The Chemical Basis of Serine Palmitoyltransferase Inhibition by Myriocin

详细信息    查看全文

• 作者：John M. Wadsworth ; David J. Clarke ; Stephen A. McMahon ; Jonathan P. Lowther ; Ashley E. Beattie ; Pat R. R. Langridge-Smith ; Howard B. Broughton ; Teresa M. Dunn ; James H. Naismith ; Dominic J. Campopiano
• 刊名：Journal of the American Chemical Society
• 出版年：2013
• 出版时间：September 25, 2013
• 年：2013
• 卷：135
• 期：38
• 页码：14276-14285
• 全文大小：557K
• 年卷期：v.135,no.38(September 25, 2013)
• ISSN：1520-5126

文摘

Sphingolipids (SLs) are essential components of cellular membranes formed from the condensation of l-serine and a long-chain acyl thioester. This first step is catalyzed by the pyridoxal-5鈥?phosphate (PLP)-dependent enzyme serine palmitoyltransferase (SPT) which is a promising therapeutic target. The fungal natural product myriocin is a potent inhibitor of SPT and is widely used to block SL biosynthesis despite a lack of a detailed understanding of its molecular mechanism. By combining spectroscopy, mass spectrometry, X-ray crystallography, and kinetics, we have characterized the molecular details of SPT inhibition by myriocin. Myriocin initially forms an external aldimine with PLP at the active site, and a structure of the resulting co-complex explains its nanomolar affinity for the enzyme. This co-complex then catalytically degrades via an unexpected 鈥榬etro-aldol-like鈥?cleavage mechanism to a C18 aldehyde which in turn acts as a suicide inhibitor of SPT by covalent modification of the essential catalytic lysine. This surprising dual mechanism of inhibition rationalizes the extraordinary potency and longevity of myriocin inhibition.