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Biosynthesis of Translation Inhibitor Klebsazolicin Proceeds through Heterocyclization and N-Terminal Amidine Formation Catalyzed by a Single YcaO Enzyme
Lomonosov Moscow State Univ, Dept Bioengn & Bioinformat, Moscow, Russia; Skolkovo Inst Sci & Technol, Ctr Data Intens Biomed & Biotechnol, Skolkovo, Russia.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Skolkovo Inst Sci & Technol, Ctr Data Intens Biomed & Biotechnol, Skolkovo, Russia; Russian Acad Sci, Inst Gene Biol, Moscow, Russia.ORCID iD: 0000-0003-2829-6395
Skolkovo Inst Sci & Technol, Ctr Data Intens Biomed & Biotechnol, Skolkovo, Russia; Lomonosov Moscow State Univ, Dept Chem, Moscow, Russia; Lomonosov Moscow State Univ, AN Belozersky Inst Physicochem Biol, Moscow, Russia.
Lomonosov Moscow State Univ, Dept Bioengn & Bioinformat, Moscow, Russia; Skolkovo Inst Sci & Technol, Ctr Data Intens Biomed & Biotechnol, Skolkovo, Russia.
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2018 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 140, no 16, p. 5625-5633Article in journal (Refereed) Published
Abstract [en]

Klebsazolicin (KLB) is a recently discovered Klebsiella pneumonia peptide antibiotic targeting the exit tunnel of bacterial ribosome. KLB contains an N-terminal amidine ring and four azole heterocycles installed into a ribosomally synthesized precursor by dedicated maturation machinery. Using an in vitro system for KLB production, we show that the YcaO-domain KlpD maturation enzyme is a bifunctional cyclodehydratase required for the formation of both the core heterocycles and the N-terminal amidine ring. We further demonstrate that the amidine ring is formed concomitantly with proteolytic cleavage of azole-containing pro-KLB by a cellular protease TldD/E. Members of the YcaO family are diverse enzymes known to activate peptide carbonyls during natural product biosynthesis leading to the formation of azoline, macroamidine, and thioamide moieties. The ability of KlpD to simultaneously perform two distinct types of modifications is unprecedented for known YcaO proteins. The versatility of KlpD opens up possibilities for rational introduction of modifications into various peptide backbones.

Place, publisher, year, edition, pages
2018. Vol. 140, no 16, p. 5625-5633
National Category
Biochemistry and Molecular Biology
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URN: urn:nbn:se:uu:diva-356098DOI: 10.1021/jacs.8b02277ISI: 000431095100038PubMedID: 29601195OAI: oai:DiVA.org:uu-356098DiVA, id: diva2:1233787
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NIH (National Institute of Health), AI117270Available from: 2018-07-19 Created: 2018-07-19 Last updated: 2018-07-19Bibliographically approved

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Metelev, Mikhail

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