Recent Advances in Glyoxalase-I Inhibition

Author(s): Qosay A. Al-Balas*, Mohammad A. Hassan, Nizar A. Al-Shar'i*, Ghazi A. Al Jabal, Ammar M. Almaaytah.

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 19 , Issue 4 , 2019

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Graphical Abstract:


Glyoxalase system is a ubiquitous system in human cells which has been examined thoroughly for its role in different disease conditions. It is composed of Glyoxalase-I (Glo-I) and Glyoxalase- II which perform an essential metabolic process inside the cell by detoxifying endogenous harmful metabolites, mainly methylglyoxal (MG) into non-toxic D-lactic acid. Tumor cells are well-known for their high metabolic rate which results in elevated levels of toxic metabolites. The over-expression of Glo-I in tumor cells makes this enzyme a pivotal target for anticancer drug development. Glo-I is metalloenzyme with two polypeptide chains and encompasses two active sites with an integral zinc atoms at their center. This review aims to highlight the important role of Glo-I in different pathogenic conditions, and more importantly, it provides a thorough discussion of all known human Glo-I inhibitors since its discovery, a hundred years ago, up to date. It embraces the different classes they belong to, their design and chemical structures. We believe this review will help guide the design of novel and potent human Glo-I inhibitors by providing a handy reference for interested researchers in this target.

Keywords: Human glyoxalase-I, metalloenzyme, pathogenesis, inhibitors, zinc-binding, GSH.

Dakin, H.D.; Dudley, H.W. An enzyme concerned with the formation of hydroxy acids from ketonic aldehydes. J. Biol. Chem., 1913, 14(2), 155-157.
Neuberg, C. The destruction of lactic aldehyde and methylglyoxal by animal organs. Biochem. Z., 1913, 49, 502-506.
Warburg, O.; Wind, F.; Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol., 1927, 8(6), 519-530.
Racker, E. The mechanism of action of glyoxalase. J. Biol. Chem., 1951, 190(2), 685-696.
Davis, K.A.; Williams, G.R. Cation activation of glyoxalase I. Biochimica et Biophysica Acta (BBA) –. Enzymol. Biol. Oxidat., 1966, 113(2), 393-395.
Aronsson, A-C.; Marmstål, E.; Mannervik, B.; Glyoxalase, I. a zinc metalloenzyme of mammals and yeast. Biochem. Biophy. Res. Communicat., 1978, 81(4), 1235-1240.
Vince, R.; Wadd, W.B. Glyoxalase inhibitors as potential anticancer agents. Biochem. Biophy. Res. Communicat., 1969, 35(5), 593-598.
Apple, M.; Greenberg, D. Arrest of cancer in mice by therapy with normal metabolites. II. Indefinite survirors among mice treated with mixtures of 2-oxopropanal (NSC-79019) and 2, 3-dihydroxypropanal (NSC67934). Cancer Chemother. Rep., 1968, 52(7), 687.
Együud, L.G.; Szent-Györgyi, A. Cancerostatic action of methylglyoxal. Science, 1968, 160(3832), 1140.
Conroy, P.J. In Carcinostatic activity of methylglyoxal and related substances in tumour-bearing mice, Submolecular Biology and Cancer Ciba Foundation Symposium, 1979, pp. 271-298.
Elvin, P.; Slater, T.F. Anti-tumour activity of novel adducts of ascorbic acid with aldehydes. Europ. J. Cancer Clin. Oncol., 1981, 17(7), 759-765.
Cameron, A.D.; Ridderström, M.; Olin, B.; Kavarana, M.J.; Creighton, D.J.; Mannervik, B. Reaction mechanism of glyoxalase I explored by an X-ray crystallographic analysis of the human enzyme in complex with a transition state analogue. Biochemistry, 1999, 38(41), 13480-13490.
Feierberg, I. > Computational Studies of Enzymatic Enolization Reactions and Inhibitor Binding to a Malarial Protease. Acta Universitatis Upsaliensis, 2003.
Holewinski, R.J. Active site directed covalent modification of human glyoxalase I; Ph.D., University of Maryland, Baltimore County, Ann Arbor, 2009.
