Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom.
Prog Lipid Res. 2013 Apr;52(2):220-30. doi: 10.1016/j.plipres.2013.01.001. Epub 2013 Jan 29.
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.
α-甲基酰基辅酶 A 消旋酶（AMACR；P504S）在支链脂肪酸、布洛芬和相关药物的代谢中催化关键的手性反转步骤。该蛋白在所有前列腺癌和一些其他癌细胞中都有增加，被用作标记物（P504S）。该酶不需要辅助因子，通过烯醇化物中间体的逐步 1,1-质子转移来催化其反应。AMACR 在癌症中的生物学作用很复杂，将脂质代谢与核受体（如 FXR 和 PPAR）活性以及环氧化酶-2（COX-2）等酶的表达联系起来。讨论了各种剪接变体的作用以及单核苷酸多态性（SNP）在癌症中的影响。文献中报道了许多合理设计的 AMACR 抑制剂，作为潜在的癌症治疗方法。从药物化学的角度讨论了酰基辅酶 A 酯作为抑制剂的发展机遇和挑战。药物开发的其他挑战包括酶活性测定和构效关系（SAR）预测的问题。AMACR 抑制剂有可能为去势抵抗性前列腺癌提供一种新的治疗方法，但只有在充分了解生物学的情况下，这一潜力才能实现。还回顾了 AMACR 在寄生虫病中的作用的最新研究工作。
