Biologically relevant chemistry of sulfur heterocycles : from redox regulation of PTP1B to the biological activity of s-deoxy leinamycin

Protein tyrosine phosphatase 1B (PTP1B) is an important member of protein tyrosine phosphatase (PTPs) family that shares a conserved catalytic cysteine thiol residue. PTP1B acts as a negative regulator of insulin mediated signaling cascade, as inhibition of PTP1B is shown to increase the insulin sensitivity. A key feature of signal transduction pathway involves transient inactivation of PTP1B by an insulin-stimulated burst of hydrogen peroxide. The catalytic cysteine thiol of PTP1B undergoes oxidation in presence of hydrogen peroxide to generate an inactive sulfenic acid, which is reactivated by the action of cellular thiols and reducing enzymes. However, recent evidences suggest an unique chemical transformation to generate sulfenyl amide (3-isothiazolidinone) from sulfenic acid at the active site of PTP1B. The mechanism for the formation of this novel sulfenyl amide is not clear. We employed 1,2-benzisothiazolidinone as chemical model to mimic the important functional groups present at the active site of enzyme and examined the chemical mechanism leading to the formation of sulfenyl amide. Our results supported a direct intramolecular attack of neighboring amide nitrogen onto the sulfenic acid to generate sulfenyl amide.