title: A new approach to control the enigmatic activity of aldose reductase.
abstract: Aldose reductase (AR) is an NADPH-dependent reductase, which acts on a variety of hydrophilic as well as hydrophobic aldehydes. It is currently defined as the first enzyme in the so-called polyol pathway, in which glucose is transformed into sorbitol by AR and then to fructose by an NAD(+)-dependent dehydrogenase. An exaggerated flux of glucose through the polyol pathway (as can occur in diabetes) with the subsequent accumulation of sorbitol, was originally proposed as the basic event in the aethiology of secondary diabetic complications. For decades this has meant targeting the enzyme for a specific and strong inhibition. However, the ability of AR to reduce toxic alkenals and alkanals, which are products of oxidative stress, poses the question of whether AR might be better classified as a detoxifying enzyme, thus raising doubts as to the unequivocal advantages of inhibiting the enzyme. This paper provides evidence of the possibility for an effective intervention on AR activity through an intra-site differential inhibition. Examples of a new generation of aldose reductase "differential" inhibitors (ARDIs) are presented, which can preferentially inhibit the reduction of either hydrophilic or hydrophobic substrates. Some selected inhibitors are shown to preferentially inhibit enzyme activity on glucose or glyceraldehyde and 3-glutathionyl-4-hydroxy-nonanal, but are less effective in reducing 4-hydroxy-2-nonenal. We question the efficacy of D, L-glyceraldehyde, the substrate commonly used in in vitro inhibition AR studies, as an in vitro reference AR substrate when the aim of the investigation is to impair glucose reduction.
authors.affiliation: Biochemistry Unit at the Department of Biology, University of Pisa, Pisa, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Del-Corso
authors.forename: Francesco
authors.initials: F
authors.lastname: Balestri
authors.forename: Elisa
authors.initials: E
authors.lastname: Di Bugno
authors.forename: Roberta
authors.initials: R
authors.lastname: Moschini
authors.forename: Mario
authors.initials: M
authors.lastname: Cappiello
authors.forename: Stefania
authors.initials: S
authors.lastname: Sartini
authors.forename: Concettina
authors.initials: C
authors.lastname: La-Motta
authors.forename: Federico
authors.initials: F
authors.lastname: Da-Settimo
authors.forename: Umberto
authors.initials: U
authors.lastname: Mura
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism; D048909:Diabetes Complications; D005947:Glucose / Q000378:metabolism; D005985:Glyceraldehyde / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D000447:Aldehydes; D005985:Glyceraldehyde; D000449:Aldehyde Reductase; D005947:Glucose; C027576:4-hydroxy-2-nonenal
references.citation: J Med Chem. 2001 Dec 6;44(25):4359-69
references.pmid: 11728182
references.citation: FASEB J. 1999 Jan;13(1):23-30
references.pmid: 9872926
references.citation: J Med Chem. 1996 Oct 25;39(22):4396-405
references.pmid: 8893834
references.citation: Curr Med Chem. 2009;16(6):734-52
references.pmid: 19199934
references.citation: Biochem Biophys Res Commun. 1995 Dec 26;217(3):741-6
references.pmid: 8554593
references.citation: Front Pharmacol. 2012 May 09;3:87
references.pmid: 22582044
references.citation: Biochemistry. 1992 Oct 27;31(42):10139-45
references.pmid: 1420136
references.citation: Biochemistry. 2000 Oct 10;39(40):12172-80
references.pmid: 11015195
references.citation: Cell Mol Life Sci. 2004 Apr;61(7-8):750-62
references.pmid: 15095000
references.citation: Int J Biochem Cell Biol. 2010 Jan;42(1):17-20
references.pmid: 19778627
references.citation: Curr Med Chem. 2008;15(15):1452-61
references.pmid: 18537622
references.citation: Expert Opin Investig Drugs. 2012 Mar;21(3):329-39
references.pmid: 22283786
references.citation: J Mol Model. 2012 May;18(5):1791-9
references.pmid: 21833829
references.citation: Biochim Biophys Acta. 1995 Jun 12;1249(2):117-26
references.pmid: 7599164
