Glyoxalase 2: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Andrea Scirè
,
Laura Cianfruglia
,
Cristina Minnelli
,
Brenda Romaldi
,
Emiliano Laudadio
,
Roberta Galeazzi
,
Cinzia Antognelli
,
Tatiana Armeni

Glyoxalase 2 is a mitochondrial and cytoplasmic protein belonging to the metallo-β-lactamase family encoded by the hydroxyacylglutathione hydrolase (HAGH) gene. This enzyme is the second enzyme of the glyoxalase system that is responsible for detoxification of the α-ketothaldehyde methylglyoxal in cells. The two enzymes glyoxalase 1 (Glo1) and glyoxalase 2 (Glo2) form the complete glyoxalase pathway, which utilizes glutathione as cofactor in eukaryotic cells.

  • glyoxalase system
  • glutathione
  • methylglyoxal

1. The Glyoxalase System

The glyoxalase system is present in the cytosol of all cells. It consists of two enzymes: a S-lactoylglutathione lyase as Glo1 (EC 4.4.1.5) and a hydroxyacylglutathione hydrolase known as Glo2 (EC 3.2.1.6), together with a catalytic amount of GSH [1][2]. The system is aimed at converting α-oxoaldehydes into the corresponding α-hydroxyacids quickly and efficiently. Typically, the major physiological α-oxoaldehyde removed is methylglyoxal that is converted to D-lactic acid via the SLG intermediate. In the first reaction, the hemithioacetal 2-hydroxyacylglutathione formed spontaneously from MGO and GSH becomes the substrate for Glo1 that catalyzes isomerization to SLG. In the second reaction, Glo2 hydrolyzes SLG to the final product D-lactic acid and simultaneously regenerates the GSH consumed in the first reaction (Figure 1) [3]. The major source of MGO formation is from the degradation of triose-phosphates during glycolysis, minor sources are from the catabolism of threonine and ketone bodies and the fragmentation of glycated proteins [4][5][6]. The glyoxalase system prevents the accumulation of these reactive oxaldehydes and thus suppresses oxaldehyde-mediated glycation reactions [7][8]. Increased MGO levels have been linked to age-related diseases and many other pathological conditions such as diabetes, obesity, cancer and Alzheimer’s disease [9]. To prevent these conditions, glyoxalase enzyme levels increase, enhancing detoxification of MGO and thus protecting cells from its deleterious effects.
Antioxidants 11 02131 g001 550
Figure 1. Conversion of methylglyoxal to D-lactic acid by glyoxalases. The GSH-dependent system is a two-enzyme pathway involving Glo1 and Glo2 enzymes. Glo1 catalyzes the formation of S-D-lactoylglutathione from the non-enzymatically formed hemimercaptal adduct of MGO with GSH, 2-hydroxyacylglutathione (MG-GSH). Glo2 catalyzes the hydrolysis of S-D-lactoylglutathione to D-lactic acid and GSH [10]. The GSH independent system involves a single Glo3 enzyme recently discovered.
Recently, some authors reported the presence of another glyoxalase member, named glyoxalase 3 (Glo3). Glo3 catalyzes the conversion of MGO into D-lactate in a single step without requiring any cofactor [11][12]. Glo3 was reported to be a member of DJ-1/Pfp1 superfamily and was first identified in E. coli [13].

2. Genetics and Molecular Properties of Glyoxalases 2

Glyoxalases are usually encoded by a single gene in microbial and eukaryotic genomes [14][15][16][17], while in plants and yeast, multiple genes are present [18][19]. For Glo2, the cytosolic and the mitochondrial forms of the enzyme are encoded by separate genes in yeast and higher plants and by a single gene in vertebrates [14]. For instance, in the rice genome, three Glo2 genes are present, while in the Arabidopsis thaliana genome, there are five [19][20][21]. A genome-wide study confirmed the presence of multiple glyoxalases in plants, with Glycine max genome possessing twelve Glo2 genes [18]. In A. thaliana, five different genes of Glo2 have been identified and three of these isoforms appears to be mitochondrial (GLX2-1, GLX2-4 and GLX2-5) [21]. The subcellular localization, molecular mechanism and functional role are currently unknown. These multiple forms of glyoxalases genes in plants probably indicate a tissue-specific MGO detoxification. Some genes encode inactive Glo2 forms, which are found in one of the three rice Glo2 and in two of the five