title: Nitrite reductase activity and inhibition of H₂S biogenesis by human cystathionine ß-synthase.
abstract: Nitrite was recognized as a potent vasodilator >130 years and has more recently emerged as an endogenous signaling molecule and modulator of gene expression. Understanding the molecular mechanisms that regulate nitrite metabolism is essential for its use as a potential diagnostic marker as well as therapeutic agent for cardiovascular diseases. In this study, we have identified human cystathionine ß-synthase (CBS) as a new player in nitrite reduction with implications for the nitrite-dependent control of H₂S production. This novel activity of CBS exploits the catalytic property of its unusual heme cofactor to reduce nitrite and generate NO. Evidence for the possible physiological relevance of this reaction is provided by the formation of ferrous-nitrosyl (Fe(II)-NO) CBS in the presence of NADPH, the human diflavin methionine synthase reductase (MSR) and nitrite. Formation of Fe(II)-NO CBS via its nitrite reductase activity inhibits CBS, providing an avenue for regulating biogenesis of H₂S and cysteine, the limiting reagent for synthesis of glutathione, a major antioxidant. Our results also suggest a possible role for CBS in intracellular NO biogenesis particularly under hypoxic conditions. The participation of a regulatory heme cofactor in CBS in nitrite reduction is unexpected and expands the repertoire of proteins that can liberate NO from the intracellular nitrite pool. Our results reveal a potential molecular mechanism for cross-talk between nitrite, NO and H₂S biology.
authors.affiliation: Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gherasim
authors.affiliation: Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Yadav
authors.affiliation: Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Omer
authors.initials: O
authors.lastname: Kabil
authors.affiliation: Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, United States of America ; School of Life Science, Northwestern Polytechnical University, Xi'an, China.
authors.forename: Wei-Ning
authors.initials: WN
authors.lastname: Niu
authors.affiliation: Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Ruma
authors.initials: R
authors.lastname: Banerjee
mesh_terms: D003541:Cystathionine beta-Synthase / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D006418:Heme / Q000378:metabolism; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism; D009572:Nitrite Reductases / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D011732:Pyridoxal Phosphate / Q000378:metabolism; D019163:Reducing Agents / Q000494:pharmacology
chemical_list: D009573:Nitrites; D019163:Reducing Agents; D009569:Nitric Oxide; D006418:Heme; D011732:Pyridoxal Phosphate; D007501:Iron; D009572:Nitrite Reductases; D003541:Cystathionine beta-Synthase; D006862:Hydrogen Sulfide