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Inhibition of nitric oxide synthase by cobalamins and cobinamides.

Publication ,  Journal Article
Weinberg, JB; Chen, Y; Jiang, N; Beasley, BE; Salerno, JC; Ghosh, DK
Published in: Free Radic Biol Med
June 15, 2009

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.

Duke Scholars

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Published In

Free Radic Biol Med

DOI

EISSN

1873-4596

Publication Date

June 15, 2009

Volume

46

Issue

12

Start / End Page

1626 / 1632

Location

United States

Related Subject Headings

  • Vitamin B 12
  • Structure-Activity Relationship
  • Recombinant Proteins
  • Rats
  • Nitric Oxide Synthase Type III
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type I
  • Nitric Oxide
  • Models, Molecular
  • Mice
 

Citation

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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 Radic Biol Med, 46(12), 1626–1632. https://doi.org/10.1016/j.freeradbiomed.2009.03.017
Weinberg, J Brice, Youwei Chen, Ning Jiang, Bethany E. Beasley, John C. Salerno, and Dipak K. Ghosh. “Inhibition of nitric oxide synthase by cobalamins and cobinamides.Free Radic Biol Med 46, no. 12 (June 15, 2009): 1626–32. https://doi.org/10.1016/j.freeradbiomed.2009.03.017.
Weinberg JB, Chen Y, Jiang N, Beasley BE, Salerno JC, Ghosh DK. Inhibition of nitric oxide synthase by cobalamins and cobinamides. Free Radic Biol Med. 2009 Jun 15;46(12):1626–32.
Weinberg, J. Brice, et al. “Inhibition of nitric oxide synthase by cobalamins and cobinamides.Free Radic Biol Med, vol. 46, no. 12, June 2009, pp. 1626–32. Pubmed, doi:10.1016/j.freeradbiomed.2009.03.017.
Weinberg JB, Chen Y, Jiang N, Beasley BE, Salerno JC, Ghosh DK. Inhibition of nitric oxide synthase by cobalamins and cobinamides. Free Radic Biol Med. 2009 Jun 15;46(12):1626–1632.
Journal cover image

Published In

Free Radic Biol Med

DOI

EISSN

1873-4596

Publication Date

June 15, 2009

Volume

46

Issue

12

Start / End Page

1626 / 1632

Location

United States

Related Subject Headings

  • Vitamin B 12
  • Structure-Activity Relationship
  • Recombinant Proteins
  • Rats
  • Nitric Oxide Synthase Type III
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type I
  • Nitric Oxide
  • Models, Molecular
  • Mice