α-Methylacyl-CoA racemase - an 'obscure' metabolic enzyme takes centre stage

Branched-chain lipids are important components of the human diet and are used as drug molecules, e.g. ibuprofen. Owing to the presence of methyl groups on their carbon chains, they cannot be metabolized in mitochondria, and instead are processed and degraded in peroxisomes. Several different oxidative degradation pathways for these lipids are known, including alpha-oxidation, beta-oxidation, and omega-oxidation. Dietary branched-chain lipids (especially phytanic acid) have attracted much attention in recent years, due to their link with prostate, breast, colon and other cancers as well as their role in neurological disease. A central role in all the metabolic pathways is played by alpha-methylacyl-CoA racemase (AMACR), which regulates metabolism of these lipids and drugs. AMACR catalyses the chiral inversion of a diverse number of 2-methyl acids (as their CoA esters), and regulates the entry of branched-chain lipids into the peroxisomal and mitochondrial beta-oxidation pathways. This review brings together advances in the different disciplines, and considers new research in both the metabolism of branched-chain lipids and their role in cancer, with particular emphasis on the crucial role played by AMACR. These recent advances enable new preventative and treatment strategies for cancer.