A. thaliana Glo2 [19][21][22], forms that probably possess a different function than that of a thiolesterase. As an example, this functional diversification has been confirmed for A. thaliana glyoxalase 2-1, which is the isoform that is essential and produced by the plant during abiotic stress but is not necessary in normal growing conditions. A. thaliana glyoxalase 2-1 shows high similarity (88%) to the functionally active glyoxalase 2-5 protein, lacks Glo2 activity, but possesses β-lactamase activity. It could be an example of ongoing gene evolution where the duplication and functional divergence of an ancestral mitochondrial Glo2 gene have led to the emergence of β-lactamase activity, although plants do not produce β-lactams. A functional investigation of the role of A. thaliana glyoxalase 2-1 shows that its loss-of-function mutants and constitutively overexpressing plants resemble wild-type plants under normal growth conditions, whereas during abiotic stress mutations in A. thaliana, glyoxalase 2-1 inhibits plant growth and survival [23]. The second Glo2 gene from A. thaliana, glyoxalase 2-3, which also lacks canonical Glo2 activity, has been shown to possess sulfur dioxygenase activity and is known to be critical for seed development and conditions that involve high protein turnover [24]. In plants, adverse environmental conditions such as extreme temperatures, salinity, drought and heavy metal toxicity are critical factors that drastically reduce crop yields [25]. Under different abiotic stresses, MGO increased and became toxic for cellular components [26][27]. The accumulation of MGO resulted in the inhibition of germination and cell proliferation in a dose-dependent manner [28][29][30]. In A. thaliana, root elongation was significantly reduced due to 1 and 10 mM MGO, and chlorosis occurred at 10 mM [31]. Thus, in recent years, the glyoxalase system and Glo2 have been studied in relation to abiotic stress tolerance. In B. campestris, exposure of 150 mM NaCl increased Glo2 activity [32]. On the other hand, Hasanuzzaman and colleagues showed a decrease in Glo2 activity with increased ROS production under salinity stress in Triticum aestivum, B. napus and O. sativa seedlings [33][34][35]. Overexpression of Glo2 in rice and tobacco can lead to better tolerance to high MGO under salinity stress [22]. Rahman et al. showed that supplementation with manganese and calcium increases Glo2 activity and reinforces MGO detoxification in salt-affected seedlings [36][37]. Not only salt-induced stress increased Glo2 expression, but also heavy metals and abscisic acid (ABA) stress. In Brassica juncea, exposure to ZnCl2 increased Glo2 transcript levels [38]. Treatment with the xenobiotic compound, 2,4,6-trinitrotoluene (TNT) of A. thaliana seedlings root, resulted in an increase in Glo2 transcripts [39]. Moreover, genome-wide expression studies in rice and A. thaliana have shown a differential response of multigene family of glyoxalases during different growth and reproductive stages and in different tissues under various abiotic stresses [19]. Stress-responsive elements such as ethylene-responsive elements, abscisic acid-responsive element (ABRE), auxin-responsive element (AuxxRR-core) and heat shock element (HSE) have been identified in the promoter region of Glo2 family members in A. thaliana and soybean (Glycine max), suggesting that these genes could be regulated by hormonal and stress response pathways [18][23]. In addition to abiotic stressors, glyoxalase genes are highly induced by biotic stress conditions in bacteria, fungi, viruses, parasites and insects. Ghosh and Islam have reported biotic stress-responsive cis elements such as the fungal elicitor-responsive element (BOX-W1), wounding- and pathogen-responsive elements (W-box and WUN-motif), jasmonate elicitor-responsive element (JERE), methyl jasmonate-responsive elements (CGTCA box and TGACG motif), defense and stress-responsive element (TC-rich) and salicylic acid-responsive element (TCA) in the promoter region of Glo2 [18]. The regulatory mechanisms for the glyoxalase expression remain unclear, and further studies must be carried out to determine if glyoxalase genes might offer protection from pathogens.
