Specific and reversible inactivation of protein tyrosine phosphatases by hydrogen peroxide: evidence for a sulfenic acid intermediate and implications for redox regulation
- PMID: 9548949
- DOI: 10.1021/bi973035t
Specific and reversible inactivation of protein tyrosine phosphatases by hydrogen peroxide: evidence for a sulfenic acid intermediate and implications for redox regulation
Abstract
Protein tyrosine phosphatases (PTPs) catalyze the hydrolysis of phosphotyrosine from specific signal-transducing proteins. Although regulatory mechanisms for protein kinases have been described, no general mechanism for controlling PTPs has been demonstrated. Numerous reports have shown that cellular redox status plays an important role in tyrosine phosphorylation-dependent signal transduction pathways. This study explores the proposal that PTPs may be regulated by reversible reduction/oxidation involving cellular oxidants such as hydrogen peroxide (H2O2). Recent reports indicated that H2O2 is transiently generated during growth factor stimulation and that H2O2 production is concomitant with relevant tyrosine phosphorylation. By use of recombinant enzymes, the effects of H2O2 on three PTPs [PTP1, LAR (leukocyte antigen-related), and VHR (vaccinia H1-related)] and three distinct serine/threonine protein phosphatases (PPs: PP2Calpha, calcineurin, and lambda phosphatase) were determined. Hydrogen peroxide had no apparent effect on PP activity. In contrast, PTPs were rapidly inactivated (kinact = 10-20 M-1 s-1) with low micromolar concentrations of H2O2 but not with large alkyl hydroperoxides. PTP inactivation was fully reversible with glutathione and other thiols. Because of the slower rate of reduction, modification occurred even in the presence of physiological thiol concentrations. By utilization of a variety of biochemical techniques including chemical modification, pH kinetic studies, and mutagenesis, the catalytic cysteine thiolate of PTPs was determined to be the selective target of oxidation by H2O2. By use of the electrophilic reagent 7-chloro-4-nitrobenzo-2-oxa-1, 3-diazole (NBD-Cl), it was shown that a cysteine sulfenic acid intermediate (Cys-SOH) is formed after attack of the catalytic thiolate on H2O2. A chemical mechanism for reversible inactivation involving a cysteine sulfenic acid intermediate is proposed.
Similar articles
-
Preferential redox regulation of cysteine-based protein tyrosine phosphatases: structural and biochemical diversity.FEBS J. 2022 Sep;289(18):5480-5504. doi: 10.1111/febs.16466. Epub 2022 May 11. FEBS J. 2022. PMID: 35490402 Review.
-
Redox regulation of protein-tyrosine phosphatases.Arch Biochem Biophys. 2005 Feb 1;434(1):11-5. doi: 10.1016/j.abb.2004.05.024. Arch Biochem Biophys. 2005. PMID: 15629103 Review.
-
Catalytic inactivation of protein tyrosine phosphatase CD45 and protein tyrosine phosphatase 1B by polyaromatic quinones.Biochemistry. 2004 Apr 13;43(14):4294-303. doi: 10.1021/bi035986e. Biochemistry. 2004. PMID: 15065873
-
Catalytic and chemical competence of regulation of cdc25 phosphatase by oxidation/reduction.Biochemistry. 2003 Sep 2;42(34):10060-70. doi: 10.1021/bi0345081. Biochemistry. 2003. PMID: 12939134
-
Effects of metal ions on the activity of protein tyrosine phosphatase VHR: highly potent and reversible oxidative inactivation by Cu2+ ion.Arch Biochem Biophys. 2000 Oct 1;382(1):72-80. doi: 10.1006/abbi.2000.1996. Arch Biochem Biophys. 2000. PMID: 11051099
Cited by
-
Redox Regulation of Phosphatase and Tensin Homolog by Bicarbonate and Hydrogen Peroxide: Implication of Peroxymonocarbonate in Cell Signaling.Antioxidants (Basel). 2024 Apr 17;13(4):473. doi: 10.3390/antiox13040473. Antioxidants (Basel). 2024. PMID: 38671920 Free PMC article.
-
RedOx regulation of LRRK2 kinase activity by active site cysteines.NPJ Parkinsons Dis. 2024 Apr 3;10(1):75. doi: 10.1038/s41531-024-00683-5. NPJ Parkinsons Dis. 2024. PMID: 38570484 Free PMC article.
-
Evidence that protein thiols are not primary targets of intracellular reactive oxygen species in growing Escherichia coli.Front Microbiol. 2023 Dec 13;14:1305973. doi: 10.3389/fmicb.2023.1305973. eCollection 2023. Front Microbiol. 2023. PMID: 38152379 Free PMC article.
-
The architecture of redox microdomains: Cascading gradients and peroxiredoxins' redox-oligomeric coupling integrate redox signaling and antioxidant protection.Redox Biol. 2024 Feb;69:103000. doi: 10.1016/j.redox.2023.103000. Epub 2023 Dec 21. Redox Biol. 2024. PMID: 38150990 Free PMC article.
-
Enzyme mechanistic studies of NMA1982, a protein tyrosine phosphatase and potential virulence factor in Neisseria meningitidis.Sci Rep. 2023 Dec 12;13(1):22015. doi: 10.1038/s41598-023-49561-9. Sci Rep. 2023. PMID: 38086986 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous