Hu Xiaoyi, Dang Yongjun, Tenney Karen, Crews Phillip, Tsai Chiawei W, Sixt Katherine M, Cole Philip A, Liu Jun O
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University, School of Medicine, 725 N. Wolfe Street Baltimore, MD 21205, USA.
Chem Biol. 2007 Jul;14(7):764-74. doi: 10.1016/j.chembiol.2007.05.010.
Methionine aminopeptidases (MetAPs) remove the N-terminal initiator methionine during protein synthesis, a prerequisite step for N-terminal myristoylation. N-myristoylation of proto-oncogene c-Src is essential for its membrane association and proper signal transduction. We used bengamides, a family of general MetAP inhibitors, to understand the downstream physiological functions of MetAPs. c-Src from bengamide A-treated cells retained its N-terminal methionine and suffered a decrease in N-terminal myristoylation, which was accompanied by a shift of its subcellular distribution from the plasma membrane to the cytosol. Furthermore, bengamide A decreased the tyrosine kinase activities of c-Src both in vitro and in vivo and eventually delayed cell-cycle progression through G(2)/M. Thus, c-Src is a physiologically relevant substrate for MetAPs whose dysfunction is likely to account for the cell-cycle effects of MetAP inhibitors including bengamide A.
甲硫氨酸氨肽酶（MetAPs）在蛋白质合成过程中去除N端起始甲硫氨酸，这是N端肉豆蔻酰化的一个先决步骤。原癌基因c-Src的N端肉豆蔻酰化对于其膜结合和正常信号转导至关重要。我们使用苯甲酰胺类化合物（一类通用的MetAP抑制剂）来了解MetAPs的下游生理功能。来自经苯甲酰胺A处理的细胞的c-Src保留了其N端甲硫氨酸，并且N端肉豆蔻酰化减少，同时其亚细胞分布从质膜转移到细胞质中。此外，苯甲酰胺A在体外和体内均降低了c-Src的酪氨酸激酶活性，并最终延迟了细胞周期通过G(2)/M期的进程。因此，c-Src是MetAPs的一个生理相关底物，其功能障碍可能是包括苯甲酰胺A在内的MetAP抑制剂产生细胞周期效应的原因。
