title: Regulation of interdomain electron transfer in the NOS output state for NO production.
abstract: There is still much that is unknown about how nitric oxide (NO) biosynthesis by NO synthase (NOS) isoform is tightly regulated at the molecular level. This is remarkable because deviated NO production in vivo has been implicated in an increasing number of diseases that currently lack effective treatments, including stroke and cancer. Given the significant public health burden of these diseases, the NOS enzyme family is a key target for development of new pharmaceuticals. Three NOS isoforms, inducible, endothelial and neuronal NOS (iNOS, eNOS and nNOS, respectively), achieve their key biological functions via stringent regulations of interdomain electron transfer (IET) processes. Unlike iNOS, eNOS and nNOS isoforms are controlled by calmodulin (CaM) binding through facilitating catalytically significant IET processes. The CaM-modulated NOS output state is an IET-competent complex between the flavin mononucleotide (FMN) domain and the catalytic heme domain. The output state facilitates the catalytically essential FMN-heme IET, and thereby enables NO production by NOS. Due to lack of reliable techniques for specifically determining the inter-domain FMN-heme interactions and their direct effects on the catalytic heme center, the molecular mechanism that underlies the output state formation remains elusive. The recent developments in our understanding of mechanisms of the NOS output state formation that are driven by a combination of molecular biology, laser flash photolysis, and spectroscopic techniques are the subject of this perspective.
authors.affiliation: College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA. cfeng@salud.unm.edu
authors.forename: Changjian
authors.initials: C
authors.lastname: Feng
authors.forename: Gordon
authors.initials: G
authors.lastname: Tollin
mesh_terms: D002147:Calmodulin / Q000378:metabolism; D004579:Electron Transport; D005486:Flavin Mononucleotide / Q000378:metabolism; D006418:Heme / Q000378:metabolism; D007700:Kinetics; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000737:chemistry / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D002147:Calmodulin; D020033:Protein Isoforms; D009569:Nitric Oxide; D006418:Heme; D005486:Flavin Mononucleotide; D019001:Nitric Oxide Synthase
references.citation: J Biol Chem. 2008 Dec 12;283(50):34762-72
references.pmid: 18852262
references.citation: J Am Chem Soc. 2006 Mar 22;128(11):3808-11
references.pmid: 16536556
references.citation: J Biol Chem. 2004 Apr 30;279(18):18323-33
references.pmid: 14966111
references.citation: J Biol Chem. 2004 Aug 27;279(35):36167-70
references.pmid: 15133020
references.citation: Biochemistry. 2007 Jul 17;46(28):8288-300
references.pmid: 17580957
references.citation: Cell. 1998 Dec 23;95(7):939-50
references.pmid: 9875848
references.citation: J Biol Inorg Chem. 2002 Mar;7(3):338-50
references.pmid: 11935358
references.citation: J Biol Chem. 2000 Apr 28;275(17):13155-63
references.pmid: 10777622
references.citation: Cancer Res. 2006 Jul 1;66(13):6459-62
references.pmid: 16818612
references.citation: J Biol Chem. 2006 May 19;281(20):14173-83
references.pmid: 16461329
references.citation: Front Biosci. 2003 Jan 01;8:d193-209
references.pmid: 12456347
references.citation: Biochemistry. 2007 May 1;46(17):5018-29
references.pmid: 17411075
references.citation: J Biol Chem. 2004 Apr 30;279(18):18759-66
references.pmid: 14715665
references.citation: J Biol Chem. 2002 May 24;277(21):19087-94
references.pmid: 11839759
references.citation: J Biol Inorg Chem. 2009 Jan;14(1):133-42
references.pmid: 18830722
references.citation: Biochim Biophys Acta. 2007 May;1774(5):527-39
references.pmid: 17459792
references.citation: J Biol Chem. 1992 Oct 15;267(29):20547-50
references.pmid: 1383204
references.citation: Biochemistry. 2005 Mar 29;44(12):4676-90
references.pmid: 15779894
references.citation: J Biol Chem. 1999 Oct 22;274(43):30589-95
references.pmid: 10521442
references.citation: Br J Pharmacol. 2006 Jan;147 Suppl 1:S193-201
references.pmid: 16402104
references.citation: J Biol Chem. 2000 Sep 22;275(38):29225-32
references.pmid: 10871625
references.citation: FEBS J. 2006 Apr;273(8):1759-71
references.pmid: 16623711
references.citation: Free Radic Biol Med. 2005 Aug 1;39(3):412-25
references.pmid: 15993340