Regarding the yeast genome, two isoforms of glyoxalase 2 have been found: Glo2p and Glo4p proteins, with different subcellular localization. Glo2p is a cytosolic isoform, while Glo4p is present in the mitochondrial matrix [40]. The GLO4 gene has been identified first as a multicopy suppressor gene for a mutant yeast strain, which has a reduced efficiency of spore germination. A second gene, named GLO2, corresponds to a protein that has glyoxalase 2 activity. The amino acid sequences of the deduced proteins showed high similarities to the sequence of the human glyoxalase 2. Analyses with mutants lacking either one or both glyoxalase 2 genes showed that (i) the proteins are localized in different cellular compartments; (ii) the two glyoxalase II isoforms are differentially expressed depending on the carbon source used: glucose or glycerol; and (iii) to obtain an active Glo4p protein in E. coli through heterologous expression, the putative mitochondrial transit peptide at the N-terminus had to be removed [40]. Similarly, in P. falciparum, there are two Glo2 genes; one encodes for the cytosolic protein and the other codes for a protein localized in the apicoplast of the parasite [41]. These two active Glo2 isozymes both show a binuclear metal center [42]. The first report of a glyoxalase pathway in apicomplexan parasites was in Plasmodium falciparum-infected erythrocytes [43]. Given the relevance in the cellular detoxification of methylglyoxal, the glyoxalase system has been studied as a potential drug target in some human parasites, such as Plasmodium falciparum, Leishmania spp. and Trypanosoma spp. Differences in the glyoxalase pathways have been identified between human and parasites. Interestingly, the trypanosomatid Trypanosoma brucei is missing the Glo1 enzyme but has two genes encoding Glo2 enzymes; of the latter, only one showed glyoxalase 2 activity [44]. The life cycle of malaria parasites alternates between a vector (mosquito) and a human host stage each with their own specific proteome [45]. Regarding Glo2 expression during the life cycle stages of P. falciparum, tGlo2 was found to be expressed only in trophozoites and gametocytes; no information was available for cGlo2 [46]. Blood stages of the P. falciparum are the principal cause for the clinical manifestation of disease. Glucose uptake of red blood cells increased 75-fold upon infection [47]. This excessive glucose consumption allows for rapid endomitotic nuclear divisions and a drastic increase in parasitemia [48]. As a consequence of this high glucose metabolism, both malaria parasites and their host cells show elevated MGO production [43]. Therefore, the glyoxalase system has received a considerable amount of attention as a possible anti-malarial target and for its possible anti-trypanosomal activity [49][50]. In contrast to most eukaryotic organisms, the glyoxalase system of the trypanosomatids, including Leishmania spp. and Trypanosoma spp., uses reduced trypanothione (N1,N8-bis(glutathionyl)spermidine) (TSH), an alternative low-molecular-weight (LMW) thiol, as the preferred substrate [51][52][53]. Trypanosomatids differ from all other organisms in their ability to conjugate glutathione and a polyamine, spermidine, to form TSH. Together with the NADPH-dependent flavoprotein, trypanothione reductase (TR), the dithiol form of trypanothione, provides an intracellular reducing environment in these parasites, substituting glutathione and glutathione reductase found in the mammalian host. TSH and TR are involved in defense against damage by oxidants, some heavy metals, and possibly xenobiotics [54]. Due to its crucial role in the protection of parasites from oxidative stress [55][56] and heavy metal toxicity [57], enzymes involved in the trypanothione biosynthesis pathway are considered interesting candidates for drug development [58]. Trypanosomatid Glo2, similar to all other glyoxalases 2, contains a binuclear metal center [17][52]. The crystal structure of the Glo2 from L. infantum has revealed that Lys143, Arg249 and Lys252 residues involved in GSH binding have been substituted with Ile171 residue and two Phe residues, Phe219-266, in order to accommodate the positively charged thioesters of T[SH]2 or glutathionylspermidine [17]. Barata et al. produced a mutant enzyme able to hydrolyze both glutathione and trypanothione-derived thioesters by replacing Tyr291 and Cys294 with Arg and Lys [59]. Substrate specificities and significant differences in catalytic sites between trypasomatid and human Glo2 give hope that specific inhibitors are an achievable goal in drug development.
Gram-positive bacteria include bacilli (e.g., Bacillus subtilis, Bacillus anthracis, Bacillus cereus, Bacillus megaterium, Bacillus pumilis), staphylococci (e.g., Staphylococcus aureus, Staphylococcus saprophyticus) and streptococci (Streptococcus agalactiae), which produce bacillithiol (BSH) as an alternative LMW thiol, which serves similar metabolic and redox cofactor functions as shown for GSH in eukaryotes [60][61][62][63]. In the past few years, some researchers have started to investigate the role of BSH in the detoxification of reactive oxidants and electrophiles, such as methylglyoxal [64] and fosfomycin [65], as well as the protection and redox regulation of protein functions by protein-S-bacillithiolation during oxidative stress [66][67]. Chandrangsu et al. showed that the BSH-dependent glyoxalase system confers protection against MGO primarily through cytoplasmic acidification resulting from the activation of the KhtSTU K+ efflux pump and secondarily by converting MGO to D-lactate. The activation of the KhtSTU K+ efflux pump is caused by the production of S-lactoyl-BSH, catalyzed from glyoxalase 1 in the conversion of the hemithioacetal adduct, while glyoxalase 2 converts S-lactoyl-BSH to D-lactate [68].
