Letters to Nature
Nature 410, 490-494 (22 March 2001) | doi:10.1038/35068596; Received 7 December 2000; Accepted 5 January 2001
A metabolic enzyme for S-nitrosothiol conserved from bacteria to humans
Limin Liu1,2, Alfred Hausladen2, Ming Zeng2, Loretta Que2, Joseph Heitman1,3 & Jonathan S. Stamler1,2,6
- Howard Hughes Medical Institute,
- Department of Medicine, Pulmonary and Cardiology Divisions, and
- Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA
- Department of Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA
Correspondence to: Jonathan S. Stamler1,2,6 Correspondence and requests for materials should be addressed to J.S.S. (e-mail: Email: STAML001@mc.duke.edu).
Considerable evidence indicates that NO biology involves a family of NO-related molecules and that S-nitrosothiols (SNOs) are central to signal transduction and host defence1, 2, 3, 4, 5. It is unknown, however, how cells switch off the signals or protect themselves from the SNOs produced for defence purposes. Here we have purified a single activity from Escherichia coli, Saccharomyces cerevisiae and mouse macrophages that metabolizes S-nitrosoglutathione (GSNO), and show that it is the glutathione-dependent formaldehyde dehydrogenase. Although the enzyme is highly specific for GSNO, it controls intracellular levels of both GSNO and S-nitrosylated proteins. Such 'GSNO reductase' activity is widely distributed in mammals. Deleting the reductase gene in yeast and mice abolishes the GSNO-consuming activity, and increases the cellular quantity of both GSNO and protein SNO. Furthermore, mutant yeast cells show increased susceptibility to a nitrosative challenge, whereas their resistance to oxidative stress is unimpaired. We conclude that GSNO reductase is evolutionarily conserved from bacteria to humans, is critical for SNO homeostasis, and protects against nitrosative stress.
