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Mechanism of nitrite-dependent NO synthesis by human sulfite oxidase.

Biochem. J.2019 Jun 28;476(12):1805-1815
Daniel Bender 1 , Alexander Tobias Kaczmarek 1 , Dimitri Niks 2 , Russ Hille 2 , Guenter Schwarz 3
Daniel Bender 1 , Alexander Tobias Kaczmarek 1 , Dimitri Niks 2 , Russ Hille 2 , Guenter Schwarz 3

[No authors listed]

Author information
  • 1 Center for Molecular Medicine Cologne, CMMC, University of Cologne, 50931 Cologne, Germany.
  • 2 Department of Biochemistry, University of California, Riverside, CA 92521, U.S.A.
  • 3 Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases, CECAD, University of Cologne, 50931 Cologne, Germany.

摘要


In addition to nitric oxide (NO) synthases, molybdenum-dependent enzymes have been reported to reduce nitrite to produce NO. Here, we report the stoichiometric reduction in nitrite to NO by human sulfite oxidase (SO), a mitochondrial intermembrane space enzyme primarily involved in cysteine catabolism. Kinetic and spectroscopic studies provide evidence for direct nitrite coordination at the molybdenum center followed by an inner shell electron transfer mechanism. In the presence of the physiological electron acceptor cytochrome c, we were able to close the catalytic cycle of sulfite-dependent nitrite reduction thus leading to steady-state NO synthesis, a finding that strongly supports a physiological relevance of SO-dependent NO formation. By engineering SO variants with reduced intramolecular electron transfer rate, we were able to increase NO generation efficacy by one order of magnitude, providing a mechanistic tool to tune NO synthesis by SO.

KEYWORDS: mitochondria, molybdenum cofactor, nitric oxide, nitrite reduction, sulfite oxidase