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Differential Kinetics of Two-Cysteine Peroxiredoxin Disulfide Formation Reveal a Novel Model for Peroxide Sensing.
Biochemistry. 2018 06 19; 57(24):3416-3424.B

Abstract

Two-cysteine peroxiredoxins (Prx) have a three-step catalytic cycle consisting of (1) reduction of peroxide and formation of sulfenic acid on the enzyme, (2) condensation of the sulfenic acid with a thiol to form disulfide, also known as resolution, and (3) reduction of the disulfide by a reductant protein. By following changes in protein fluorescence, we have studied the pH dependence of reaction 2 in human peroxiredoxins 1, 2, and 5 and in Salmonella typhimurium AhpC and obtained rate constants for the reaction and p Ka values of the thiol and sulfenic acid involved for each system. The observed reaction 2 rate constant spans 2 orders of magnitude, but in all cases, reaction 2 appears to be slow compared to the same reaction in small-molecule systems, making clear the rates are limited by conformational features of the proteins. For each Prx, reaction 2 will become rate-limiting at some critical steady-state concentration of H2O2 producing the accumulation of Prx as sulfenic acid. When this happens, an alternative and faster-resolving Prx (or other peroxidase) may take over the antioxidant role. The accumulation of sulfenic acid Prx at distinct concentrations of H2O2 is embedded in the kinetic limitations of the catalytic cycle and may constitute the basis of a H2O2-mediated redox signal transduction pathway requiring neither inactivation nor posttranslational modification. The differences in the rate constants of resolution among Prx coexisting in the same compartment may partially explain their complementation in antioxidant function and stepwise sensing of H2O2 concentration.

Authors+Show Affiliations

No affiliation info availableLaboratorio de I+D de Moléculas Bioactivas, CENUR Litoral Norte , Universidad de la República , Paysandú , Uruguay.Department of Biochemistry and Centers for Structural Biology and for Redox Biology and Medicine , Wake Forest School of Medicine , Winston-Salem , North Carolina 27157 , United States.No affiliation info availableDepartment of Biochemistry and Biophysics , Oregon State University , 2011 Agricultural & Life Sciences Building , Corvallis , Oregon 97331 , United States.Department of Biochemistry and Centers for Structural Biology and for Redox Biology and Medicine , Wake Forest School of Medicine , Winston-Salem , North Carolina 27157 , United States.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29553725

Citation

Portillo-Ledesma, Stephanie, et al. "Differential Kinetics of Two-Cysteine Peroxiredoxin Disulfide Formation Reveal a Novel Model for Peroxide Sensing." Biochemistry, vol. 57, no. 24, 2018, pp. 3416-3424.
Portillo-Ledesma S, Randall LM, Parsonage D, et al. Differential Kinetics of Two-Cysteine Peroxiredoxin Disulfide Formation Reveal a Novel Model for Peroxide Sensing. Biochemistry. 2018;57(24):3416-3424.
Portillo-Ledesma, S., Randall, L. M., Parsonage, D., Dalla Rizza, J., Karplus, P. A., Poole, L. B., Denicola, A., & Ferrer-Sueta, G. (2018). Differential Kinetics of Two-Cysteine Peroxiredoxin Disulfide Formation Reveal a Novel Model for Peroxide Sensing. Biochemistry, 57(24), 3416-3424. https://doi.org/10.1021/acs.biochem.8b00188
Portillo-Ledesma S, et al. Differential Kinetics of Two-Cysteine Peroxiredoxin Disulfide Formation Reveal a Novel Model for Peroxide Sensing. Biochemistry. 2018 06 19;57(24):3416-3424. PubMed PMID: 29553725.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential Kinetics of Two-Cysteine Peroxiredoxin Disulfide Formation Reveal a Novel Model for Peroxide Sensing. AU - Portillo-Ledesma,Stephanie, AU - Randall,Lía M, AU - Parsonage,Derek, AU - Dalla Rizza,Joaquín, AU - Karplus,P Andrew, AU - Poole,Leslie B, AU - Denicola,Ana, AU - Ferrer-Sueta,Gerardo, Y1 - 2018/03/30/ PY - 2018/3/20/pubmed PY - 2019/1/9/medline PY - 2018/3/20/entrez SP - 3416 EP - 3424 JF - Biochemistry JO - Biochemistry VL - 57 IS - 24 N2 - Two-cysteine peroxiredoxins (Prx) have a three-step catalytic cycle consisting of (1) reduction of peroxide and formation of sulfenic acid on the enzyme, (2) condensation of the sulfenic acid with a thiol to form disulfide, also known as resolution, and (3) reduction of the disulfide by a reductant protein. By following changes in protein fluorescence, we have studied the pH dependence of reaction 2 in human peroxiredoxins 1, 2, and 5 and in Salmonella typhimurium AhpC and obtained rate constants for the reaction and p Ka values of the thiol and sulfenic acid involved for each system. The observed reaction 2 rate constant spans 2 orders of magnitude, but in all cases, reaction 2 appears to be slow compared to the same reaction in small-molecule systems, making clear the rates are limited by conformational features of the proteins. For each Prx, reaction 2 will become rate-limiting at some critical steady-state concentration of H2O2 producing the accumulation of Prx as sulfenic acid. When this happens, an alternative and faster-resolving Prx (or other peroxidase) may take over the antioxidant role. The accumulation of sulfenic acid Prx at distinct concentrations of H2O2 is embedded in the kinetic limitations of the catalytic cycle and may constitute the basis of a H2O2-mediated redox signal transduction pathway requiring neither inactivation nor posttranslational modification. The differences in the rate constants of resolution among Prx coexisting in the same compartment may partially explain their complementation in antioxidant function and stepwise sensing of H2O2 concentration. SN - 1520-4995 UR - https://www.unboundmedicine.com/medline/citation/29553725/Differential_Kinetics_of_Two_Cysteine_Peroxiredoxin_Disulfide_Formation_Reveal_a_Novel_Model_for_Peroxide_Sensing_ L2 - https://dx.doi.org/10.1021/acs.biochem.8b00188 DB - PRIME DP - Unbound Medicine ER -