[5 Crystal Structures of Oxidized and Reduced Forms of NADH Peroxidase

By JOANNE I. YEH and AL CLAIBORNE

Introduction

Modulations of protein function by oxidation-reduction reactions through co-factors such as FAD, iron-sulfur centers, heme prosthetic groups, and redox-active disulfides are well known. However, only more recently have cysteine-sulfenic acid (Cys-SOH) derivatives been recognized as novel moieties (cofactors) functioning in enzyme catalysis and redox regulation. A major reason for the delayed recognition of the functional importance of this moiety in proteins is that sulfenic acids are difficult to identify and have long been characterized primarily as transient intermediates because of their highly reactive and unstable chemical nature. There are three major simple organic oxyacids of sulfur: (1) sulfenic acids (RSOH), (2) sulfinic acids (RS02H), and (3) sulfonic acids (RSO3H).1 Of these, sulfonic acids are by far the most stable; sulfinic acids are somewhat unstable thermally,

radical is much less oxidant. The two cysteines responsible for the redox properties of thioredoxin (Cys-36 and Cys-39) have different properties. Cys-36 is solvent accessible,25 whereas Cys-39 has a p/sfa that is at least 4 units higher than physiological pH,26-28 and is relatively unreactive. Our results would indicate a preferential localization of the thiyl radical on Cys-39, and thus a nonsymmetric bond opening of the disulfide radical. Thiyl radicals are responsible for the pro-oxidant side of sulfur compounds. Although thioredoxin and glutathione play similar roles in antioxidant defense, thioredoxin would be a much better antioxidant because of its weak pro-oxidant properties. It would be interesting to know whether this specificity is also found in other members of the thiol-disulfide oxidoreductase family.

Acknowledgment

I thank the Curie Institute (Dr. V. Favaudon) for the use of the accelerator.

25 P. T. Chivers and R. T. Raines, Biochemistry 36, 15810 (1997).

26 P. T. Chivers, K. E. Prehoda, B. F. Volkman,B. M. Kim, J. L. Markley,andR. T. Raines,Biochemistry 36, 14985 (1997).

27 J. F. Andersen, D. A. Sanders, J. R. Gasdaska, A. Weichsel, G. Powis, and W. R. Montfort, Biochemistry 36, 13979 (1997).

28 D. M. LeMaster, P. A. Springer, and C. J. Unkefer, J. Biol. Chem. 272, 29998 (1997).

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