Abstract
Nitric Oxide (NO), an important biological mediator, is involved in the regulation of the cardiovascular, nervous and immune systems in mammals. Synthesis of NO is catalyzed by its biosynthetic enzyme, Nitric Oxide Synthase (NOS). There are three main isoforms of the enzyme, neuronal NOS, endothelial NOS and inducible NOS, which have very similar structures but differ in their expression and activities. NO is produced in the active site of the enzyme in two distinct cycles from oxidation of the substrate L-arg (L-arginine) in nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reaction. NOS has gained considerable attention of biochemists due to its complexity and unique catalytic mechanism. The review focuses on NOS structure, its function and catalytic reaction mechanism. In particular, the review is concluded with a discussion on the role of all three isoforms of NOS in physiological and pathological conditions and their inhibitors with a focus on the role of computational techniques in their development.
Keywords: Nitric oxide, nitric oxide synthase, selectivity, computational, arginine, inhibition, heme.
Graphical Abstract
[http://dx.doi.org/10.1042/BJ20080192] [PMID: 19046139]
[http://dx.doi.org/10.1016/S0005-2728(99)00016-X] [PMID: 10320659]
[http://dx.doi.org/10.1016/j.tim.2009.02.003] [PMID: 19375324]
[http://dx.doi.org/10.1016/j.niox.2009.03.001] [PMID: 19298861]
[http://dx.doi.org/10.1016/j.niox.2010.03.001] [PMID: 20303412]
[http://dx.doi.org/10.1016/S0378-1119(99)00121-3] [PMID: 10333518]
[http://dx.doi.org/10.1002/iub.1136] [PMID: 23441062]
[PMID: 7693663]
[http://dx.doi.org/10.1016/j.ccr.2011.10.011] [PMID: 22523434]
[http://dx.doi.org/10.1124/pr.56.4.3] [PMID: 15602010]
[PMID: 17658499]
[http://dx.doi.org/10.1038/nrd960] [PMID: 12461516]
[http://dx.doi.org/10.1016/j.jinorgbio.2004.10.016] [PMID: 15598508]
[http://dx.doi.org/10.1111/j.1440-1681.1992.tb00433.x] [PMID: 1325878]
[http://dx.doi.org/10.1096/fasebj.6.12.1381691] [PMID: 1381691]
[http://dx.doi.org/10.1038/sj.bjp.0703944] [PMID: 11309233]
[PMID: 11303032]
[PMID: 12512688]
[http://dx.doi.org/10.1126/science.278.5337.425] [PMID: 9334294]
[http://dx.doi.org/10.1126/science.279.5359.2121] [PMID: 9516116]
[http://dx.doi.org/10.1021/bi020417c] [PMID: 12437343]
[http://dx.doi.org/10.1016/S0092-8674(00)81718-3] [PMID: 9875848]
[http://dx.doi.org/10.1074/jbc.M406204200] [PMID: 15208315]
[http://dx.doi.org/10.1074/jbc.M105503200] [PMID: 11473123]
[http://dx.doi.org/10.1146/annurev.pharmtox.37.1.339] [PMID: 9131257]
[http://dx.doi.org/10.1074/jbc.271.13.7309] [PMID: 8631749]
[http://dx.doi.org/10.1146/annurev.pharmtox.39.1.191] [PMID: 10331082]
[http://dx.doi.org/10.1074/jbc.273.10.5451] [PMID: 9488666]
[http://dx.doi.org/10.1021/bi061011t] [PMID: 17029414]
[http://dx.doi.org/10.1074/jbc.M400872200] [PMID: 15180983]
[http://dx.doi.org/10.1074/jbc.M310391200] [PMID: 14966111]
[http://dx.doi.org/10.1074/jbc.M111967200] [PMID: 11823464]
[http://dx.doi.org/10.1016/0952-7915(94)90044-2] [PMID: 7513523]
[http://dx.doi.org/10.1038/6675] [PMID: 10074942]