In vertebrates, the single gene encoding Glo2 produces two transcripts of nine and ten exons. The transcript derived from the nine exons encodes for mitochondrial Glo2 that has the start codon AUG in a previously uncharacterized upstream part of the mRNA. Also in this transcript is a downstream start codon that encodes for the cytosolic form. The 10-exon transcript only encodes for the cytosolic form because it has an in-frame termination codon. The double initiation by alternative AUG codons is conserved in all species [14]. The gene for Glo2 is conventionally referred to as HAGH (hydroxyacylglutahione hydrolase). The molecular mass of the cytosolic form of Glo2 is around 29 kDa, while that of the mitochondrial is approximately 34 kDa. The different molecular masses of the two isoforms are due to the absence of the first 48 amino acids in the cytosolic sequence. In fact, the amino-terminal extension of the mitochondrial isoform of Glo2 (mGlo2) contains a mitochondrial targeting sequence that has been identified in spinach [69], A. thaliana [21] and vertebrates such as mammals, birds and fish. In human HepG2 cells, it was seen, by confocal fluorescence microscopy, that the mitochondrial form of Glo2 is present in the mitochondrial matrix [14]. In rat liver mitochondria, two separate pools of mGlo2 (purified by affinity chromatography) were found: one in the intermembrane space and the other in the mitochondrial matrix. From both crude and purified preparations, polyacrylamide gel-electrophoresis resolved multiple forms of Glo2, two from the intermembrane space and five from the matrix [70]. The presence of mGlo2 was also demonstrated in the bovine liver extracts, which accounted for about 10% of the total Glo2 activity of the whole homogenate. Electrophoresis and isoelectric focusing of the crude mitochondrial extract or purified mGlo2 resolved the enzyme activity into five isoforms (pl 6.3, 6.7, 7.1, 7.7 and 7.9). Since the bovine liver cytosol showed only one Glo2 isoform (pl 7.5), it was assumed that at least four isoforms were exclusively mitochondrial [71]. The study also showed differences between cytosolic and mitochondrial Glo2. Indeed, it was shown that the activity of cytosolic Glo2 was inhibited by contact with liposomes formed from negatively charged phospholipids, whereas no inhibition on enzymatic activity was detected on mGlo2 [72]. Considering that a single gene encodes Glo2 (HAGH) and that there are two mRNA transcripts, it is possible to assume that there are other post-transcriptional rearrangements that give rise to different mitochondrial isoforms. The mGlo2 within the mitochondria has SLG as its substrate of choice but also hydrolyzes other acyl-GSH derivatives such as S-acetyl-GSH and S-succinyl-GSH. One of the studies showed that SLG can enter mitochondria and provide the substrate for mGlo2, and it was hypothesized that this could be an alternative GSH supply route for the mitochondria and ATP production through the oxidation of D-lactate to pyruvate by the enzyme D-lactate dehydrogenase [73]. It was pointed out that it is unlikely that SLG is a substrate for GSH uptake in mitochondria since SLG levels are low, usually less than 1% of GSH, and a role as an acceptor of acetyl groups was proposed [3][74]. In light of the new findings concerning the involvement of Glo2 in PTMs, there is a good chance that mGlo2 can be involved in the post-translational regulation of proteins (see paragraph 5), and in particular that GSH derived from the hydrolysis of SLG can be utilized by mGlo2 for the S-glutathionylation of specific target proteins.
Recently, the presence of Glo2 protein into the nuclei of human prostate cancer cells but not in normal cells has been reported [75]. Further investigation will be required in order to identify as best as possible the nuclear localization of Glo2 and its possible role(s). The amino acid sequences of Glo2 proteins from different species revealed two different domains (Figure 2). One is the metallo-β-lactamase domain (present in all members of the metallo-β-lactamase superfamily and required for the catalytic activity), and the other is a hydroxyacylglutathione hydrolase C-terminus (HAGH-C) domain that forms the substrate-binding site (usually present at the C-terminus of Glo2 proteins) [76]. The length of these domains varies among different species, but the overall domain architecture of Glo2 proteins remains the same (Figure 2).
Antioxidants 11 02131 g002 550
Figure 2. Schematic representation of the domains found in living systems for Glo2. Glo2 features a metallo-β-lactamase domain required for the catalytic activity and a hydroxyacylglutathione hydrolase C-terminus (HAGH-C) that represents the substrate-binding site. The length of these domains varies among different species and is indicated below each domain.

This entry is adapted from the peer-reviewed paper 10.3390/antiox11112131

References

  1. Carrington, S.J.; Douglas, K.T. The glyoxalase enigma—The biological consequences of a ubiquitous enzyme. IRCS Med. Sci. 1986, 14, 763–768.
  2. Thornalley, P.J. The glyoxalase system: New developments towards functional characterization of a metabolic pathway fundamental to biological life. Biochem. J. 1990, 269, 1–11.
  3. Rabbani, N.; Xue, M.; Thornalley, P.J. Activity, regulation, copy number and function in the glyoxalase system. Biochem. Soc. Trans. 2014, 42, 419–424.
  4. Rabbani, N.; Thornalley, P.J. Dicarbonyl stress in cell and tissue dysfunction contributing to ageing and disease. Biochem. Biophys. Res. Commun. 2015, 458, 221–226.
