BioModelsapplication/xmlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000199?filename=curation_notes.txthttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000199?filename=BIOMD0000000199.pdfhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000199?filename=BIOMD0000000199-biopax3.owlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000199?filename=BIOMD0000000199-biopax2.owlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000199?filename=manifest.xmlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000199?filename=BIOMD0000000199_url.xmlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000199?filename=BIOMD0000000199.odehttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000199?filename=BIOMD0000000199.pnghttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000199?filename=BIOMD0000000199-octave.mhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000199?filename=BIOMD0000000199.mhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000199?filename=BIOMD0000000199-matlab.mhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000199?filename=curation_image.pnghttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000199?filename=metadata.rdfhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000199?filename=BIOMD0000000199_url.sedmlprimaryOK200Sharat VayttadenManually curatedordinary differential equation modelL2V3https://www.ebi.ac.uk/biomodels/BIOMD000000019911038356falseBioModelsSBMLModelsSantolini2001 nNOS Mechanism Regulation2001MODEL4734733125J Santolini, S Adak, C M Curran, D J StuehrJ Santolini11038356, After initiating NO synthesis a majority of neuronal NO synthase (nNOS) quickly partitions into a ferrous heme-NO complex. This down-regulates activity and increases enzyme K(m,O(2)). To understand this process, we developed a 10-step kinetic model in which the ferric heme-NO enzyme forms as the immediate product of catalysis, and then partitions between NO dissociation versus reduction to a ferrous heme-NO complex. Rate constants used for the model were derived from recent literature or were determined here. Computer simulations of the model precisely described both pre-steady and steady-state features of nNOS catalysis, including NADPH consumption and NO production, buildup of a heme-NO complex, changes between pre-steady and steady-state rates, and the change in enzyme K(m,O(2)) in the presence or absence of NO synthesis. The model also correctly simulated the catalytic features of nNOS mutants W409F and W409Y, which are hyperactive and display less heme-NO complex formation in the steady state. Model simulations showed how the rate of heme reduction influences several features of nNOS catalysis, including populations of NO-bound versus NO-free enzyme in the steady state and the rate of NO synthesis. The simulation predicts that there is an optimum rate of heme reduction that is close to the measured rate in nNOS. Ratio between NADPH consumption and NO synthesis is also predicted to increase with faster heme reduction. Our kinetic model is an accurate and versatile tool for understanding catalytic behavior and will provide new perspectives on NOS regulation.. 2, 276. Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.doqcs@ncbs.res.inDOQCSBIOMD0000000199After initiating NO synthesis a majority of neuronal NO synthase (nNOS) quickly partitions into a ferrous heme-NO complex. This down-regulates activity and increases enzyme K(m,O(2)). To understand this process, we developed a 10-step kinetic model in which the ferric heme-NO enzyme forms as the immediate product of catalysis, and then partitions between NO dissociation versus reduction to a ferrous heme-NO complex. Rate constants used for the model were derived from recent literature or were determined here. Computer simulations of the model precisely described both pre-steady and steady-state features of nNOS catalysis, including NADPH consumption and NO production, buildup of a heme-NO complex, changes between pre-steady and steady-state rates, and the change in enzyme K(m,O(2)) in the presence or absence of NO synthesis. The model also correctly simulated the catalytic features of nNOS mutants W409F and W409Y, which are hyperactive and display less heme-NO complex formation in the steady state. Model simulations showed how the rate of heme reduction influences several features of nNOS catalysis, including populations of NO-bound versus NO-free enzyme in the steady state and the rate of NO synthesis. The simulation predicts that there is an optimum rate of heme reduction that is close to the measured rate in nNOS. Ratio between NADPH consumption and NO synthesis is also predicted to increase with faster heme reduction. Our kinetic model is an accurate and versatile tool for understanding catalytic behavior and will provide new perspectives on NOS regulation.A kinetic simulation model that describes catalysis and regulation in nitric-oxide synthase.Santolini J J, Adak S S, Curran C M CM, Stuehr D J DJfalseSantolini2001_nNOS_Mechanism_Regulation This is a model of neuronal Nitric Oxide Synthase expressed in Escherichia coli based on Santolini J. et al. J Biol Chem. (2001) 276(2):1233-43. Differing from the article, oxygen explicitly included in the reaction 2, 5 and 10 (numbers as in scheme 1 in the article). In the article the assumed oxygen concentration of 140 uM was included in the pseudo first order rate constant. Fig 2E in the article shows different time courses for citrulline and NO than the ones produced by this model. Dr. Santolini, one of the authors of the article, wrote that the legends in fig. 2E might be mixed up and should rather denote NO and NO3 instead of citrulline and NO. This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2009 The BioModels Team. For more information see the terms of use. To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691. 2024-08-212024-09-022008-11-10BIOMD000000019916373111038356CHEBI:17627CHEBI:29034CHEBI:29033CHEBI:15379CHEBI:16480CHEBI:16474CHEBI:16349CHEBI:17632CHEBI:18009MODEL4734733125BIOMD0000000199GO:0004517GO:0005829GO:0016651C00005C00007C00327C00244C00533C0000610116P29476