Himo, F.; Siegbahn, P.E. Catalytic mechanism of glyoxalase I: A theoretical study. J. Am. Chem. Soc., 2001, 123(42), 10280-10289.
Phillips, S.A.; Thornalley, P.J. The formation of methylglyoxal from triose phosphates. Investigation using a specific assay for methylglyoxal. Eur. J. Biochem., 1993, 212(1), 101-105.
Reichard, G.A., Jr; Skutches, C.L.; Hoeldtke, R.D.; Owen, O.E. Acetone metabolism in humans during diabetic ketoacidosis. Diabetes, 1986, 35(6), 668-674.
Lyles, G.A.; Chalmers, J. The metabolism of aminoacetone to methylglyoxal by semicarbazide-sensitive amine oxidase in human umbilical artery. Biochem. Pharmacol., 1992, 43(7), 1409-1414.
Vander Jagt, D.L.; Hunsaker, L.A. Methylglyoxal metabolism and diabetic complications: Roles of aldose reductase, glyoxalase-I, betaine aldehyde dehydrogenase and 2-oxoaldehyde dehydrogenase. Chem. Biol. Interact., 2003, 143-144, 341-351.
Thornalley, P.J.; Langborg, A.; Minhas, H.S. Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose. Biochem. J., 1999, 344(Pt 1), 109-116.
Rulli, A.; Carli, L.; Romani, R.; Baroni, T.; Giovannini, E.; Rosi, G.; Talesa, V. Expression of glyoxalase I and II in normal and breast cancer tissues. Breast Cancer Res. Treat., 2001, 66(1), 67-72.
Phillips, S.A.; Thornalley, P.J. The formation of methylglyoxal from triose phosphates. Investigation using a specific assay for methylglyoxal. Europ. J. Biochem. FEBS, 1993, 212(1), 101-105.
Chan, W.H.; Wu, H.J.; Shiao, N.H. Apoptotic signaling in methylglyoxal-treated human osteoblasts involves oxidative stress, c-Jun N-terminal kinase, caspase-3, and p21-activated kinase 2. J. Cell. Biochem., 2007, 100(4), 1056-1069.
Thornalley, P.J. Protein and nucleotide damage by glyoxal and methylglyoxal in physiological systems--role in ageing and disease. Drug Metabol. Drug Interact., 2008, 23(1-2), 125-150.
Belanger, M.; Yang, J.; Petit, J.M.; Laroche, T.; Magistretti, P.J.; Allaman, I. Role of the glyoxalase system in astrocyte-mediated neuroprotection. J. Neurosci., 2011, 31(50), 18338-18352.
Rabbani, N.; Shaheen, F.; Anwar, A.; Masania, J.; Thornalley, P.J. Assay of methylglyoxal-derived protein and nucleotide AGEs; Portland Press Limited, 2014.
Rabbani, N.; Thornalley, P.J. Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome. Amino acids, 2012, 42(4), 1133-1142.
Talukdar, D.; Chaudhuri, B.S.; Ray, M.; Ray, S. Critical evaluation of toxic versus beneficial effects of methylglyoxal. Biochem. Biokhimiia, 2009, 74(10), 1059-1069.
McLellan, A.C.; Thornalley, P.J. Glyoxalase activity in human red blood cells fractioned by age. Mechanis. Ageing Develop., 1989, 48(1), 63-71.
Rabbani, N.; Xue, M.; Thornalley, P.J. Dicarbonyls and glyoxalase in disease mechanisms and clinical therapeutics. Glycoconj. J., 2016, 33(4), 513-525.
Frandsen, J.R.; Narayanasamy, P. Neuroprotection through flavonoid: Enhancement of the glyoxalase pathway. Redox Biol., 2018, 14, 465-473.
Thornalley, P.J.; Battah, S.; Ahmed, N.; Karachalias, N.; Agalou, S.; Babaei-Jadidi, R.; Dawnay, A. Quantitative screening of advanced glycation endproducts in cellular and extracellular proteins by tandem mass spectrometry. Biochem. J., 2003, 375(3), 581-592.