[http://dx.doi.org/10.1093/jn/134.10.2748S] [PMID: 15465779]
[http://dx.doi.org/10.1021/bi970331x] [PMID: 9136868]
[http://dx.doi.org/10.1021/bi00011a025] [PMID: 7534476]
[http://dx.doi.org/10.1042/bj3570593] [PMID: 11463332]
[http://dx.doi.org/10.1016/S0008-6363(99)00115-7] [PMID: 10690324]
[http://dx.doi.org/10.1074/jbc.274.34.24100] [PMID: 10446182]
[http://dx.doi.org/10.1074/jbc.M000534200] [PMID: 10846172]
[http://dx.doi.org/10.1021/bi011182s] [PMID: 11669618]
[PMID: 2584226]
[PMID: 2584186]
[PMID: 7691806]
[http://dx.doi.org/10.1074/jbc.272.2.1276] [PMID: 8995432]
[http://dx.doi.org/10.1021/bi992409a] [PMID: 10769116]
[http://dx.doi.org/10.2174/1389200024605154] [PMID: 12003347]
[http://dx.doi.org/10.1021/bi992026c] [PMID: 10625434]
[http://dx.doi.org/10.1002/j.1460-2075.1995.tb00038.x] [PMID: 7543842]
[http://dx.doi.org/10.1111/j.1476-5381.1993.tb12886.x] [PMID: 7682140]
[http://dx.doi.org/10.1016/0006-291X(92)91550-A] [PMID: 1280418]
[PMID: 7520440]
[http://dx.doi.org/10.1161/hh0102.102330] [PMID: 11786514]
[http://dx.doi.org/10.1023/A:1009772307518]
[http://dx.doi.org/10.1046/j.1365-2567.2001.01261.x] [PMID: 11454054]
[http://dx.doi.org/10.1165/ajrcmb.21.2.f158] [PMID: 10423393]
[http://dx.doi.org/10.1093/jnen/60.9.906] [PMID: 11556547]
[http://dx.doi.org/10.1006/mcne.2000.0914] [PMID: 11124893]
[http://dx.doi.org/10.1023/A:1003958312508] [PMID: 10805384]
[http://dx.doi.org/10.1016/S0002-9440(10)64677-9] [PMID: 11395383]
[http://dx.doi.org/10.1155/2012/318087] [PMID: 22988346]
[http://dx.doi.org/10.1016/j.bmc.2005.12.043] [PMID: 16431112]
[http://dx.doi.org/10.1111/j.1476-5381.1990.tb14151.x] [PMID: 1706208]
[http://dx.doi.org/10.1016/0006-291X(89)92517-5] [PMID: 2719705]
[http://dx.doi.org/10.1021/jm00056a009] [PMID: 7682617]
[http://dx.doi.org/10.1021/bi00253a017] [PMID: 7527657]
[http://dx.doi.org/10.1097/00003246-199905000-00025] [PMID: 10362413]
[http://dx.doi.org/10.1097/01.CCM.0000104209.07273.FC] [PMID: 14707555]
[http://dx.doi.org/10.1016/0140-6736(91)92376-D] [PMID: 1720856]
[http://dx.doi.org/10.1093/cvr/28.1.34] [PMID: 7509259]
[http://dx.doi.org/10.1021/bi00088a020] [PMID: 7690590]
[PMID: 7507482]
[http://dx.doi.org/10.1016/0006-291X(90)91245-N] [PMID: 2372300]
[http://dx.doi.org/10.1111/j.1440-1681.1991.tb01470.x] [PMID: 1914242]
[http://dx.doi.org/10.1021/jm970550g] [PMID: 9397167]
[http://dx.doi.org/10.1021/jm00084a020] [PMID: 1372655]
[http://dx.doi.org/10.1016/S0968-0896(97)00109-0] [PMID: 9313865]
[http://dx.doi.org/10.1016/S0076-6879(96)68040-9] [PMID: 8782604]
[http://dx.doi.org/10.1074/jbc.270.46.27423] [PMID: 7499198]
[PMID: 7523410]
[http://dx.doi.org/10.1016/j.bmcl.2005.03.078] [PMID: 15911272]
[http://dx.doi.org/10.1038/sj.bjp.0704023] [PMID: 11309260]
[http://dx.doi.org/10.1111/j.1476-5381.1991.tb12159.x] [PMID: 1710525]
[http://dx.doi.org/10.1074/jbc.273.15.8882] [PMID: 9535869]
[http://dx.doi.org/10.1021/jm00049a007] [PMID: 7525961]
[http://dx.doi.org/10.1021/acs.biochem.5b00135] [PMID: 25811913]
[http://dx.doi.org/10.1074/jbc.272.8.4959] [PMID: 9030556]
[http://dx.doi.org/10.1111/1440-1681.12998] [PMID: 29924417]
