FIG. 2.

Regulation of PTPase catalytic activity by oxidation, conjugation, and reduction of the catalytic cysteine residue.A key feature of PTPases in the regulation of signal transduction is the modulation of their activity by alterations of the oxidation-reduction state of the enzyme catalytic center. The catalytic cysteine of the PTPases is especially reactive because of the low pK_a of the sulfhydryl that favors a relatively ionized state of the cysteinyl hydrogen (61), and stepwise oxidation of the catalytic cysteine residue of PTPases by reactive oxygen species to more inert forms is a major source of enzymatic regulation in vivo (17, 23, 53). Oxidation of the catalytic thiol to the sulfenic (—SOH) form is reversible. Higher order oxidation to sulfinic (—SO₂H) and sulfonic (—SO₃H) forms can lead to irreversible PTPase inactivation. Mildly oxidized PTPases can undergo disulfide conjugation in the cell with glutathione (6). A novel sulfenyl-amide derivative of PTP1B has been shown to undergo GSH conjugation or direct biochemical reduction with DTT (62, 72). Active enzyme can be regenerated from glutathiolated enzyme by cellular GSH reductases. Whereas the sulfonic-acid derivative of the active site cysteine is felt to be irreversible, the sulfinic-acid derivative may be reduced by a novel class of recently described sulfiredoxin enzymes (7) to a conjugated form that precedes the regeneration of the active enzyme. These mechanisms of PTPase regulation are an active area of current research. See text for further discussion and references.