Targeting Reactive Carbonyls for Identifying Natural Products and Their Biosynthetic Origins.
J Am Chem Soc
; 138(46): 15157-15166, 2016 11 23.
Article
em En
| MEDLINE
| ID: mdl-27797509
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Streptomyces
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Produtos Biológicos
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Aldeídos
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Cetonas
Idioma:
En
Revista:
J Am Chem Soc
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Estados Unidos