IUPHAR/BPS Guide to Pharmacology CITE
https://doi.org/10.2218/gtopdb/F253/2019.4

Nitric oxide synthases (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database



Timothy R. Billiar1, Giuseppe Cirino2, David Fulton3, Roberto Motterlini4, Andreas Papapetropoulos5 and Csaba Szabo6
  1. University of Pittsburgh, USA
  2. University of Naples-Federico II, Italy
  3. Georgia Regents University, USA
  4. University of Paris Est Creteil, France
  5. University of Athens, Greece
  6. University of Texas, USA


Abstract

Nitric oxide synthases (NOS, E.C. 1.14.13.39) are a family of oxidoreductases that synthesize nitric oxide (NO.) via the NADPH and oxygen-dependent consumption of L-arginine with the resultant by-product, L-citrulline. There are 3 NOS isoforms and they are related by their capacity to produce NO, highly conserved organization of functional domains and significant homology at the amino acid level. NOS isoforms are functionally distinguished by the cell type where they are expressed, intracellular targeting and transcriptional and post-translation mechanisms regulating enzyme activity. The nomenclature suggested by NC-IUPHAR of NOS I, II and III [11] has not gained wide acceptance, and the 3 isoforms are more commonly referred to as neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS) which reflect the location of expression (nNOS and eNOS) and inducible expression (iNOS). All are dimeric enzymes that shuttle electrons from NADPH, which binds to a C-terminal reductase domain, through the flavins FAD and FMN to the oxygenase domain of the other monomer to enable the BH4-dependent reduction of heme bound oxygen for insertion into the substrate, L-arginine. Electron flow from reductase to oxygenase domain is controlled by calmodulin binding to canonical calmodulin binding motif located between these domains. eNOS and nNOS isoforms are activated at concentrations of calcium greater than 100 nM, while iNOS shows higher affinity for Ca2+/calmodulin with great avidity and is essentially calcium-independent and constitutively active. Efficient stimulus-dependent coupling of nNOS and eNOS is achieved via subcellular targeting through respective N-terminal PDZ and fatty acid acylation domains whereas iNOS is largely cytosolic and function is independent of intracellular location. nNOS is primarily expressed in the brain and neuronal tissue, iNOS in immune cells such as macrophages and eNOS in the endothelial layer of the vasculature although exceptions in other cells have been documented. L-NAME and related modified arginine analogues are inhibitors of all three isoforms, with IC50 values in the micromolar range.

Contents

This is a citation summary for Nitric oxide synthases in the Guide to Pharmacology database (GtoPdb). It exists purely as an adjunct to the database to facilitate the recognition of citations to and from the database by citation analyzers. Readers will almost certainly want to visit the relevant sections of the database which are given here under database links.

GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database. As in any publication this work should be appropriately cited, and the papers it cites should also be recognized. This document provides a citation for the relevant parts of the database, and also provides a reference list for the research cited by those parts.

Please note that the database version for the citations given in GtoPdb are to the most recent preceding version in which the family or its subfamilies and targets were substantially changed. The links below are to the current version. If you need to consult the cited version, rather than the most recent version, please contact the GtoPdb curators.

Database links

Nitric oxide synthases
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=253
    Enzymes
            eNOS(Endothelial NOS)
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1249
            iNOS(Inducible NOS)
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1250
            nNOS(Neuronal NOS)
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1251

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