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: Exp Eye Res. 2000 Nov;71(5):515-21
references.pmid: 11040087
references.citation: J Med Chem. 2007 Oct 4;50(20):4917-27
references.pmid: 17845019
references.citation: Farmaco. 1997 Oct;52(10):583-8
references.pmid: 9507669
references.citation: Am J Physiol. 1995 Jun;268(6 Pt 2):F983-96
references.pmid: 7611465
references.citation: Exp Eye Res. 2000 Jun;70(6):795-803
references.pmid: 10843784
references.citation: Biochemistry. 1999 Jan 5;38(1):42-54
references.pmid: 9890881
references.citation: Biochem Biophys Res Commun. 1991 Mar 29;175(3):738-44
references.pmid: 1902669
references.citation: Biochimie. 2010 May;92(5):530-7
references.pmid: 20144905
references.citation: J Biochem. 2009 Jul;146(1):51-60
references.pmid: 19273550
references.citation: Front Pharmacol. 2012 Jun 06;3:104
references.pmid: 22685431
references.citation: Front Pharmacol. 2012 May 25;3:98
references.pmid: 22654757
references.citation: Arch Biochem Biophys. 2009 Jul 1;487(1):1-9
references.pmid: 19464995
references.citation: Adv Exp Med Biol. 1997;414:465-73
references.pmid: 9059652
references.citation: J Biol Chem. 1965 Feb;240:877-82
references.pmid: 14275148
references.citation: Farmaco. 1996 Apr;51(4):261-7
references.pmid: 8645413
references.citation: J Med Chem. 2008 Jun 12;51(11):3182-93
references.pmid: 18452283
references.citation: Chem Res Toxicol. 1998 Oct;11(10):1176-83
references.pmid: 9778314
references.citation: Biochem Biophys Res Commun. 1996 Nov 12;228(2):539-43
references.pmid: 8920948
references.citation: Eur J Med Chem. 2011 Jul;46(7):2797-806
references.pmid: 21531055
references.citation: Eur J Biochem. 1983 Mar 15;131(2):423-6
references.pmid: 6403351
references.citation: J Biol Chem. 2006 Nov 3;281(44):33019-29
references.pmid: 16956889
references.citation: Nephrol Dial Transplant. 2003 Nov;18(11):2255-61
references.pmid: 14551351
references.citation: Biochem J. 1998 Feb 1;329 ( Pt 3):469-75
references.pmid: 9445372
references.citation: Endocr Rev. 2005 May;26(3):380-92
references.pmid: 15814847
references.citation: J Biol Chem. 1977 May 10;252(9):2998-3002
references.pmid: 856810
references.citation: Biochim Biophys Acta. 1965 Jul 29;105(1):193-5
references.pmid: 4221326
references.citation: J Med Chem. 2005 Nov 3;48(22):6897-907
references.pmid: 16250648
references.citation: Biochim Biophys Acta. 1956 Oct;22(1):202-3
references.pmid: 13373872
references.citation: Proc Natl Acad Sci U S A. 1972 Jun;69(6):1435-9
references.pmid: 4402538
references.citation: Biochim Biophys Acta. 1994 Apr 13;1205(2):207-14
references.pmid: 8155699
references.citation: Diabet Med. 1993;10 Suppl 2:44S-48S
references.pmid: 8334842
references.citation: Invest Ophthalmol. 1974 Oct;13(10):713-24
references.pmid: 4278188
references.citation: Diabetes Metab Rev. 1993 Oct;9(3):189-217
references.pmid: 8187607
references.citation: Biochem Biophys Res Commun. 1995 Feb 15;207(2):775-82
references.pmid: 7864872
references.citation: J Biol Chem. 1990 Jul 5;265(19):10912-8
references.pmid: 2113526
references.citation: Biomed Res Int. 2013;2013:727143
references.pmid: 23586057
references.citation: Curr Drug Targets. 2005 Jun;6(4):475-86
references.pmid: 16026266
references.citation: Arch Biochem Biophys. 1990 Dec;283(2):512-8
references.pmid: 2125822
references.citation: Free Radic Biol Med. 1991;11(1):81-128
references.pmid: 1937131
references.citation: Exp Eye Res. 1994 Apr;58(4):491-501
references.pmid: 7925685
references.citation: FEBS Lett. 2012 Jan 2;586(1):55-9
references.pmid: 22155003
references.citation: J Biol Chem. 1992 Dec 5;267(34):24833-40
references.pmid: 1332968
references.citation: Bioorg Med Chem. 2000 Aug;8(8):2167-73
references.pmid: 11003161
references.citation: J Biol Chem. 1992 Mar 5;267(7):4364-9
references.pmid: 1537826
references.citation: Chem Biol Interact. 2013 Feb 25;202(1-3):146-52
references.pmid: 23261715
references.citation: Lancet. 1997 Feb 8;349(9049):399-400
references.pmid: 9033472
references.citation: Arch Biochem Biophys. 1998 Feb 15;350(2):245-8
references.pmid: 9473298