Nitric oxide synthase enzymology in the 20 years after the Nobel Prize

This review briefly summarizes what was known about NOS enzymology at the time of the Nobel Prize award in 1998 and then discusses from the author's perspective some of the advances in NOS enzymology over the subsequent 20 years, focused on five aspects: the maturation process of NOS enzymes and its regulation; the mechanism of NO synthesis; the redox roles played by the 6R‐tetrahydrobiopterin cofactor; the role of protein conformational behaviour in enabling NOS electron transfer and its regulation by NOS structural elements and calmodulin, and the catalytic cycling pathways of NOS enzymes and their influence on NOS activity.

[1]  M. Marletta,et al.  Reactions catalyzed by the heme domain of inducible nitric oxide synthase: evidence for the involvement of tetrahydrobiopterin in electron transfer. , 2002, Biochemistry.

[2]  T. Poulos,et al.  Crystal Structure of Constitutive Endothelial Nitric Oxide Synthase A Paradigm for Pterin Function Involving a Novel Metal Center , 1998, Cell.

[3]  Arthur Christopoulos,et al.  THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Overview , 2017, British journal of pharmacology.

[4]  K. Panda,et al.  Versatile regulation of neuronal nitric oxide synthase by specific regions of its C-terminal tail. , 2007, Biochemistry.

[5]  S. Kaufman,et al.  Reduction of Quinonoid Dihydrobiopterin to Tetrahydrobiopterin by Nitric Oxide Synthase (*) , 1996, The Journal of Biological Chemistry.

[6]  M. Mewies,et al.  Crystal structure of the ascorbate peroxidase–ascorbate complex , 2003, Nature Structural Biology.

[7]  Alasdair J. G. Gray,et al.  The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY , 2017, Nucleic Acids Res..

[8]  J. Tainer,et al.  Structural Basis for Isozyme-specific Regulation of Electron Transfer in Nitric-oxide Synthase*[boxs] , 2004, Journal of Biological Chemistry.

[9]  B. Mayer,et al.  Analysis of neuronal NO synthase under single-turnover conditions: conversion of Nomega-hydroxyarginine to nitric oxide and citrulline. , 1997, Biochemistry.

[10]  J. Tainer,et al.  Structure of nitric oxide synthase oxygenase dimer with pterin and substrate. , 1998, Science.

[11]  Jérôme Santolini,et al.  Fast ferrous heme–NO oxidation in nitric oxide synthases , 2009, The FEBS journal.

[12]  M. Marletta,et al.  The second step of the nitric oxide synthase reaction: evidence for ferric-peroxo as the active oxidant. , 2009, Journal of the American Chemical Society.

[13]  Brian C. Smith,et al.  Nitric oxide synthase domain interfaces regulate electron transfer and calmodulin activation , 2013, Proceedings of the National Academy of Sciences.

[14]  Qian Wang,et al.  Arginine Conversion to Nitroxide by Tetrahydrobiopterin-free Neuronal Nitric-oxide Synthase , 2000, The Journal of Biological Chemistry.

[15]  Zhi‐qiang Wang,et al.  How does a valine residue that modulates heme-NO binding kinetics in inducible NO synthase regulate enzyme catalysis? , 2010, Journal of inorganic biochemistry.

[16]  D. Rousseau,et al.  Substrate- and isoform-specific dioxygen complexes of nitric oxide synthase. , 2007, Journal of the American Chemical Society.

[17]  M. Haque,et al.  Single-molecule spectroscopy reveals how calmodulin activates NO synthase by controlling its conformational fluctuation dynamics , 2015, Proceedings of the National Academy of Sciences.

[18]  M. Marletta,et al.  Reactions catalyzed by tetrahydrobiopterin-free nitric oxide synthase. , 1998, Biochemistry.

[19]  D. Laskowski,et al.  Nitric oxide synthesis in the lung. Regulation by oxygen through a kinetic mechanism. , 1998, The Journal of clinical investigation.

[20]  T. Michel,et al.  The regulation and pharmacology of endothelial nitric oxide synthase. , 2006, Annual review of pharmacology and toxicology.