references.citation: Biochemistry. 2002 Nov 26;41(47):13868-75
references.pmid: 12437343
references.citation: Proc Natl Acad Sci U S A. 2007 May 29;104(22):9254-9
references.pmid: 17517617
references.citation: J Biol Chem. 2006 Nov 10;281(45):34246-57
references.pmid: 16966328
references.citation: J Biol Chem. 2006 Aug 11;281(32):23111-8
references.pmid: 16782703
references.citation: J Biol Chem. 2001 Oct 5;276(40):37506-13
references.pmid: 11473123
references.citation: J Biol Chem. 1994 Dec 23;269(51):32318-26
references.pmid: 7528212
references.citation: J Am Chem Soc. 2007 May 2;129(17):5621-9
references.pmid: 17425311
references.citation: J Biol Chem. 2000 Feb 18;275(7):5052-8
references.pmid: 10671547
references.citation: Chem Rev. 2002 Apr;102(4):1191-200
references.pmid: 11942793
references.citation: EMBO J. 2003 Feb 17;22(4):766-75
references.pmid: 12574113
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15833-8
references.pmid: 16249336
references.citation: J Biol Chem. 2003 Aug 22;278(34):31814-24
references.pmid: 12805387
references.citation: Chem Biol. 1998 Jul;5(7):355-64
references.pmid: 9662510
references.citation: FEBS Lett. 2008 Aug 6;582(18):2768-72
references.pmid: 18625229
references.citation: J Biol Chem. 2000 Jul 21;275(29):21914-9
references.pmid: 10781602
references.citation: Biochemistry. 2007 Dec 18;46(50):14418-28
references.pmid: 18020458
references.citation: Biochemistry. 1996 Feb 27;35(8):2804-10
references.pmid: 8611587
references.citation: Biochemistry. 2008 Feb 26;47(8):2231-43
references.pmid: 18237198
references.citation: Biochemistry. 2008 Jul 15;47(28):7557-66
references.pmid: 18558722
references.citation: Biochemistry. 2007 Nov 27;46(47):13533-40
references.pmid: 17973404
references.citation: Chem Rev. 2003 Jun;103(6):2365-83
references.pmid: 12797834
references.citation: Biochemistry. 1999 Dec 14;38(50):16413-8
references.pmid: 10600101
references.citation: J Biol Chem. 2002 Sep 13;277(37):33987-94
references.pmid: 12089147
references.citation: Biochemistry. 2006 May 23;45(20):6354-62
references.pmid: 16700546
references.citation: J Biol Chem. 1996 Dec 20;271(51):32563-71
references.pmid: 8955082
references.citation: Chem Rev. 2002 Apr;102(4):1179-90
references.pmid: 11942792
references.citation: J Biol Chem. 2004 Aug 6;279(32):33547-57
references.pmid: 15138276
references.citation: J Biol Chem. 1997 Nov 21;272(47):29769-77
references.pmid: 9368047
references.citation: J Biol Chem. 2001 Jun 29;276(26):23349-56
references.pmid: 11325964
references.citation: Biochemistry. 2008 Sep 16;47(37):9771-80
references.pmid: 18717591
references.citation: Biochem J. 2001 Aug 1;357(Pt 3):593-615
references.pmid: 11463332
references.citation: J Biol Chem. 2006 Dec 1;281(48):36819-27
references.pmid: 17001078
references.citation: J Biol Chem. 1996 Aug 23;271(34):20594-602
references.pmid: 8702805
references.citation: Biochemistry. 1997 Oct 7;36(40):12337-45
references.pmid: 9315874
references.citation: J Biol Chem. 2008 Jul 11;283(28):19603-15
references.pmid: 18487202
references.citation: Am J Physiol Lung Cell Mol Physiol. 2004 May;286(5):L1066-74
references.pmid: 14729513
references.citation: Biochem Soc Trans. 2001 May;29(Pt 2):147-52
references.pmid: 11356143
references.citation: Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8411-6
references.pmid: 9237990
references.citation: J Biol Chem. 2004 Sep 3;279(36):37918-27
references.pmid: 15208315
references.citation: J Am Chem Soc. 2009 May 27;131(20):6940-1
references.pmid: 19405537
references.citation: Nat Rev Drug Discov. 2002 Dec;1(12):939-50
references.pmid: 12461516
references.citation: Biochim Biophys Acta. 2008 Dec;1784(12):2065-70
references.pmid: 18845278
references.citation: Nat Chem Biol. 2008 Nov;4(11):700-7
references.pmid: 18849972
references.citation: J Biol Chem. 2004 Aug 27;279(35):36876-83
references.pmid: 15210721
references.citation: J Biol Chem. 2001 Jun 8;276(23):20116-24
references.pmid: 11264292
references.citation: Science. 1998 Mar 27;279(5359):2121-6
references.pmid: 9516116
references.citation: Biochemistry. 2009 May 12;48(18):3864-76
references.pmid: 19290671
references.citation: J Inorg Biochem. 2005 Jan;99(1):293-305
references.pmid: 15598508
references.citation: Cell. 1994 Sep 23;78(6):919-25
references.pmid: 7923361
references.citation: Biochim Biophys Acta. 2007 Mar;1770(3):432-45
references.pmid: 17014963