[http://dx.doi.org/10.1021/jm800846u] [PMID: 19203270]
[http://dx.doi.org/10.1016/j.bmcl.2010.09.059] [PMID: 20933416]
[http://dx.doi.org/10.1002/cmdc.201100125] [PMID: 21567968]
[http://dx.doi.org/10.1021/acsmedchemlett.5b00149] [PMID: 26101565]
[http://dx.doi.org/10.1016/j.ejmech.2018.04.027] [PMID: 29689474]
[http://dx.doi.org/10.1021/jm970840x] [PMID: 9733492]
[http://dx.doi.org/10.1021/jm9704715] [PMID: 9554868]
[http://dx.doi.org/10.1021/jm950766n] [PMID: 8576908]
[http://dx.doi.org/10.1021/jm9705059] [PMID: 9438025]
[http://dx.doi.org/10.1016/S0960-894X(02)00455-9] [PMID: 12161118]
[http://dx.doi.org/10.1016/S0223-5234(03)00017-5] [PMID: 12667694]
[http://dx.doi.org/10.1006/bbrc.2000.2474] [PMID: 10753680]
[http://dx.doi.org/10.1016/S0960-894X(01)00119-6] [PMID: 11327580]
[http://dx.doi.org/10.1016/S0960-894X(01)00120-2] [PMID: 11327581]
[http://dx.doi.org/10.1021/jm0255926] [PMID: 12620067]
[http://dx.doi.org/10.1111/j.1476-5381.1996.tb16010.x] [PMID: 8937711]
[http://dx.doi.org/10.1016/S0960-894X(00)00389-9] [PMID: 10987430]
[http://dx.doi.org/10.1021/jm030519g] [PMID: 14998342]
[http://dx.doi.org/10.1038/nchembio.115] [PMID: 18849972]
[PMID: 23617077]
[http://dx.doi.org/10.1007/s12539-016-0176-5] [PMID: 27272764]
[http://dx.doi.org/10.1007/s12539-015-0004-3] [PMID: 26202943]
[http://dx.doi.org/10.1021/jm990111c] [PMID: 10447959]
[http://dx.doi.org/10.1021/jm030297m] [PMID: 14736250]
[http://dx.doi.org/10.1021/jm0202932] [PMID: 12699384]
[http://dx.doi.org/10.1021/jm0101491] [PMID: 11472219]
[http://dx.doi.org/10.1038/nsmb704] [PMID: 14718923]
[http://dx.doi.org/10.1021/jm030301u] [PMID: 14667223]
[http://dx.doi.org/10.1021/ja0772041] [PMID: 18321097]
[http://dx.doi.org/10.1021/jm00145a002] [PMID: 3892003]
[http://dx.doi.org/10.1002/prot.340110104] [PMID: 1961699]
[http://dx.doi.org/10.1016/j.bmc.2009.02.017] [PMID: 19268602]
[http://dx.doi.org/10.1021/ja302269r] [PMID: 22731813]
[http://dx.doi.org/10.1016/j.bmc.2012.12.019] [PMID: 23352768]
[http://dx.doi.org/10.1021/ja106175q] [PMID: 20843082]
[http://dx.doi.org/10.1007/s00894-012-1677-8] [PMID: 23263357]
[http://dx.doi.org/10.1021/jm101071n] [PMID: 21410186]
[http://dx.doi.org/10.1021/jm4000984] [PMID: 23451760]
[http://dx.doi.org/10.1016/j.bmcl.2013.08.034] [PMID: 23993333]
[http://dx.doi.org/10.1021/ml400381s] [PMID: 24660051]
[http://dx.doi.org/10.1021/jm5004182] [PMID: 24758147]
[http://dx.doi.org/10.1016/S0960-894X(00)00055-X] [PMID: 10741561]
[http://dx.doi.org/10.1038/sj.bjp.0706168] [PMID: 15778742]
[http://dx.doi.org/10.1016/S0014-2999(01)01327-9] [PMID: 11698048]
[http://dx.doi.org/10.1038/sj.bjp.0705683] [PMID: 14769784]
[http://dx.doi.org/10.2337/diab.41.4.552] [PMID: 1376704]
[http://dx.doi.org/10.1016/j.jneuroim.2016.12.007] [PMID: 28065581]
[http://dx.doi.org/10.1016/0006-2952(93)90461-5] [PMID: 8216363]
[http://dx.doi.org/10.1111/j.1476-5381.1996.tb15236.x] [PMID: 8646406]
[PMID: 7523409]
[http://dx.doi.org/10.1111/j.1476-5381.1995.tb13256.x] [PMID: 7533622]
[http://dx.doi.org/10.1016/0024-3205(96)00393-1] [PMID: 8795706]
[http://dx.doi.org/10.1074/jbc.M102255200] [PMID: 11331290]