  5. Lyles, G.A.; Chalmers, J. The metabolism of aminoacetone to methylglyoxal by semicarbazide-sensitive amine oxidase in human umbilical artery. Biochem. Pharmacol. 1992, 43, 1409–1414.
  6. Richard, J.P. Mechanism for the formation of methylglyoxal from triosephosphates. Biochem. Soc. Trans. 1993, 21, 549–553.
  7. Xue, M.; Rabbani, N.; Thornalley, P.J. Glyoxalase in ageing. Semin. Cell Dev. Biol. 2011, 22, 293–301.
  8. Cianfruglia, L.; Morresi, C.; Bacchetti, T.; Armeni, T.; Ferretti, G. Protection of Polyphenols against Glyco-Oxidative Stress: Involvement of Glyoxalase Pathway. Antioxidants 2020, 9, 1006.
  9. de Bari, L.; Atlante, A.; Armeni, T.; Kalapos, M.P. Synthesis and metabolism of methylglyoxal, S-D-lactoylglutathione and D-lactate in cancer and Alzheimer’s disease. Exploring the crossroad of eternal youth and premature aging. Age. Res. Rev. 2019, 53, 100915.
  10. Vander Jagt, D.L. Glyoxalase II: Molecular characteristics, kinetics and mechanism. Biochem. Soc. Trans. 1993, 21, 522–527.
  11. Ghosh, A.; Kushwaha, H.R.; Hasan, M.R.; Pareek, A.; Sopory, S.K.; Singla-Pareek, S.L. Presence of unique glyoxalase III proteins in plants indicates the existence of shorter route for methylglyoxal detoxification. Sci. Rep. 2016, 6, 18358.
  12. Kwon, K.; Choi, D.; Hyun, J.K.; Jung, H.S.; Baek, K.; Park, C. Novel glyoxalases from Arabidopsis thaliana. FEBS J. 2013, 280, 3328–3339.
  13. Lee, J.Y.; Song, J.; Kwon, K.; Jang, S.; Kim, C.; Baek, K.; Kim, J.; Park, C. Human DJ-1 and its homologs are novel glyoxalases. Hum. Mol. Genet. 2012, 21, 3215–3225.
  14. Cordell, P.A.; Futers, T.S.; Grant, P.J.; Pease, R.J. The Human hydroxyacylglutathione hydrolase (HAGH) gene encodes both cytosolic and mitochondrial forms of glyoxalase II. J. Biol. Chem. 2004, 279, 28653–28661.
  15. Cameron, A.D.; Ridderstrom, M.; Olin, B.; Mannervik, B. Crystal structure of human glyoxalase II and its complex with a glutathione thiolester substrate analogue. Structure 1999, 7, 1067–1078.
  16. O’Young, J.; Sukdeo, N.; Honek, J.F. Escherichia coli glyoxalase II is a binuclear zinc-dependent metalloenzyme. Arch. Biochem. Biophys. 2007, 459, 20–26.
  17. Silva, M.S.; Barata, L.; Ferreira, A.E.; Romao, S.; Tomas, A.M.; Freire, A.P.; Cordeiro, C. Catalysis and structural properties of Leishmania infantum glyoxalase II: Trypanothione specificity and phylogeny. Biochemistry 2008, 47, 195–204.
  18. Ghosh, A.; Islam, T. Genome-wide analysis and expression profiling of glyoxalase gene families in soybean (Glycine max) indicate their development and abiotic stress specific response. BMC Plant Biol. 2016, 16, 87.
  19. Mustafiz, A.; Singh, A.K.; Pareek, A.; Sopory, S.K.; Singla-Pareek, S.L. Genome-wide analysis of rice and Arabidopsis identifies two glyoxalase genes that are highly expressed in abiotic stresses. Funct. Integr. Genom. 2011, 11, 293–305.
  20. Crowder, M.W.; Maiti, M.K.; Banovic, L.; Makaroff, C.A. Glyoxalase II from A. thaliana requires Zn(II) for catalytic activity. FEBS Lett. 1997, 418, 351–354.
  21. Marasinghe, G.P.; Sander, I.M.; Bennett, B.; Periyannan, G.; Yang, K.W.; Makaroff, C.A.; Crowder, M.W. Structural studies on a mitochondrial glyoxalase II. J. Biol. Chem. 2005, 280, 40668–40675.
  22. Yadav, S.K.; Singla-Pareek, S.L.; Kumar, M.; Pareek, A.; Saxena, M.; Sarin, N.B.; Sopory, S.K. Characterization and functional validation of glyoxalase II from rice. Protein Expr. Purif. 2007, 51, 126–132.
