α-Methylacyl-CoA racemase (AMACR): Metabolic enzyme, drug metabolizer and cancer marker P504S

摘要

α-Methylacyl-CoA racemase (AMACR; P504S) catalyzes a key chiral inversion step in the metabolism of branched-chain fatty acids, ibuprofen and related drugs. Protein levels are increased in all prostate and some other cancer cells and it is used as a marker (P504S). The enzyme requires no cofactors and catalyzes its reaction by a stepwise 1,1-proton transfer via an enolate intermediate. The biological role of AMACR in cancer is complex, linking lipid metabolism with nuclear receptor (e.g. FXR and PPAR) activity and expression of enzymes such as cyclooxygenase-2 (COX-2). The roles of the various splice variants and the effects of single-nucleotide polymorphisms (SNPs) in cancers are discussed. A number of rationally designed AMACR inhibitors have been reported in the literature as potential cancer treatments. The opportunities and challenges for development of acyl-CoA esters as inhibitors are discussed from a medicinal chemical viewpoint. Other challenges for drug development include the problems in assaying enzymatic activity and the prediction of structure-activity relationships (SAR). Inhibitors of AMACR have potential to provide a novel treatment for castrate-resistant prostate cancers but this potential can only be realized once the biology is well understood. Recent work on the role of AMACR in parasitic diseases is also reviewed.