N-Phenylacetylation and Nonribosomal Peptide Synthetases with Substrate Promiscuity for Biosynthesis of Heptapeptide Variants, JBIR-78 and JBIR-95

ACS Chemical Biology
Kunpei TakedaTohru Dairi

Abstract

JBIR-78 (1) and JBIR-95 (2), both of which are heptapeptide derivatives isolated from Kibdelosporangium sp. AK-AA56, have the same amino acid sequences except for the second amino acid: phenylacetic acid (Paa)-l-Val-d-Asp (1)/d-cysteic acid (2)-l-Ala-(3S)-3-hydroxy-d-Leu-Gly-d-Ala-l-Phe. Heterologous expression of the biosynthetic gene cluster including genes encoding nonribosomal peptide synthetases (NRPS) and in vitro assays with recombinant Orf3, an l-cysteic acid synthase homologue, suggested the single A domain in module 2 activates both l-Asp and l-cysteic acid to yield 1 and 2, respectively, although the substrate specificities of the A domains of NRPSs are usually strict. Biosynthetic mechanism of introduction of N-terminal Paa was also investigated. Recombinant Orf1 and Orf2 similar to subunits of pyruvate dehydrogenase complex catalyzed the conversion of phenylpyruvate into phenylacetyl-CoA together with dihydrolipoyl dehydrogenase whose encoding gene is located outside of the gene cluster. Moreover, we showed that phenylacetyl-CoA was directly condensed with l-Val, which was tethered to a peptidyl carrier protein, at the first condensation domain in the NRPS.

References

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Nov 18, 2014·Nature Chemical Biology·Motoyoshi NoikeTohru Dairi
Jan 19, 2017·Angewandte Chemie·Chengzhang FuRolf Müller

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Citations

Dec 24, 2019·Chemical Reviews·Jason B Hedges, Katherine S Ryan
Aug 14, 2020·Journal of Natural Products·Paulina BekieschSergey B Zotchev
Sep 8, 2021·Environmental Microbiology·Bin WeiHong Wang

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