Santarius, T.; Bignell, G.R.; Greenman, C.D.; Widaa, S.; Chen, L.; Mahoney, C.L.; Butler, A.; Edkins, S.; Waris, S.; Thornalley, P.J. GLO1—a novel amplified gene in human cancer. Genes Chromosom Cancer, 2010, 49(8), 711-725.
Xue, M. Rabbani, N.; Thornalley, P.J. In: Glyoxalase in ageing, Seminars in cell & developmental biology; Elsevier, 2011; pp. 293-301.
Maessen, D.E.; Stehouwer, C.D.; Schalkwijk, C.G. The role of methylglyoxal and the glyoxalase system in diabetes and other agerelated diseases. Clin. Sci.(London, England : 1979), 2015, 128(12), 839-861.
Kuhla, B.; Boeck, K.; Schmidt, A.; Ogunlade, V.; Arendt, T.; Münch, G.; Lüth, H-J. Age-and stage-dependent glyoxalase I expression and its activity in normal and Alzheimer’s disease brains. Neurobiol. Aging, 2007, 28(1), 29-41.
Chen, F.; Wollmer, M.A.; Hoerndli, F.; Münch, G.; Kuhla, B.; Rogaev, E.I.; Tsolaki, M.; Papassotiropoulos, A.; Götz, J. Role for glyoxalase I in Alzheimer’s disease. Proceed. Nat. Acad. Sci. USA, 2004, 101(20), 7687-7692.
Thornalley, P. Modification of the human red blood cell glucose system by glucose in vitro. Biochem. J., 1988, 254, 751-755.
Atkins, T.; Thornalley, P. Glyoxalase activity in tissues of lean (HO) and genetically obese diabetic (ob/ob) mice. Med. Sci. Res., 1989, 17, 777-778.
Atkins, T.; Thornalley, P. Modification of the red blood cell glyoxalase system in genetically (ob/ob) and streptozotocin induced diabetic mice. Diabetes Res., 1989, 11, 125-129.
Phillips, S.A.; Mirrlees, D.; Thornalley, P.J. Modification of the glyoxalase system in streptozotocin-induced diabetic rats: effect of the aldose reductase inhibitor Statil. Biochem. Pharmacol., 1993, 46(5), 805-811.
McLellan, A.C.; Thornalley, P.J.; Benn, J.; Sonksen, P.H. Glyoxalase system in clinical diabetes mellitus and correlation with diabetic complications. Clin. Sci. , 1994, 87(1), 21-29.
Giacco, F.; Du, X.; D’Agati, V.D.; Milne, R.; Sui, G.; Geoffrion, M.; Brownlee, M. Knockdown of Glyoxalase 1 Mimics Diabetic Nephropathy in Nondiabetic Mice. Diabetes, 2014, 63(1), 291-299.
Rabbani, N.; Thornalley, P.J. Glyoxalase 1 Modulation in Obesity and Diabetes. Antioxid. Redox Signal., 2018.
Matafome, P.; Rodrigues, T.; Sena, C.; Seica, R. Methylglyoxal in Metabolic Disorders: Facts, Myths, and Promises. Med. Res. Rev., 2017, 37(2), 368-403.
Gatenby, R.A.; Gillies, R.J. Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer, 2004, 4(11), 891-899.
Tennant, D.A.; Duran, R.V.; Gottlieb, E. Targeting metabolic transformation for cancer therapy. Nat. Rev. Cancer, 2010, 10(4), 267-277.
Geng, X.; Ma, J.; Zhang, F.; Xu, C. Glyoxalase I in tumor cell proliferation and survival and as a potential target for anticancer therapy. Oncol. Res. Treat., 2014, 37(10), 570-574.
Thornalley, P.J.; Rabbani, N. Glyoxalase in tumourigenesis and multidrug resistance. Seminars Cell Develop.Biol., 2011, 22(3), 318-325.
Mearini, E.; Romani, R.; Mearini, L.; Antognelli, C.; Zucchi, A.; Baroni, T.; Porena, M.; Talesa, V.N. Differing expression of enzymes of the glyoxalase system in superficial and invasive bladder carcinomas. Europ. J. Cancer(Oxford, England : 1990) , 2002, 38(14), 1946 -1950.
