Sulfone-stabilized carbanions for the reversible covalent capture of a posttranslationally-generated cysteine oxoform found in protein tyrosine phosphatase 1B (PTP1B)

• Published in: Bioorganic & medicinal chemistry 2016-06, Vol.24 (12), p.2631-2640
• Main Authors: Parsons, Zachary D., Ruddraraju, Kasi Viswanatharaju, Santo, Nicholas, Gates, Kent S.
• Format: Article
• Language: English
• Subjects: Amides - chemistry; Amides - metabolism; Catalytic Domain - drug effects; Covalent enzyme inactivation; Cysteine - analogs & derivatives; Cysteine - chemistry; Cysteine - metabolism; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - enzymology; Dithioerythritol - metabolism; Humans; Insulin - metabolism; Models, Molecular; Oxidation-Reduction - drug effects; Protein tyrosine phosphatase (PTP); Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - chemistry; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Redox-regulation; Sulfhydryl Reagents - metabolism; Sulfones - chemistry; Sulfones - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.03.054

[Display omitted] 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.