Protein-tyrosine phosphatases with vicinal catalytic cysteines

Protein-tyrosine phosphatases (PTPs) with vicinal catalytic cysteines represent a specialized subclass of the PTP superfamily characterized by a unique structural motif: a catalytic cysteine residue and a nearby regulatory or "backdoor" cysteine. This arrangement is found in several key therapeutic targets, including low molecular weight protein tyrosine phosphatase (LMW-PTP/ACP1), PTEN, and CDC25, as well as PTP-like enzymes such as bacterial arsenate reductases (ArsC). The primary biological significance of these vicinal cysteines lies in their role as a redox-sensitive switch; upon oxidation by reactive oxygen species (ROS), the catalytic cysteine forms a reversible intramolecular disulfide bond with the vicinal cysteine. This mechanism protects the enzyme from irreversible over-oxidation to sulfinic or sulfonic acid and allows cellular signaling to be modulated by the redox environment. These enzymes are critical regulators of pathways involved in cell growth, metabolism, and the cell cycle, and their dysregulation is linked to cancer, diabetes, and obesity. Pharmacologically, they are targeted by small molecules that either inhibit their phosphatase activity or exploit their redox sensitivity, with compounds like phenylarsine oxide serving as classic probes due to their high affinity for vicinal thiols.

Other names

Redox-regulated protein tyrosine phosphatasesPTPs with regulatory cysteinesLow molecular weight protein tyrosine phosphatase (LMW-PTP)Acid phosphatase 1 (ACP1)PTEN (Phosphatase and tensin homolog)CDC25 (Cell division cycle 25)Arsenate reductase (ArsC)

Inhibition of phosphatase activity by binding to the catalytic and vicinal cysteines; stabilization of the inactive oxidized disulfide state; competitive inhibition at the active site.