[http://dx.doi.org/10.1002/cmdc.201500007] [PMID: 25801086]
[http://dx.doi.org/10.3390/ijms15058553] [PMID: 24830557]
[http://dx.doi.org/10.1021/bi026313j] [PMID: 12437348]
[http://dx.doi.org/10.1016/j.bmcl.2011.02.061] [PMID: 21398123]
[http://dx.doi.org/10.1016/j.bmc.2008.04.056] [PMID: 18502134]
[http://dx.doi.org/10.1016/j.bmcl.2007.10.073] [PMID: 18024030]
[http://dx.doi.org/10.1073/pnas.97.4.1506] [PMID: 10677491]
[http://dx.doi.org/10.1021/ja908544f] [PMID: 20014790]
[http://dx.doi.org/10.1074/jbc.M105691200] [PMID: 11689556]
[PMID: 7683651]
[http://dx.doi.org/10.1016/0006-2952(77)90241-6] [PMID: 880256]
[http://dx.doi.org/10.1016/S0968-0896(99)00117-0] [PMID: 10530943]
[http://dx.doi.org/10.1021/jm501719e] [PMID: 25489882]
[http://dx.doi.org/10.1021/jm900173b] [PMID: 19374401]
[http://dx.doi.org/10.1021/jm100828n] [PMID: 20931971]
[http://dx.doi.org/10.3390/ijms130911210] [PMID: 23109848]
[http://dx.doi.org/10.1111/j.1476-5381.1993.tb13796.x] [PMID: 7693279]
[http://dx.doi.org/10.1016/0028-3908(94)90024-8] [PMID: 7532811]
[http://dx.doi.org/10.1016/j.niox.2017.09.003 PMID: 28943472]
[http://dx.doi.org/10.1016/0024-3205(95)02046-L] [PMID: 7544863]
[http://dx.doi.org/10.1016/S0024-3205(97)00295-6 PMID: 9194695]
[http://dx.doi.org/10.1042/bj3200193] [PMID: 8947486]
[http://dx.doi.org/10.1074/jbc.273.50.33142] [PMID: 9837881]
[http://dx.doi.org/10.1021/jm981129a] [PMID: 10514281]
[http://dx.doi.org/10.1021/jm020074g] [PMID: 12086480]
[http://dx.doi.org/10.1021/jm050007x] [PMID: 16033258]
[http://dx.doi.org/10.1073/pnas.1313331110] [PMID: 24003111]
[http://dx.doi.org/10.1016/j.bbagen.2006.10.002] [PMID: 17098364]
[http://dx.doi.org/10.1016/S0006-2952(97)00316-X] [PMID: 9464453]
[http://dx.doi.org/10.1016/S0006-2952(00)00370-1] [PMID: 10927028]
[http://dx.doi.org/10.1016/j.bbapap.2008.09.002] [PMID: 18845278]
[http://dx.doi.org/10.1016/0922-4106(95)90107-8] [PMID: 7542607]
[http://dx.doi.org/10.1006/bbrc.1993.2246] [PMID: 7692850]
[http://dx.doi.org/10.1016/j.abb.2009.03.015] [PMID: 19358819]
[http://dx.doi.org/10.1006/abbi.1994.1240] [PMID: 7515612]
[PMID: 7683652]
[http://dx.doi.org/10.1111/j.1600-079X.1995.tb00133.x] [PMID: 7776173]
[http://dx.doi.org/10.1016/0024-3205(94)00532-X] [PMID: 7527477]
[http://dx.doi.org/10.1046/j.1365-2826.1998.00203.x] [PMID: 9630400]
[http://dx.doi.org/10.1021/jm0407714] [PMID: 15509163]
[http://dx.doi.org/10.1111/j.1527-3466.2006.00088.x] [PMID: 16961723]
[http://dx.doi.org/10.1021/jm401838x] [PMID: 24472039]
[http://dx.doi.org/10.1021/acs.jmedchem.5b01330] [PMID: 26469213]
[http://dx.doi.org/10.1021/acs.jmedchem.7b00259] [PMID: 28422508]
[http://dx.doi.org/10.1021/acs.jmedchem.7b00835] [PMID: 28776992]
[http://dx.doi.org/10.1039/C3CS60467E] [PMID: 24549364]
[http://dx.doi.org/10.1016/S0891-5849(00)00250-1] [PMID: 10927171]
[http://dx.doi.org/10.1016/j.ejmech.2012.07.006] [PMID: 22840695]
[http://dx.doi.org/10.1021/acs.biochem.8b00895] [PMID: 30335983]
[http://dx.doi.org/10.1016/j.freeradbiomed.2017.12.027] [PMID: 29275014]
[http://dx.doi.org/10.1016/j.intimp.2016.12.009] [PMID: 27988460]
[http://dx.doi.org/10.1155/2018/9242616]