[21]  D. Stuehr,et al.  Calmodulin controls neuronal nitric-oxide synthase by a dual mechanism. Activation of intra- and interdomain electron transfer. , 1994, The Journal of biological chemistry.

[22]  F. Raushel,et al.  The Ferrous-dioxy Complex of Neuronal Nitric Oxide Synthase , 1997, The Journal of Biological Chemistry.

[23]  W. Pratt,et al.  Modulation of Heme/Substrate Binding Cleft of Neuronal Nitric-oxide Synthase (nNOS) Regulates Binding of Hsp90 and Hsp70 Proteins and nNOS Ubiquitination* , 2011, The Journal of Biological Chemistry.

[24]  Y. Sheng,et al.  Insight into structural rearrangements and interdomain interactions related to electron transfer between flavin mononucleotide and heme in nitric oxide synthase: A molecular dynamics study. , 2015, Journal of inorganic biochemistry.

[25]  Brian C. Smith,et al.  Molecular architecture of mammalian nitric oxide synthases , 2014, Proceedings of the National Academy of Sciences.

[26]  S. Erzurum,et al.  Comparative functioning of dihydro- and tetrahydropterins in supporting electron transfer, catalysis, and subunit dimerization in inducible nitric oxide synthase. , 1998, Biochemistry.

[27]  T. Poulos,et al.  Exploring the Electron Transfer Properties of Neuronal Nitric-oxide Synthase by Reversal of the FMN Redox Potential* , 2008, Journal of Biological Chemistry.

[28]  A. Persechini,et al.  Phosphorylation within an autoinhibitory domain in endothelial nitric oxide synthase reduces the Ca(2+) concentrations required for calmodulin to bind and activate the enzyme. , 2008, Biochemistry.

[29]  D. Stuehr,et al.  Stopped-flow analysis of CO and NO binding to inducible nitric oxide synthase. , 1998, Biochemistry.

[30]  Arnab Ghosh,et al.  Regulation of sGC via hsp90, Cellular Heme, sGC Agonists, and NO: New Pathways and Clinical Perspectives. , 2017, Antioxidants & redox signaling.

[31]  Ritu Chakravarti,et al.  GAPDH regulates cellular heme insertion into inducible nitric oxide synthase , 2010, Proceedings of the National Academy of Sciences.

[32]  F. Murad,et al.  Phosphorylation by calcium calmodulin-dependent protein kinase II and protein kinase C modulates the activity of nitric oxide synthase. , 1991, Biochemical and biophysical research communications.

[33]  D. Stuehr,et al.  Comparative Effects of Substrates and Pterin Cofactor on the Heme Midpoint Potential in Inducible and Neuronal Nitric Oxide Synthases , 1998 .

[34]  Adam J Pawson,et al.  THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Enzymes , 2017, British journal of pharmacology.

[35]  M. Hentze,et al.  Iron regulates nitric oxide synthase activity by controlling nuclear transcription , 1994, The Journal of experimental medicine.

[36]  R. Lewis,et al.  Theoretical studies of the second step of the nitric oxide synthase reaction: Electron tunneling prevents uncoupling. , 2018, Journal of inorganic biochemistry.

[37]  B. Crane,et al.  Nitrosyl-heme structures of Bacillus subtilis nitric oxide synthase have implications for understanding substrate oxidation. , 2006, Biochemistry.

[38]  Yukio Nakamura,et al.  Hsp90 chaperones hemoglobin maturation in erythroid and nonerythroid cells , 2018, Proceedings of the National Academy of Sciences.

[39]  M. Haque,et al.  Charge-pairing interactions control the conformational setpoint and motions of the FMN domain in neuronal nitric oxide synthase. , 2013, The Biochemical journal.

[40]  D. Stuehr Structure-function aspects in the nitric oxide synthases. , 1997, Annual review of pharmacology and toxicology.

[41]  Zhi‐qiang Wang,et al.  Update on Mechanism and Catalytic Regulation in the NO Synthases* , 2004, Journal of Biological Chemistry.