Hosoda, F.; Arai, Y.; Okada, N.; Shimizu, H.; Miyamoto, M.; Kitagawa, N.; Katai, H.; Taniguchi, H.; Yanagihara, K.; Imoto, I. Integrated genomic and functional analyses reveal glyoxalase I as a novel metabolic oncogene in human gastric cancer. Oncogene, 2015, 34(9), 1196-1206.
Cheng, W-L.; Tsai, M-M.; Tsai, C-Y.; Huang, Y-H.; Chen, C-Y.; Chi, H-C.; Tseng, Y-H.; Chao, I-W.; Lin, W-C.; Wu, S-M. Glyoxalase-I is a novel prognosis factor associated with gastric cancer progression. PLoS One, 2012, 7(3), e34352.
Wang, Y.; Kuramitsu, Y.; Tokuda, K.; Okada, F.; Baron, B.; Akada, J.; Kitagawa, T.; Nakamura, K. Proteomic analysis indicates that overexpression and nuclear translocation of lactoylglutathione lyase (GLO1) is associated with tumor progression in murine fibrosarcoma. Electrophoresis, 2014, 35(15), 2195-2202.
Wang, Y.; Kuramitsu, Y.; Ueno, T.; Suzuki, N.; Yoshino, S.; Iizuka, N.; Akada, J.; Kitagawa, T.; Oka, M.; Nakamura, K.; Glyoxalase, I. GLO1) is up-regulated in pancreatic cancerous tissues compared with related non-cancerous tissues. Anticancer Res., 2012, 32(8), 3219-3222.
Chen, Y.; Fang, L.; Li, G.; Zhang, J.; Li, C.; Ma, M.; Guan, C.; Bai, F.; Lyu, J.; Meng, Q.H. Synergistic inhibition of colon cancer growth by the combination of methylglyoxal and silencing of glyoxalase I mediated by the STAT1 pathway. Oncotarget, 2017, 8(33), 54838-54857.
Burdelski, C.; Shihada, R.; Hinsch, A.; Angerer, A.; Gobel, C.; Friedrich, E.; Hube-Magg, C.; Burdak-Rothkamm, S.; Kluth, M.; Simon, R.; Moller-Koop, C.; Sauter, G.; Buscheck, F.; Wittmer, C.; Clauditz, T.S.; Krech, T.; Tsourlakis, M.C.; Minner, S.; Graefen, M.; Schlomm, T.; Wilczak, W.; Jacobsen, F. High-Level Glyoxalase 1 (GLO1) expression is linked to poor prognosis in prostate cancer. Prostate, 2017, 77(15), 1528-1538.
Dong, L.; Zhou, Q.; Zhang, Z.; Zhu, Y.; Duan, T.; Feng, Y. Metformin sensitizes endometrial cancer cells to chemotherapy by repressing glyoxalase I expression. J. Obstet. Gynaecol. Res., 2012, 38(8), 1077-1085.
Sakamoto, H.; Mashima, T.; Kizaki, A.; Dan, S.; Hashimoto, Y.; Naito, M.; Tsuruo, T. Glyoxalase I is involved in resistance of human leukemia cells to antitumor agent-induced apoptosis. Blood, 2000, 95(10), 3214-3218.
Sakamoto, H.; Mashima, T.; Sato, S.; Hashimoto, Y.; Yamori, T.; Tsuruo, T. Selective activation of apoptosis program by Sp-bromobenzylglutathione cyclopentyl diester in glyoxalase I-overexpressing human lung cancer cells. Clin. Cancer Res., 2001, 7(8), 2513-2518.
Al-Shar’i, N.; Hassan, M.; Al-Balas, Q.; Almaaytah, A. Identification of possible glyoxalase ii inhibitors as anticancer agents by a customized 3D structure-based pharmacophore model. Jordan J. Pharmaceut. Sci., 2015, 8(2)
Armstrong, R.N. Mechanistic diversity in a metalloenzyme superfamily†. Biochemistry, 2000, 39(45), 13625-13632.
Kargatov, A.M.; Boshkova, E.A.; Chirgadze, Y.N. Novel approach for structural identification of protein family: glyoxalase I. J. Biomol. Struct. Dyn., 2017, 1-14.
