title: Sulfone-stabilized carbanions for the reversible covalent capture of a posttranslationally-generated cysteine oxoform found in protein tyrosine phosphatase 1B (PTP1B).
abstract: Redox regulation of protein tyrosine phosphatase 1B (PTP1B) involves oxidative conversion of the active site cysteine thiolate into an electrophilic sulfenyl amide residue. Reduction of the sulfenyl amide by biological thiols regenerates the native cysteine residue. Here we explored fundamental chemical reactions that may enable covalent capture of the sulfenyl amide residue in oxidized PTP1B. Various sulfone-containing carbon acids were found to react readily with a model peptide sulfenyl amide via attack of the sulfonyl carbanion on the electrophilic sulfur center in the sulfenyl amide. Both the products and the rates of these reactions were characterized. The results suggest that capture of a peptide sulfenyl amide residue by sulfone-stabilized carbanions can slow, but not completely prevent, thiol-mediated generation of the corresponding cysteine-containing peptide. Sulfone-containing carbon acids may be useful components in the construction of agents that knock down PTP1B activity in cells via transient covalent capture of the sulfenyl amide oxoform generated during insulin signaling processes.
authors.affiliation: University of Missouri, Department of Chemistry, 125 Chemistry Building, Columbia, MO 65211, United States.
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Parsons
authors.affiliation: University of Missouri, Department of Chemistry, 125 Chemistry Building, Columbia, MO 65211, United States.
authors.forename: Kasi Viswanatharaju
authors.initials: KV
authors.lastname: Ruddraraju
authors.affiliation: University of Missouri, Department of Chemistry, 125 Chemistry Building, Columbia, MO 65211, United States.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Santo
authors.affiliation: University of Missouri, Department of Chemistry, 125 Chemistry Building, Columbia, MO 65211, United States; University of Missouri, Department of Biochemistry, Columbia, MO 65211, United States. Electronic address: gatesk@missouri.edu.
authors.forename: Kent S
authors.initials: KS
authors.lastname: Gates
mesh_terms: D000577:Amides / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology; D004226:Dithioerythritol / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008958:Models, Molecular; D010084:Oxidation-Reduction / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013439:Sulfhydryl Reagents / Q000378:metabolism; D013450:Sulfones / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000577:Amides; D007328:Insulin; D013439:Sulfhydryl Reagents; D013450:Sulfones; C545158:cysteine thiolate; D004226:Dithioerythritol; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D003545:Cysteine
keywords: Covalent enzyme inactivation; Protein tyrosine phosphatase (PTP); Redox-regulation