Inhibition of nitric oxide synthase by cobalamins and cobinamides.

Published

Journal Article

Cobalamins are important cofactors for methionine synthase and methylmalonyl-CoA mutase. Certain corrins also bind nitric oxide (NO), quenching its bioactivity. To determine if corrins would inhibit NO synthase (NOS), we measured their effects on -L-[(14)C]arginine-to-L-[(14)C]citrulline conversion by NOS1, NOS2, and NOS3. Hydroxocobalamin (OH-Cbl), cobinamide, and dicyanocobinamide (CN(2)-Cbi) potently inhibited all isoforms, whereas cyanocobalamin, methylcobalamin, and adenosylcobalamin had much less effect. OH-Cbl and CN(2)-Cbi prevented binding of the oxygen analog carbon monoxide (CO) to the reduced NOS1 and NOS2 heme active site. CN(2)-Cbi did not react directly with NO or CO. Spectral perturbation analysis showed that CN(2)-Cbi interacted directly with the purified NOS1 oxygenase domain. NOS inhibition by corrins was rapid and not reversed by dialysis with L-arginine or tetrahydrobiopterin. Molecular modeling indicated that corrins could access the unusually large heme- and substrate-binding pocket of NOS. Best fits were obtained in the "base-off" conformation of the lower axial dimethylbenzimidazole ligand. CN(2)-Cbi inhibited interferon-gamma-activated Raw264.7 mouse macrophage NO production. We show for the first time that certain corrins directly inhibit NOS, suggesting that these agents (or their derivatives) may have pharmacological utility. Endogenous cobalamins and cobinamides might play important roles in regulating NOS activity under normal and pathological conditions.

Full Text

Duke Authors

Cited Authors

  • Weinberg, JB; Chen, Y; Jiang, N; Beasley, BE; Salerno, JC; Ghosh, DK

Published Date

  • June 15, 2009

Published In

Volume / Issue

  • 46 / 12

Start / End Page

  • 1626 - 1632

PubMed ID

  • 19328848

Pubmed Central ID

  • 19328848

Electronic International Standard Serial Number (EISSN)

  • 1873-4596

Digital Object Identifier (DOI)

  • 10.1016/j.freeradbiomed.2009.03.017

Language

  • eng

Conference Location

  • United States