Irreversible inactivation of macrophage and brain nitric oxide synthase by L-NG-methylarginine requires NADPH-dependent hydroxylation.

doi:10.1021/JM00056A009

Paper

Irreversible inactivation of macrophage and brain nitric oxide synthase by L-NG-methylarginine requires NADPH-dependent hydroxylation.

Published Feb 19, 1993 · P. Feldman, O. Griffith, H. Hong

Journal of medicinal chemistry

Q1 SJR score

110

Citations

1

Influential Citations

Full textSemantic Scholar

Abstract

L-NG-Methylarginine (NMA) is an established mechanism-based inactivator of murine macrophage nitric oxide synthase (mNOS). In this report, NMA is shown to irreversibly inhibit both mNOS (k(inact) = 0.08 min-1) and the recombinant constitutive brain NOS (bNOS). For both NOS isoforms, metabolism of NMA parallels that of the natural substrate L-arginine (ARG), in that it undergoes a regiospecific, NADPH-dependent hydroxylation to form L-NG-hydroxy-NG-methylarginine (NOHNMA). This intermediate then undergoes further NADPH-dependent oxidation to form L-citrulline (CIT). Authentic NOHNMA, synthesized from L-ornithine, irreversibly inhibited both mNOS (k(inact) = 0.10 min-1) and bNOS in an NADPH-dependent reaction. The conversion of either NMA or NOHNMA to CIT correlated with irreversible enzyme inactivation. Thus, the data suggest that enzyme inhibition occurs as a consequence of oxidative metabolism of the intermediate, NOHNMA. A unified mechanism is proposed that accounts for NO biosynthesis from ARG, for the inactivation of NOS by NMA and for the intermediacy of hydroxylated ARG or NMA derivatives in these processes.

Highly Cited

Study Snapshot

L-NG-methylarginine (NMA) irreversibly inhibits macrophage and brain nitric oxide synthase (mNOS) through NADPH-dependent hydroxylation of NOHNMA, a regiospecific intermediate in nitric oxide biosynthesis.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Sign up to use Study Snapshot

Consensus is limited without an account. Create an account or sign in to get more searches and use the Study Snapshot.

Create an account

Paper

Irreversible inactivation of macrophage and brain nitric oxide synthase by L-NG-methylarginine requires NADPH-dependent hydroxylation.

Sign up to use Study Snapshot

References

Citations

Nitric Oxide Synthases and Their Inhibitors: A Review

Nitric oxide synthases (NOS) play a crucial role in regulating various systems in mammals, and computational techniques can help develop inhibitors for their various isoforms.

Nitric oxide release from a photoactive water-soluble ruthenium nitrosyl. Biological effects

The photoactive water-soluble ruthenium nitrosyl, Ru(salenCO2H)(NO)Cl, releases nitric oxide upon photolysis, with pH-dependent quantum yield and cytotoxicity and vascular relaxivity properties.

Accurate real-time sensing tip for aqueous NO with optical fibers embedded in active hydrogel waveguide

This new sensing tip, using optical fibers embedded in a polyHEMA hydrogel waveguide, can accurately detect aqueous NO concentrations down to 1 M, potentially aiding in monitoring medical conditions inside the brain after stroke or injury.

Does the Inhibitory Action of Asymmetric Dimethylarginine (ADMA) on the Endothelial Nitric Oxide Synthase Activity Explain Its Importance in the Cardiovascular System? The ADMA Paradox

ADMA's importance in the cardiovascular system may be due to other, yet unrecognized, biological actions beyond its weak inhibitory action on nitric oxide synthase activity.

Anticancer effects of synthetic hexahydrobenzo [g]chromen-4-one derivatives on human breast cancer cell lines

Most synthetic hexahydrobenzo [g]chromen-4-one derivatives show significant anti-proliferative activity against six human cancer cell lines and induce cell death through apoptosis.

Caractérisation physico-chimique, au niveau nanométrique, des surfaces de biomatériaux utilisés pour la délivrance de médicaments et pour la croissance osseuse

Nanoparticles have low toxicity, but their synthesis and functionalization processes need improvement to minimize biocompatibility issues.

Development of nitric oxide synthase inhibitors for neurodegeneration and neuropathic pain.

Selective inhibition of nitric oxide synthase (nNOS) may offer therapeutic benefits for neurodegeneration and neuropathic pain by targeting the enzyme's role in neurodegeneration and pain.

Polycarbonateurethane films containing complex of copper(II) catalyzed generation of nitric oxide

Polycarbonateurethane films with Cu(II)-complex can catalyze continuous generation of nitric oxide, potentially reducing the risk of thrombosis on medical devices.

Theoretical investigation of nitric oxide interaction with aluminum phthalocyanine.

Nitric oxide's interaction with aluminum phthalocyanine depends on its oxidation state, with stronger bonds in the reduced state.