Thornalley, P.J. Glyoxalase I--structure, function and a critical role in the enzymatic defence against glycation. Biochem. Soc. Transact., 2003, 31(Pt 6), 1343-1348.
Cameron, A.D.; Olin, B.; Ridderstrom, M.; Mannervik, B.; Jones, T.A. Crystal structure of human glyoxalase I--evidence for gene duplication and 3D domain swapping. EMBO J., 1997, 16(12), 3386-3395.
Chiba, T.; Ohwada, J.; Sakamoto, H.; Kobayashi, T.; Fukami, T.A.; Irie, M.; Miura, T.; Ohara, K.; Koyano, H. Design and evaluation of azaindole-substituted N-hydroxypyridones as glyoxalase I inhibitors. Bioorg. Med. Chem. Lett., 2012, 22(24), 7486-7489.
Yadav, A.; Kumar, R.; Sunkaria, A.; Singhal, N.; Kumar, M.; Sandhir, R. Evaluation of potential flavonoid inhibitors of glyoxalase-I based on virtual screening and in vitro studies. J. Biomol. Struct. Dynam., 2015, 1, 1-15.
N-Hydroxypyridone-based glyoxalase I inhibitors mimicking binding interactions of the substrate.http://www rcsb org/structure/ 3W0U.
Al-Balas, Q.; Hassan, M.; Al Jabal, G.; Al-Shar’i, N.; Almaaytah, A.; El-Elimat, T. Novel thiazole carboxylic acid derivatives possessing a “zinc binding feature” as potential human glyoxalase-i inhibitors. Lett. Drug Design . Discov., 2017, 14(11), 1324-1334.
Al-Balas, Q.; Hassan, M.; Al-Oudat, B.; Alzoubi, H.; Mhaidat, N.; Almaaytah, A. Generation of the first structure-based pharmacophore model containing a selective “zinc binding group” feature to identify potential glyoxalase-1 inhibitors. Mol.(Basel, Switzerland), 2012, 17(12), 13740-13758.
Schasteen, C.S.; Reed, D.J. Involvement of arginine residues in glutathione binding to yeast glyoxalase I. Biochim. Biophys. Acta, 1983, 742(2), 419-425.
Vander Jagt, D.L.; Han, L.P. Deuterium isotope effects and chemically modified coenzymes as mechanism probes of yeast glyoxalase-I. Biochemistry, 1973, 12(25), 5161-5167.
Ridderstrom, M.; Cameron, A.D.; Jones, T.A.; Mannervik, B. Involvement of an active-site Zn2+ ligand in the catalytic mechanism of human glyoxalase I. J. Biol. Chem., 1998, 273(34), 21623-21628.
Vince, R.; Daluge, S.; Wadd, W.B. Inhibition of glyoxalase I by S-substituted glutathiones. J. Med. Chem., 1971, 14(5), 402-404.
More, S.S.; Vince, R. A metabolically stable tight-binding transition-state inhibitor of glyoxalase-I. Bioorg. Med. Chem. Lett., 2006, 16(23), 6039-6042.
Lo, T.W.C.; Thornalley, P.J. Inhibition of proliferation of human leukaemia 60 cells by diethyl esters of glyoxalase inhibitors in vitro. Biochem. Pharmacol., 1992, 44(12), 2357-2363.
Hamilton, D.S.; Creighton, D.J. Inhibition of glyoxalase I by the enediol mimic S-(N-hydroxy-N-methylcarbamoyl)glutathione. The possible basis of a tumor-selective anticancer strategy. J. Biol. Chem., 1992, 267(35), 24933-24936.
More, S.S.; Vince, R. Inhibition of Glyoxalase I: The first low-nanomolar tight-binding inhibitors. J. Med. Chem., 2009, 52(15), 4650-4656.
Swati, S.; More, R.V. Design, synthesis, and binding studies of bidentate Zn-chelating peptidic inhibitors of glyoxalase-I. Bioorg. Med. Chem. Lett., 2007, 17, 3793-3797.
