new insights into the mechanisms involved with emphasis on the role of P E X l l P and YPR128CP, two peroxisomal membrane proteins, in betaoxidation and peroxisomal proliferation.

A new defect of peroxisomal function involving pristanic acid: a case report

“…20 The biochemical defect in this case has only recently been characterised as an absence of the α-methylacyl-CoA racemase. 16 There is stereoselectivity of the α-methyl branched acyl CoA esters and the bile acid intermediates, and these must be converted to their S forms before degradation by peroxisomal β-oxidation. Absence of the racemase has the same consequences as a deficiency of the branched chain acyl-CoA oxidase, although in the second R and S stereoisomers accumulate, and in racemase deficiency only R isomers accumulate.…”

Genetics of familial intrahepatic cholestasis syndromes

“…All patients manifest the neurological deficiencies but only some patients have symptoms of liver failure, 23 probably due to excretion of C27 bile acid intermediates into bile. [24][25][26] Effective therapy for D-bifunctional protein deficiency has not yet been reported.…”

“…It is thought that the bile acid intermediates that are substrates for these enzymes can function as bile acids. 24 Both enzymes are not only involved in bile acid synthesis but also act on branched chain fatty acids such as pristanic acid. This explains the accumulation of pristanic acid in both disorders.…”

-Methylacyl CoA racemase (P504S): overview and potential uses in diagnostic pathology as applied to prostate needle biopsies

“…This is thought to be a consequence of sustained rises in plasma branched chain fatty acids, such as pristinic acid. 13 With respect to prostate cancer, Zheng and colleagues 14 found that particular sequence variants in the AMACR gene strongly co-segregate with prostate cancer development in families affected by hereditary prostate cancer. It is also known that men who consume diets rich in dairy products and red meat are at increased risk for developing prostate cancer.…”