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Making and Breaking Leupeptin Protease Inhibitors in Pathogenic Gammaproteobacteria
Author(s) -
Li JheHao,
Oh Joonseok,
Kienesberger Sabine,
Kim Nam Yoon,
Clarke David J.,
Zechner Ellen L.,
Crawford Jason M.
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202005506
Subject(s) - biology , proteases , protease , photorhabdus , microbiology and biotechnology , leupeptin , proteolysis , enzyme , biochemistry , gammaproteobacteria , gene , 16s ribosomal rna
Leupeptin is a bacterial small molecule that is used worldwide as a protease inhibitor. However, its biosynthesis and genetic distribution remain unknown. We identified a family of leupeptins in gammaproteobacterial pathogens, including Photorhabdus , Xenorhabdus , and Klebsiella species, amongst others. Through genetic, metabolomic, and heterologous expression analyses, we established their construction by discretely expressed ligases and accessory enzymes. In Photorhabdus species, a hypothetical protein required for colonizing nematode hosts was established as a new class of proteases. This enzyme cleaved the tripeptide aldehyde protease inhibitors, leading to the formation of “pro‐pyrazinones” featuring a hetero‐tricyclic architecture. In Klebsiella oxytoca , the pathway was enriched in clinical isolates associated with respiratory tract infections. Thus, the bacterial production and proteolytic degradation of leupeptins can be associated with animal colonization phenotypes.