Huntley, C.F.M.; Hamilton, D.S.; Creighton, D.J.; Ganem, B. Reaction of COTC with Glutathione: Structure of the Putative Glyoxalase I Inhibitor. Org. Lett., 2000, 2(20), 3143-3144.
Zheng, Z-B.; Creighton, D.J. Bivalent Transition-State Analogue Inhibitors of Human Glyoxalase I. Org. Lett., 2003, 5(25), 4855-4858.
Holewinski, R.J.; Creighton, D.J. Inhibition by active site directed covalent modification of human glyoxalase I. Bioorg. Med. Chem., 2014, 22(13), 3301-3308.
Takasawa, R.; Takahashi, S.; Saeki, K.; Sunaga, S.; Yoshimori, A.; Tanuma, S. Structure-activity relationship of human GLO I inhibitory natural flavonoids and their growth inhibitory effects. Bioorg. Med. Chem., 2008, 16(7), 3969-3975.
Takasawa, R.; Saeki, K.; Tao, A.; Yoshimori, A.; Uchiro, H.; Fujiwara, M.; Tanuma, S-i. Delphinidin, a dietary anthocyanidin in berry fruits, inhibits human glyoxalase I. Bioorg. Med. Chem., 2010, 18(19), 7029-7033.
Takasawa, R.; Tao, A.; Saeki, K.; Shionozaki, N.; Tanaka, R.; Uchiro, H.; Takahashi, S.; Yoshimori, A.; Tanuma, S-i. Discovery of a new type inhibitor of human glyoxalase I by myricetin-based 4-point pharmacophore. Bioorg. Med. Chem. Lett., 2011, 21(14), 4337-4342.
Takasawa, R.; Akahane, H.; Tanaka, H.; Shimada, N.; Yamamoto, T.; Uchida-Maruki, H.; Sai, M.; Yoshimori, A.; Tanuma, S.I. Piceatannol, a natural trans-stilbene compound, inhibits human glyoxalase I. Bioorg. Med. Chem. Lett., 2017, 27(5), 1169-1174.
Zhang, H.; Zhai, J.; Zhang, L.; Li, C.; Zhao, Y.; Chen, Y.; Li, Q.; Hu, X.P. In Vitro Inhibition of Glyoxalase capital I, Ukrainian by Flavonoids: New insights from crystallographic analysis. Curr. Top. Med. Chem., 2016, 16(4), 460-466.
Al-Balas, Q.A.; Hassan, M.A.; Al-Shar’i, N.A.; El-Elimat, T.; Almaaytah, A.M. Computational and experimental exploration of the structure-activity relationships of flavonoids as potent glyoxalase-I inhibitors. Drug Develop. Res., 2017.
Liu, M.; Yuan, M.; Luo, M.; Bu, X.; Luo, H-B.; Hu, X. Binding of curcumin with glyoxalase I: Molecular docking, molecular dynamics simulations, and kinetics analysis. Biophys. Chem., 2010, 147(1-2), 28-34.
Yuan, M.; Luo, M.; Song, Y.; Xu, Q.; Wang, X.; Cao, Y.; Bu, X.; Ren, Y.; Hu, X. Identification of curcumin derivatives as human glyoxalase I inhibitors: A combination of biological evaluation, molecular docking, 3D-QSAR and molecular dynamics simulation studies. Bioorg. Med. Chem., 2011, 19(3), 1189-1196.
Zhai, J.; Zhang, H.; Zhang, L.; Zhao, Y.; Chen, S.; Chen, Y.; Peng, X.; Li, Q.; Yuan, M.; Hu, X. Zopolrestat as a Human Glyoxalase I Inhibitor and Its Structural Basis. ChemMedChem, 2013, 8(9), 1462-1464.
Al-Balas, Q.A.; Hassan, M.A.; Al-Shar’i, N.A.; Mhaidat, N.M.; Almaaytah, A.M.; Al-Mahasneh, F.M.; Isawi, I.H. Novel glyoxalase-I inhibitors possessing a “zinc-binding feature” as potential anticancer agents. Drug Design Develop. Ther., 2016, 10, 2623-2629.

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Year: 2019
Page: [281 - 291]
Pages: 11
DOI: 10.2174/1389557518666181009141231
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