Inhibition of nitric oxide synthase by cobalamins and cobinamides.
Publication/Presentation Date
6-15-2009
Abstract
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.
Volume
46
Issue
12
First Page
1626
Last Page
1632
ISSN
1873-4596
Published In/Presented At
Weinberg, J. B., Chen, Y., Jiang, N., Beasley, B. E., Salerno, J. C., & Ghosh, D. K. (2009). Inhibition of nitric oxide synthase by cobalamins and cobinamides. Free radical biology & medicine, 46(12), 1626–1632. https://doi.org/10.1016/j.freeradbiomed.2009.03.017
Disciplines
Medicine and Health Sciences
PubMedID
19328848
Department(s)
Fellows and Residents
Document Type
Article