  23. Devanathan, S.; Erban, A.; Perez-Torres, R., Jr.; Kopka, J.; Makaroff, C.A. Arabidopsis thaliana glyoxalase 2-1 is required during abiotic stress but is not essential under normal plant growth. PLoS ONE 2014, 9, e95971.
  24. Holdorf, M.M.; Owen, H.A.; Lieber, S.R.; Yuan, L.; Adams, N.; Dabney-Smith, C.; Makaroff, C.A. Arabidopsis ETHE1 encodes a sulfur dioxygenase that is essential for embryo and endosperm development. Plant Physiol. 2012, 160, 226–236.
  25. Bray, E.A.; Bailey-Serres, J.; Weretilnyk, E. Responses to abiotic stresses. In Biochemistry and Molecular Biology of Plants; Gruissem, W., Buchannan, B., Jones, R., Eds.; American Society of Plant Physiologists: Rockville, MD, USA, 2000; pp. 1158–1249.
  26. Apel, K.; Hirt, H. Reactive oxygen species: Metabolism, oxidative stress, and signal transduction. Annu. Rev. Plant Biol. 2004, 55, 373–399.
  27. Hasanuzzaman, M.; Bhuyan, M.; Zulfiqar, F.; Raza, A.; Mohsin, S.M.; Mahmud, J.A.; Fujita, M.; Fotopoulos, V. Reactive Oxygen Species and Antioxidant Defense in Plants under Abiotic Stress: Revisiting the Crucial Role of a Universal Defense Regulator. Antioxidants 2020, 9, 681.
  28. Hoque, T.S.; Hossain, M.A.; Mostofa, M.G.; Burritt, D.J.; Fujita, M.; Tran, L.S. Methylglyoxal: An Emerging Signaling Molecule in Plant Abiotic Stress Responses and Tolerance. Front. Plant Sci. 2016, 7, 1341.
  29. Hoque, T.S.; Uraji, M.; Ye, W.; Hossain, M.A.; Nakamura, Y.; Murata, Y. Methylglyoxal-induced stomatal closure accompanied by peroxidase-mediated ROS production in Arabidopsis. J. Plant Physiol. 2012, 169, 979–986.
  30. Kaur, C.; Singla-Pareek, S.L.; Sopory, S.K. Glyoxalase and Methylglyoxal as Biomarkers for Plant Stress Tolerance. Crit. Rev. Plant Sci. 2014, 33, 429–456.
  31. Hossain, M.A.; Hossain, M.Z.; Fujita, M. Stress-induced changes of methylglyoxal level and glyoxalase I activity in pumpkin seedlings and cDNA cloning of glyoxalase I gene. Aust. J. Crop Sci. 2009, 3, 53–64.
  32. Hossain, M.A.; Mostofa, M.G.; Fujita, M. Heat-shock positively modulates oxidative protection of salt and drought-stressed mustard (Brassica campestris L.) seedlings. J. Plant Sci. Mol. Breed. 2013, 2, 2.
  33. Hasanuzzaman, M.; Alam, M.M.; Rahman, A.; Hasanuzzaman, M.; Nahar, K.; Fujita, M. Exogenous proline and glycine betaine mediated upregulation of antioxidant defense and glyoxalase systems provides better protection against salt-induced oxidative stress in two rice (Oryza sativa L.) varieties. BioMed. Res. Int. 2014, 2014, 757219.
  34. Hasanuzzaman, M.; Hossain, M.A.; Fujita, M. Selenium-induced up-regulation of the antioxidant defense and methylglyoxal detoxification system reduces salinity-induced damage in rapeseed seedlings. Biol. Trace Elem. Res. 2011, 143, 1704–1721.
  35. Yan, Y.; Pan, C.; Du, Y.; Li, D.; Liu, W. Exogenous salicylic acid regulates reactive oxygen species metabolism and ascorbate-glutathione cycle in Nitraria tangutorum Bobr. under salinity stress. Physiol. Mol. Biol. Plants 2018, 24, 577–589.
  36. Rahman, A.; Hossain, M.S.; Mahmud, J.A.; Nahar, K.; Hasanuzzaman, M.; Fujita, M. Manganese-induced salt stress tolerance in rice seedlings: Regulation of ion homeostasis, antioxidant defense and glyoxalase systems. Physiol. Mol. Biol. Plants 2016, 22, 291–306.
  37. Rahman, A.; Nahar, K.; Hasanuzzaman, M.; Fujita, M. Calcium Supplementation Improves Na(+)/K(+) Ratio, Antioxidant Defense and Glyoxalase Systems in Salt-Stressed Rice Seedlings. Front. Plant Sci. 2016, 7, 609.
