Decoding the Papain Inhibitor from Streptomyces mobaraensis as Being Hydroxylated Chymostatin Derivatives: Purification, Structure Analysis, and Putative Biosynthetic Pathway.

Autor:	Juettner NE; The Department of Chemical Engineering and Biotechnology, University of Applied Sciences of Darmstadt, Stephanstraße 7, 64295 Darmstadt, Germany.; The Department of Biology, Technische Universität Darmstadt, Schnittspahnstraße 10, 64287 Darmstadt, Germany., Bogen JP; The Department of Chemical Engineering and Biotechnology, University of Applied Sciences of Darmstadt, Stephanstraße 7, 64295 Darmstadt, Germany., Bauer TA; The Department of Chemical Engineering and Biotechnology, University of Applied Sciences of Darmstadt, Stephanstraße 7, 64295 Darmstadt, Germany., Knapp S; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences (BMLS), Goethe University Frankfurt, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, Germany., Pfeifer F; The Department of Biology, Technische Universität Darmstadt, Schnittspahnstraße 10, 64287 Darmstadt, Germany., Huettenhain SH; The Department of Chemical Engineering and Biotechnology, University of Applied Sciences of Darmstadt, Stephanstraße 7, 64295 Darmstadt, Germany., Meusinger R; The Department of Chemistry, Technische Universität Darmstadt, Alarich-Weiss-Straße 8, 64287 Darmstadt, Germany., Kraemer A; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt am Main, Germany., Fuchsbauer HL; The Department of Chemical Engineering and Biotechnology, University of Applied Sciences of Darmstadt, Stephanstraße 7, 64295 Darmstadt, Germany.
Jazyk:	angličtina
Zdroj:	Journal of natural products [J Nat Prod] 2020 Oct 23; Vol. 83 (10), pp. 2983-2995. Date of Electronic Publication: 2020 Sep 30.
DOI:	10.1021/acs.jnatprod.0c00201
Abstrakt:	Streptomyces mobaraensis produces the papain inhibitor SPI consisting of a 12 kDa protein and small active compounds (SPI ac ). Purification of the papain inhibitory compounds resulted in four diverse chymostatin derivatives that were characterized by NMR and MS analysis. Chymostatins are hydrophobic tetrapeptide aldehydes from streptomycetes, e.g., S. lavendulae and S. hygroscopicus , that reverse chymosin-mediated angiotensin activation and inhibit other serine and cysteine proteases. Chymotrypsin and papain were both inhibited by the SPI ac compounds in the low nanomolar range. SPI ac differs from the characterized chymostatins by the exchange of phenylalanine for tyrosine. The crystal structure of one of these chymostatin variants confirmed its molecular structure and revealed a S-configured hemithioacetal bond with the catalytic Cys25 thiolate as well as close interactions with hydrophobic S1 and S2 subsite amino acids. A model for chymostatin biosynthesis is provided based on the discovery of clustered genes encoding several putative nonribosomal peptide synthetases; among them, there is the unusual CstF enzyme that accommodates two canonical amino acid activation domains as well as three peptide carrier protein domains.
Databáze:	MEDLINE
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