title: Proteomics guided discovery of flavopeptins: anti-proliferative aldehydes synthesized by a reductase domain-containing non-ribosomal peptide synthetase.
abstract: Due to the importance of proteases in regulating cellular processes, the development of protease inhibitors has garnered great attention. Peptide-based aldehydes are a class of compounds that exhibit inhibitory activities against various proteases and proteasomes in the context of anti-proliferative treatments for cancer and other diseases. More than a dozen peptide-based natural products containing aldehydes have been discovered such as chymostatin, leupeptin, and fellutamide; however, the biosynthetic origin of the aldehyde functionality has yet to be elucidated. Herein we describe the discovery of a new group of lipopeptide aldehydes, the flavopeptins, and the corresponding biosynthetic pathway arising from an orphan gene cluster in Streptomyces sp. NRRL-F6652, a close relative of Streptomyces flavogriseus ATCC 33331. This research was initiated using a proteomics approach that screens for expressed enzymes involved in secondary metabolism in microorganisms. Flavopeptins are synthesized through a non-ribosomal peptide synthetase containing a terminal NAD(P)H-dependent reductase domain likely for the reductive release of the peptide with a C-terminal aldehyde. Solid-phase peptide synthesis of several flavopeptin species and derivatives enabled structural verification and subsequent screening of biological activity. Flavopeptins exhibit sub-micromolar inhibition activities against cysteine proteases such as papain and calpain as well as the human 20S proteasome. They also show anti-proliferative activities against multiple myeloma and lymphoma cell lines.
authors.affiliation: Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States.
authors.forename: Yunqiu
authors.initials: Y
authors.lastname: Chen
authors.forename: Ryan A
authors.initials: RA
authors.lastname: McClure
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Zheng
authors.forename: Regan J
authors.initials: RJ
authors.lastname: Thomson
authors.forename: Neil L
authors.initials: NL
authors.lastname: Kelleher
mesh_terms: D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008968:Molecular Conformation; D009842:Oligopeptides / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*; D010088:Oxidoreductases / Q000737:chemistry / Q000378:metabolism*; D010206:Papain / Q000037:antagonists & inhibitors / Q000378:metabolism; D010453:Peptide Synthases / Q000737:chemistry / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D040901:Proteomics; D013329:Structure-Activity Relationship
chemical_list: D000447:Aldehydes; D000970:Antineoplastic Agents; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D010088:Oxidoreductases; D002154:Calpain; D010206:Papain; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase