期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 135, 期 38, 页码 14276-14285出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja4059876
关键词
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资金
- BBSRC [BB/I013687/1, BB/F009739/1, BB/G53045X/I]
- University of Edinburgh
- Lily pharmaceuticals
- Derek Stewart Charitable Trust
- Biotechnology and Biological Sciences Research Council [BB/F008503/1, BB/F009739/1, BB/G53045X/1, BB/I014632/1, BB/I013687/1] Funding Source: researchfish
- BBSRC [BB/F009739/1, BB/G53045X/1, BB/I013687/1, BB/I014632/1, BB/F008503/1] Funding Source: UKRI
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'-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 'retro-aldol-like' 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.
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