title: Xanthine oxidoreductase-catalyzed reactive species generation: A process in critical need of reevaluation.
abstract: Nearly 30 years have passed since the discovery of xanthine oxidoreductase (XOR) as a critical source of reactive species in ischemia/reperfusion injury. Since then, numerous inflammatory disease processes have been associated with elevated XOR activity and allied reactive species formation solidifying the ideology that enhancement of XOR activity equates to negative clinical outcomes. However, recent evidence may shatter this paradigm by describing a nitrate/nitrite reductase capacity for XOR whereby XOR may be considered a crucial source of beneficial (•)NO under ischemic/hypoxic/acidic conditions; settings similar to those that limit the functional capacity of nitric oxide synthase. Herein, we review XOR-catalyzed reactive species generation and identify key microenvironmental factors whose interplay impacts the identity of the reactive species (oxidants vs. (•)NO) produced. In doing so, we redefine existing dogma and shed new light on an enzyme that has weathered the evolutionary process not as gadfly but a crucial component in the maintenance of homeostasis.
authors.affiliation: Department of Anesthesiology, University of Pittsburgh, United States ; Vascular Medicine Institute, University of Pittsburgh, United States.
authors.forename: Nadiezhda
authors.initials: N
authors.lastname: Cantu-Medellin
authors.forename: Eric E
authors.initials: EE
authors.lastname: Kelley
mesh_terms: D000818:Animals; D055162:Biocatalysis; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014968:Xanthine Dehydrogenase / Q000378:metabolism*
chemical_list: D005609:Free Radicals; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D014968:Xanthine Dehydrogenase
keywords: Free radicals; GAGs, glycosaminoglycans; H2O2, hydrogen peroxide; Hypoxia; I/R, ischemia/reperfusion; Inflammation; NOS, nitric oxide synthase; Nitric oxide; Nitrite; O2•−, superoxide; Oxygen tension; ROS, reactive oxygen species; XDH, xanthine dehydrogenase; XO, xanthine oxidase; XOR, xanthine oxidoreductase); Xanthine oxidoreductase; •NO, nitric oxide
references.citation: Free Radic Biol Med. 2011 Jul 1;51(1):179-84
references.pmid: 21554948
references.citation: J Biochem. 2000 May;127(5):771-8
references.pmid: 10788785
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10723-8
references.pmid: 11005854
references.citation: J Inorg Biochem. 2000 Nov;82(1-4):43-9
references.pmid: 11132637
references.citation: J Biol Chem. 1962 Mar;237:916-21
references.pmid: 13895169
references.citation: Anesthesiology. 2012 Sep;117(3):592-601
references.pmid: 22820847
references.citation: J Physiol. 2005 Dec 15;569(Pt 3):925-37
references.pmid: 16223766
references.citation: Free Radic Biol Med. 2002 Sep 15;33(6):774-97
references.pmid: 12208366
references.citation: J Biol Inorg Chem. 2011 Mar;16(3):443-60
references.pmid: 21170563
references.citation: Circulation. 2002 Dec 10;106(24):3073-8
references.pmid: 12473554
references.citation: J Am Soc Nephrol. 2007 Feb;18(2):570-80
references.pmid: 17202421
references.citation: J Biol Chem. 1969 Nov 25;244(22):6049-55
references.pmid: 5389100
references.citation: Crit Care Med. 2003 Feb;31(2):525-30
references.pmid: 12576961
references.citation: Am J Physiol. 1999 Dec;277(6):R1697-704
references.pmid: 10600916
references.citation: Hypertension. 2000 Mar;35(3):746-51
references.pmid: 10720589
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15215-20
references.pmid: 11752464
references.citation: J Biol Chem. 1997 Nov 7;272(45):28335-41
references.pmid: 9353290
references.citation: J Clin Invest. 2011 Apr;121(4):1646-56
references.pmid: 21436585
references.citation: J Biol Chem. 2004 Apr 23;279(17):16939-46
references.pmid: 14766900
references.citation: Free Radic Biol Med. 2010 Feb 15;48(4):493-8
references.pmid: 19941951
references.citation: Circulation. 2010 Jan 5;121(1):98-109
references.pmid: 20026772
references.citation: Am J Respir Crit Care Med. 1997 Feb;155(2):479-84
references.pmid: 9032182
references.citation: Circulation. 2002 Jul 9;106(2):221-6
references.pmid: 12105162
references.citation: Proc Natl Acad Sci U S A. 2004 Sep 14;101(37):13683-8
references.pmid: 15347817
references.citation: J Biol Chem. 1970 Aug 25;245(16):4053-7
references.pmid: 5496991
references.citation: Life Sci. 2005 Mar 4;76(16):1835-47
references.pmid: 15698861
references.citation: Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8745-9
references.pmid: 8710942
references.citation: Free Radic Biol Med. 2006 Mar 15;40(6):952-9
references.pmid: 16540390
references.citation: Am J Transplant. 2012 Nov;12(11):2938-48
references.pmid: 23016570
references.citation: J Biol Chem. 2001 Jul 6;276(27):24482-9
references.pmid: 11312267
references.citation: Nitric Oxide. 2013 Nov 1;34:19-26
references.pmid: 23454592
references.citation: Am J Physiol. 1988 May;254(5 Pt 1):G768-74
references.pmid: 3163236
references.citation: Nitric Oxide. 2010 Feb 15;22(2):191-5
references.pmid: 20142047
references.citation: J Biol Chem. 1999 Feb 19;274(8):4985-94
references.pmid: 9988743
references.citation: J Biol Chem. 1997 Mar 28;272(13):8370-9
references.pmid: 9079661
references.citation: J Mol Cell Cardiol. 2007 Oct;43(4):437-44
references.pmid: 17765919
references.citation: Free Radic Biol Med. 2012 Oct 1;53(7):1431-9
references.pmid: 22917977
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8170-5
references.pmid: 12817083
references.citation: Hepatobiliary Pancreat Dis Int. 2005 Aug;4(3):350-5
references.pmid: 16109514
references.citation: J Biol Chem. 2000 Mar 17;275(11):7757-63
references.pmid: 10713088
references.citation: Biol Pharm Bull. 1995 Jan;18(1):156-8
references.pmid: 7735231
references.citation: J Chromatogr. 1990 Jul 13;529(1):93-101
references.pmid: 2211944
references.citation: Gastroenterology. 1998 May;114(5):1009-15
references.pmid: 9558291
references.citation: Biochem J. 1993 Jan 15;289 ( Pt 2):523-7
references.pmid: 8424793
references.citation: Circ Res. 2004 Nov 26;95(11):1118-24
references.pmid: 15528468
references.citation: J Biol Chem. 2004 Sep 3;279(36):37231-4
references.pmid: 15231841
references.citation: Cell Mol Biol (Noisy-le-grand). 2004 Feb;50(1):95-105
references.pmid: 15040433
references.citation: Diabetes. 2002 Apr;51(4):1118-24
references.pmid: 11916934
references.citation: FEBS Lett. 1998 May 8;427(2):225-8
references.pmid: 9607316
references.citation: Gastroenterology. 1981 Jul;81(1):22-9
references.pmid: 6263743
references.citation: Cell Metab. 2007 Feb;5(2):115-28
references.pmid: 17276354