  38. Saxena, M.; Bisht, R.; Roy, S.D.; Sopory, S.K.; Bhalla-Sarin, N. Cloning and characterization of a mitochondrial glyoxalase II from Brassica juncea that is upregulated by NaCl, Zn, and ABA. Biochem. Biophys. Res. Commun. 2005, 336, 813–819.
  39. Ekman, D.R.; Lorenz, W.W.; Przybyla, A.E.; Wolfe, N.L.; Dean, J.F. SAGE analysis of transcriptome responses in Arabidopsis roots exposed to 2,4,6-trinitrotoluene. Plant Physiol. 2003, 133, 1397–1406.
  40. Bito, A.; Haider, M.; Hadler, I.; Breitenbach, M. Identification and phenotypic analysis of two glyoxalase II encoding genes from Saccharomyces cerevisiae, GLO2 and GLO4, and intracellular localization of the corresponding proteins. J. Biol. Chem. 1997, 272, 21509–21519.
  41. Urscher, M.; Przyborski, J.M.; Imoto, M.; Deponte, M. Distinct subcellular localization in the cytosol and apicoplast, unexpected dimerization and inhibition of Plasmodium falciparum glyoxalases. Mol. Microbiol. 2010, 76, 92–103.
  42. Akoachere, M.; Iozef, R.; Rahlfs, S.; Deponte, M.; Mannervik, B.; Creighton, D.J.; Schirmer, H.; Becker, K. Characterization of the glyoxalases of the malarial parasite Plasmodium falciparum and comparison with their human counterparts. Biol. Chem. 2005, 386, 41–52.
  43. Vander Jagt, D.L.; Hunsaker, L.A.; Campos, N.M.; Baack, B.R. D-lactate production in erythrocytes infected with Plasmodium falciparum. Mol. Biochem. Parasitol. 1990, 42, 277–284.
  44. Wendler, A.; Irsch, T.; Rabbani, N.; Thornalley, P.J.; Krauth-Siegel, R.L. Glyoxalase II does not support methylglyoxal detoxification but serves as a general trypanothione thioesterase in African trypanosomes. Mol. Biochem. Parasitol. 2009, 163, 19–27.
  45. Florens, L.; Washburn, M.P.; Raine, J.D.; Anthony, R.M.; Grainger, M.; Haynes, J.D.; Moch, J.K.; Muster, N.; Sacci, J.B.; Tabb, D.L.; et al. A proteomic view of the Plasmodium falciparum life cycle. Nature 2002, 419, 520–526.
  46. Le Roch, K.G.; Johnson, J.R.; Florens, L.; Zhou, Y.; Santrosyan, A.; Grainger, M.; Yan, S.F.; Williamson, K.C.; Holder, A.A.; Carucci, D.J.; et al. Global analysis of transcript and protein levels across the Plasmodium falciparum life cycle. Genome Res. 2004, 14, 2308–2318.
  47. Sherman, I.W. Biochemistry of Plasmodium (Malarial parasites). Microbiol. Rev. 1979, 43, 453–495.
  48. Kappe, S.H.; Vaughan, A.M.; Boddey, J.A.; Cowman, A.F. That was then but this is now: Malaria research in the time of an eradication agenda. Science 2010, 328, 862–866.
  49. D’Silva, C.; Daunes, S. Structure-activity study on the in vitro antiprotozoal activity of glutathione derivatives. J. Med. Chem. 2000, 43, 2072–2078.
  50. Thornalley, P.J.; Strath, M.; Wilson, R.J. Antimalarial activity in vitro of the glyoxalase I inhibitor diester, S-p-bromobenzylglutathione diethyl ester. Biochem. Pharm. 1994, 47, 418–420.
  51. Ariza, A.; Vickers, T.J.; Greig, N.; Armour, K.A.; Dixon, M.J.; Eggleston, I.M.; Fairlamb, A.H.; Bond, C.S. Specificity of the trypanothione-dependent Leishmania major glyoxalase I: Structure and biochemical comparison with the human enzyme. Mol. Microbiol. 2006, 59, 1239–1248.
  52. Irsch, T.; Krauth-Siegel, R.L. Glyoxalase II of African trypanosomes is trypanothione-dependent. J. Biol. Chem. 2004, 279, 22209–22217.
  53. Sousa Silva, M.; Ferreira, A.E.; Tomas, A.M.; Cordeiro, C.; Ponces Freire, A. Quantitative assessment of the glyoxalase pathway in Leishmania infantum as a therapeutic target by modelling and computer simulation. FEBS J. 2005, 272, 2388–2398.
  54. Fairlamb, A.H.; Cerami, A. Metabolism and functions of trypanothione in the Kinetoplastida. Annu. Rev. Microbiol. 1992, 46, 695–729.