[42]  D. Wolan,et al.  Antifungal Imidazoles Block Assembly of Inducible NO Synthase into an Active Dimer* , 1999, The Journal of Biological Chemistry.

[43]  M. Marletta,et al.  Pterin-centered radical as a mechanistic probe of the second step of nitric oxide synthase. , 2010, Journal of the American Chemical Society.

[44]  Zhi‐qiang Wang,et al.  Exploring the redox reactions between heme and tetrahydrobiopterin in the nitric oxide synthases. , 2005, Dalton transactions.

[45]  Zhi‐qiang Wang,et al.  Neutralizing a Surface Charge on the FMN Subdomain Increases the Activity of Neuronal Nitric-oxide Synthase by Enhancing the Oxygen Reactivity of the Enzyme Heme-Nitric Oxide Complex* , 2009, The Journal of Biological Chemistry.

[46]  D. Wendehenne,et al.  Nitric oxide synthase in plants: Where do we stand? , 2017, Nitric oxide : biology and chemistry.

[47]  L. Waskell,et al.  Distinct conformational behaviors of four mammalian dual‐flavin reductases (cytochrome P450 reductase, methionine synthase reductase, neuronal nitric oxide synthase, endothelial nitric oxide synthase) determine their unique catalytic profiles , 2014, The FEBS journal.

[48]  T. Iyanagi,et al.  Regulation of Interdomain Interactions by Calmodulin in Inducible Nitric-oxide Synthase* , 2009, The Journal of Biological Chemistry.

[49]  T. Poulos,et al.  Elucidating nitric oxide synthase domain interactions by molecular dynamics , 2015, Protein science : a publication of the Protein Society.

[50]  M. Haque,et al.  Tetrahydrobiopterin redox cycling in nitric oxide synthase: evidence supports a through‐heme electron delivery , 2016, The FEBS journal.

[51]  T. Poulos,et al.  Calmodulin activates neuronal nitric oxide synthase by enabling transitions between conformational states , 2013, FEBS letters.

[52]  B. Mayer,et al.  Tetrahydrobiopterin in nitric oxide synthesis: a novel biological role for pteridines. , 2002, Current drug metabolism.

[53]  G. Tollin,et al.  Deletion of the autoregulatory insert modulates intraprotein electron transfer in rat neuronal nitric oxide synthase , 2008, FEBS letters.

[54]  S. P. Visser Density functional theory (DFT) and combined quantum mechanical/molecular mechanics (QM/MM) studies on the oxygen activation step in nitric oxide synthase enzymes. , 2009 .

[55]  W. Sessa,et al.  Endothelial NOS: perspective and recent developments , 2018, British journal of pharmacology.

[56]  D. Stuehr,et al.  Intracellular Assembly of Inducible NO Synthase Is Limited by Nitric Oxide-mediated Changes in Heme Insertion and Availability , 1996, The Journal of Biological Chemistry.

[57]  M. Haque,et al.  A Bridging Interaction Allows Calmodulin to Activate NO Synthase through a Bi-modal Mechanism* , 2010, The Journal of Biological Chemistry.

[58]  Zhi‐qiang Wang,et al.  A Tetrahydrobiopterin Radical Forms and then Becomes Reduced during Nω-Hydroxyarginine Oxidation by Nitric-oxide Synthase* , 2003, Journal of Biological Chemistry.

[59]  Michael T. Green,et al.  Reactive Intermediates in Cytochrome P450 Catalysis* , 2013, The Journal of Biological Chemistry.

[60]  H. Kohno,et al.  Nitric oxide-mediated inactivation of mammalian ferrochelatase in vivo and in vitro: possible involvement of the iron-sulphur cluster of the enzyme. , 1995, The Biochemical journal.

[61]  M. Marletta,et al.  Nitric oxide synthase: Aspects concerning structure and catalysis , 1994, Cell.

[62]  Min Su,et al.  Architecture of the Nitric-oxide Synthase Holoenzyme Reveals Large Conformational Changes and a Calmodulin-driven Release of the FMN Domain*♦ , 2014, The Journal of Biological Chemistry.

[63]  N. Scrutton,et al.  A perspective on conformational control of electron transfer in nitric oxide synthases , 2017, Nitric oxide : biology and chemistry.

