期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 138, 期 46, 页码 15157-15166出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.6b06848
关键词
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资金
- NIH [DP2 OD008463]
- David and Lucile Packard Fellowship for Science and Engineering
- Department of Chemistry at the University of Illinois at Urbana-Champaign
- NIH Chemical Biology Interface Training Program [T32 GM070421]
- Robert C. and Carolyn J. Springborn Endowment, an ACS Division of Medicinal Chemistry Predoctoral Fellowship
- National Center for Research Resources, National Institutes of Health [S10 RR027109 A]
Natural products (NPs) serve important roles as drug candidates and as tools for chemical biology. However, traditional NP discovery, largely based on bioassay-guided approaches, is biased toward abundant compounds and rediscovery rates are high. Orthogonal methods to facilitate discovery of new NPs are thus needed, and herein we describe an isotope tag-based expansion of reactivity-based NP screening to address these shortcomings. Reactivity-based screening is a directed discovery approach in which a specific reactive handle on the NP is targeted by a chemoselective probe to enable its detection by mass spectrometry. In this study, we have developed an aminooxy-containing probe to guide the discovery of aldehyde- and ketone-containing NPs. To facilitate the detection of labeling events, the probe was dibrominated, imparting a unique isotopic signature to distinguish labeled metabolites from spectral noise. As a proof of concept, the probe was then utilized to screen a collection of bacterial extracts, leading to the identification of a new analogue of antipain, deimino-antipain. The bacterial producer of deimino-antipain was sequenced and the responsible biosynthetic gene cluster was identified by bioinformatic analysis and heterologous expression. These data reveal the previously undetermined genetic basis for a well-known family of aldehyde-containing, peptidic protease inhibitors, including antipain, chymostatin, leupeptin, elastatinal, and microbial alkaline protease inhibitor, which have been widely used for over 40 years.
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