Cited by 192Redox biology and oxidative stressGlutathione Transferases and PolymorphismsSulfur Compounds in Biology

Regulation of the Catalytic Activity and Structure of Human Thioredoxin 1 via Oxidation and S-Nitrosylation of Cysteine Residues

Open access
Hashemy, Seyed Isaac, Holmgren, Arne·2008·Journal of Biological Chemistry

Abstract

The mammalian cytosolic/nuclear thioredoxin system, comprising thioredoxin (Trx), selenoenzyme thioredoxin reductase (TrxR), and NADPH, is the major protein-disulfide reductase of the cell and has numerous functions. The active site of reduced Trx comprises Cys(32)-Gly-Pro-Cys(35) thiols that catalyze target disulfide reduction, generating a disulfide. Human Trx1 has also three structural Cys residues in positions 62, 69, and 73 that upon diamide oxidation induce a second Cys(62)-Cys(69) disulfide as well as dimers and multimers. We have discovered that after incubation with H(2)O(2) only monomeric two-disulfide molecules are generated, and they are inactive but able to regain full activity in an autocatalytic process in the presence of NADPH and TrxR. There are conflicting results regarding the effects of S-nitrosylation on Trx antioxidant functions and which residues are involved. We found that S-nitrosoglutathione-mediated S-nitrosylation at physiological pH is critically dependent on the redox state of Trx. Starting from fully reduced human Trx, both Cys(69) and Cys(73) were nitrosylated, and the active site formed a disulfide; the nitrosylated Trx was not a substrate for TrxR but regained activity after a lag phase consistent with autoactivation. Treatment of a two-disulfide form of Trx1 with S-nitrosoglutathione resulted in nitrosylation of Cys(73), which can act as a trans-nitrosylating agent as observed by others to control caspase 3 activity (Mitchell, D. A., and Marletta, M. A. (2005) Nat. Chem. Biol. 1, 154-158). The reversible inhibition of human Trx1 activity by H(2)O(2) and NO donors is suggested to act in cell signaling via temporal control of reduction for the transmission of oxidative and/or nitrosative signals in thiol redox control.

Integrity signals

Registry

Crossref · 10.1074/jbc.m801047200

Cites

60 of 60 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Hashemy, S. I., & Holmgren, A.
Affiliations
Karolinska Institutet (SE)
Corresponding author
Holmgren, Arne
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2008-08
Volume
283
Issue
32
Pages
21890-21898
ISSN
0021-9258 (ISSN-L)
OpenAlex
W1993780555
Cited by
192
References
60
Citations by year
2026: 3 · 2025: 9 · 2024: 6 · 2023: 6 · 2022: 11 · 2021: 14 · 2020: 11 · 2019: 6 · 2018: 13 · 2017: 14 · 2016: 10 · 2015: 9 · 2014: 15 · 2013: 9 · 2012: 15
FWCI
5.60
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
Keywords
thioredoxin-1, S-nitrosylation, S-nitrosoglutathione, cysteine residues, disulfide bond formation, thioredoxin reductase, protein disulfide isomerase, self-activation, hydrogen peroxide, nitric oxide donors, protein dimerization, caspase-3, antioxidant activity
MeSH terms
Catalysis, Cysteine, Diamide, Humans, Hydrogen Peroxide, Models, Molecular, Oxidation-Reduction, Proline, Sulfhydryl Reagents, Thioredoxins, Time Factors, Oxidants, Protein Structure, Tertiary, Nitric Oxide Donors, S-Nitrosoglutathione

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review