[64]  Zhi‐qiang Wang,et al.  Dynamic Regulation of the Inducible Nitric-oxide Synthase by NO , 2004, Journal of Biological Chemistry.

[65]  N. Volkmann,et al.  Holoenzyme structures of endothelial nitric oxide synthase - an allosteric role for calmodulin in pivoting the FMN domain for electron transfer. , 2014, Journal of structural biology.

[66]  Sanjay Ghosh,et al.  Mechanistic Studies with Potent and Selective Inducible Nitric-oxide Synthase Dimerization Inhibitors* , 2002, The Journal of Biological Chemistry.

[67]  G. Garcı́a-Cardeña,et al.  Endothelial Nitric Oxide Synthase Is Regulated by Tyrosine Phosphorylation and Interacts with Caveolin-1* , 1996, The Journal of Biological Chemistry.

[68]  B. Masters,et al.  Electron Transfer by Neuronal Nitric-oxide Synthase Is Regulated by Concerted Interaction of Calmodulin and Two Intrinsic Regulatory Elements* , 2006, Journal of Biological Chemistry.

[69]  D. Rousseau,et al.  Regulation of the Monomer-Dimer Equilibrium in Inducible Nitric-oxide Synthase by Nitric Oxide* , 2006, Journal of Biological Chemistry.

[70]  Zhi‐qiang Wang,et al.  Catalytic Reduction of a Tetrahydrobiopterin Radical within Nitric-oxide Synthase* , 2008, Journal of Biological Chemistry.

[71]  M. Marletta,et al.  S-Nitrosation and regulation of inducible nitric oxide synthase. , 2005, Biochemistry.

[72]  N. Scrutton,et al.  Conformational and thermodynamic control of electron transfer in neuronal nitric oxide synthase. , 2007, Biochemistry.

[73]  S. M. Waheed,et al.  Nitric oxide blocks cellular heme insertion into a broad range of heme proteins. , 2010, Free radical biology & medicine.

[74]  E. Sheta,et al.  Neuronal nitric oxide synthase, a modular enzyme formed by convergent evolution: structure studies of a cysteine thiolate‐liganded heme protein that hydroxylates L‐arginine to produce NO as a cellular signal , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[75]  A. Astashkin,et al.  Pulsed EPR determination of the distance between heme iron and FMN centers in a human inducible nitric oxide synthase. , 2010, Journal of the American Chemical Society.

[76]  S Moncada,et al.  Nitric oxide synthases in mammals. , 1994, The Biochemical journal.

[77]  Anuradha Singh,et al.  Glyceraldehyde-3-phosphate dehydrogenase is a chaperone that allocates labile heme in cells , 2018, The Journal of Biological Chemistry.

[78]  Arnab Ghosh,et al.  Hsp90 interacts with inducible NO synthase client protein in its heme‐free state and then drives heme insertion by an ATP‐dependent process , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[79]  Sarah E. Chobot,et al.  Enzymatic and Cryoreduction EPR Studies of the Hydroxylation of Methylated Nω-Hydroxy-l-arginine Analogues by Nitric Oxide Synthase from Geobacillus stearothermophilus , 2014, Biochemistry.

[80]  D. Rousseau,et al.  Nitric Oxide Binding to the Heme of Neuronal Nitric-oxide Synthase Links Its Activity to Changes in Oxygen Tension* , 1996, The Journal of Biological Chemistry.

[81]  Arnab Ghosh,et al.  Control of Electron Transfer and Catalysis in Neuronal Nitric-oxide Synthase (nNOS) by a Hinge Connecting Its FMN and FAD-NADPH Domains* , 2012, The Journal of Biological Chemistry.

[82]  Kenneth K. Wu,et al.  Structural Elements Contribute to the Calcium/Calmodulin Dependence on Enzyme Activation in Human Endothelial Nitric-oxide Synthase* , 2003, Journal of Biological Chemistry.

[83]  A. Persechini,et al.  Fluorescence quenching studies of structure and dynamics in calmodulin–eNOS complexes , 2015, FEBS letters.