Mechanistic studies of thioether crosslink formation in peptides

肽中硫醚交联形成的机理研究

• 批准号: 9169902
• 负责人: VAHE BANDARIAN
• 金额: $ 28.7万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9169902
• 关键词: Active Sites; Address; Adoption; Anabolism; Anti-Bacterial Agents; Antineoplastic Agents; Antiviral Agents; Area; Binding; Biochemical; Carbon; Catalysis; Cells; Chemistry; Cleaved cell; Clinic; Cysteine; Electron Spin Resonance Spectroscopy; Electrons; Engineering; Enzymatic Biochemistry; Enzymes; Family; Future; Goals; Housing; Label; Lead; Life; Mediating; Methionine; Methods; Modification; Molecular; Mutation; Natural Products; Outcome; Oxidation-Reduction; Pathway interactions; Peptide Synthesis; Peptides; Play; Post-Translational Protein Processing; Property; Protein Family; Publishing; Reaction; Reporting; Research; Roentgen Rays; Role; Site; Structure; Structure-Activity Relationship; Sulfur; System; Therapeutic Agents; Therapeutic Uses; Time; Variant; base; cofactor; crosslink; enzyme mechanism; insight; killings; member; novel; oxidation; peptide synthase; polypeptide; quorum sensing; reconstitution; spectroscopic survey; thioether; tool

PROJECT SUMMARY All domains of life produce peptidic natural products that play roles as diverse as quorum sensing molecules and redox cofactors. The ability of these peptides to function as antibacterial, antiviral, or anticancer agents makes understanding their biosynthesis an important area of contemporary research. Peptide-based secondary metabolites are produced by distinct biosynthetic pathways that differ in whether the peptide is synthesized by the action of non-ribosomal peptide synthetases (NRPS), or ribosomally produced from a genomically encoded orf. These peptides are often extensively modified. While in the NRPS systems many of the modifications occur concurrently with peptide synthesis, the ribosomally encoded peptides undergo posttranslational modification. These so-called ribosomally encoded posttranslationally modified polypeptides (RiPP) are a new emerging class of polypeptides that have extensive modifications that are introduced by mechansims that are mostly poorly understood. This application will focus on enzymes introduce sulfur-to-alpha carbon thioether crosslinks into ribosomally encoded peptides to produce sactipeptides. These linkages are distinct from the well-studied lanthipeptide, where thioether crosslinks form between a Cys residue and a dehydrated Thr/Ser. The sactipeptide maturases are members of the radical SAM family of enzymes and catalyze thioether crosslinks by a radical- mediated reaction that is not understood. While The biochemical, spectroscopic, and structural studies in this application will lead to a mechanistic paradigm for this important class of enzymes. While sactipeptides themselves have various therapeutic uses, understanding the substrate profiles and mechanisms of these enzymes would provide a tool for synthesis of crosslinked peptides, which are increasing finding utility in the clinic.

项目总结