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

Juettner, Norbert E. and Bogen, Jan P. and Bauer, Tobias A. and Knapp, Stefan and Pfeifer, Felicitas and Huettenhain, Stefan H. and Meusinger, Reinhard and Kraemer, Andreas and Fuchsbauer, Hans-Lothar (2020):
Decoding the Papain Inhibitor from Streptomyces mobaraensis as Being Hydroxylated Chymostatin Derivatives: Purification, Structure Analysis, and Putative Biosynthetic Pathway.
In: Journal of natural products, 83 (10), pp. 2983-2995. ISSN 1520-6025,
DOI: 10.1021/acs.jnatprod.0c00201,
[Article]

Abstract

produces the papain inhibitor SPI consisting of a 12 kDa protein and small active compounds (SPI). 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., and , that reverse chymosin-mediated angiotensin activation and inhibit other serine and cysteine proteases. Chymotrypsin and papain were both inhibited by the SPI compounds in the low nanomolar range. SPI 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.

Item Type: Article
Erschienen: 2020
Creators: Juettner, Norbert E. and Bogen, Jan P. and Bauer, Tobias A. and Knapp, Stefan and Pfeifer, Felicitas and Huettenhain, Stefan H. and Meusinger, Reinhard and Kraemer, Andreas and Fuchsbauer, Hans-Lothar
Title: Decoding the Papain Inhibitor from Streptomyces mobaraensis as Being Hydroxylated Chymostatin Derivatives: Purification, Structure Analysis, and Putative Biosynthetic Pathway.
Language: English
Abstract:

produces the papain inhibitor SPI consisting of a 12 kDa protein and small active compounds (SPI). 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., and , that reverse chymosin-mediated angiotensin activation and inhibit other serine and cysteine proteases. Chymotrypsin and papain were both inhibited by the SPI compounds in the low nanomolar range. SPI 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.

Journal or Publication Title: Journal of natural products
Journal volume: 83
Number: 10
Divisions: 10 Department of Biology
10 Department of Biology > Microbiology and Archaea
Date Deposited: 12 Oct 2020 10:01
DOI: 10.1021/acs.jnatprod.0c00201
Identification Number: pmid:32998509
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