  55. Ariyanayagam, M.R.; Fairlamb, A.H. Ovothiol and trypanothione as antioxidants in trypanosomatids. Mol. Biochem. Parasitol. 2001, 115, 189–198.
  56. Krauth-Siegel, R.L.; Comini, M.A. Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism. Biochim. Biophys. Acta 2008, 1780, 1236–1248.
  57. Mandal, G.; Wyllie, S.; Singh, N.; Sundar, S.; Fairlamb, A.H.; Chatterjee, M. Increased levels of thiols protect antimony unresponsive Leishmania donovani field isolates against reactive oxygen species generated by trivalent antimony. Parasitology 2007, 134, 1679–1687.
  58. Ilari, A.; Fiorillo, A.; Genovese, I.; Colotti, G. Polyamine-trypanothione pathway: An update. Future Med. Chem. 2017, 9, 61–77.
  59. Barata, L.; Sousa Silva, M.; Schuldt, L.; Ferreira, A.E.; Gomes, R.A.; Tomas, A.M.; Weiss, M.S.; Ponces Freire, A.; Cordeiro, C. Enlightening the molecular basis of trypanothione specificity in trypanosomatids: Mutagenesis of Leishmania infantum glyoxalase II. Exp. Parasitol. 2011, 129, 402–408.
  60. Chandrangsu, P.; Loi, V.V.; Antelmann, H.; Helmann, J.D. The Role of Bacillithiol in Gram-Positive Firmicutes. Antioxid. Redox Signal. 2018, 28, 445–462.
  61. Newton, G.L.; Rawat, M.; La Clair, J.J.; Jothivasan, V.K.; Budiarto, T.; Hamilton, C.J.; Claiborne, A.; Helmann, J.D.; Fahey, R.C. Bacillithiol is an antioxidant thiol produced in Bacilli. Nat. Chem. Biol. 2009, 5, 625–627.
  62. Perera, V.R.; Newton, G.L.; Pogliano, K. Bacillithiol: A key protective thiol in Staphylococcus aureus. Expert Rev. Anti. Infect. Ther. 2015, 13, 1089–1107.
  63. Sharma, S.V.; Arbach, M.; Roberts, A.A.; Macdonald, C.J.; Groom, M.; Hamilton, C.J. Biophysical features of bacillithiol, the glutathione surrogate of Bacillus subtilis and other firmicutes. Chembiochem 2013, 14, 2160–2168.
  64. Gaballa, A.; Newton, G.L.; Antelmann, H.; Parsonage, D.; Upton, H.; Rawat, M.; Claiborne, A.; Fahey, R.C.; Helmann, J.D. Biosynthesis and functions of bacillithiol, a major low-molecular-weight thiol in Bacilli. Proc. Natl. Acad. Sci. USA 2010, 107, 6482–6486.
  65. Roberts, A.A.; Sharma, S.V.; Strankman, A.W.; Duran, S.R.; Rawat, M.; Hamilton, C.J. Mechanistic studies of FosB: A divalent-metal-dependent bacillithiol-S-transferase that mediates fosfomycin resistance in Staphylococcus aureus. Biochem. J. 2013, 451, 69–79.
  66. Chi, B.K.; Gronau, K.; Mader, U.; Hessling, B.; Becher, D.; Antelmann, H. S-bacillithiolation protects against hypochlorite stress in Bacillus subtilis as revealed by transcriptomics and redox proteomics. Mol. Cell. Proteom. 2011, 10, M111.009506.
  67. Chi, B.K.; Roberts, A.A.; Huyen, T.T.; Basell, K.; Becher, D.; Albrecht, D.; Hamilton, C.J.; Antelmann, H. S-bacillithiolation protects conserved and essential proteins against hypochlorite stress in firmicutes bacteria. Antioxid. Redox Signal. 2013, 18, 1273–1295.
  68. Chandrangsu, P.; Dusi, R.; Hamilton, C.J.; Helmann, J.D. Methylglyoxal resistance in Bacillus subtilis: Contributions of bacillithiol-dependent and independent pathways. Mol. Microbiol. 2014, 91, 706–715.
  69. Talesa, V.; Rosi, G.; Contenti, S.; Mangiabene, C.; Lupattelli, M.; Norton, S.J.; Giovannini, E.; Principato, G.B. Presence of glyoxalase II in mitochondria from spinach leaves: Comparison with the enzyme from cytosol. Biochem. Int. 1990, 22, 1115–1120.
  70. Talesa, V.; Uotila, L.; Koivusalo, M.; Principato, G.; Giovannini, E.; Rosi, G. Isolation of glyoxalase II from two different compartments of rat liver mitochondria. Kinetic and immunochemical characterization of the enzymes. Biochim. Biophys. Acta 1989, 993, 7–11.
  71. Talesa, V.; Principato, G.B.; Norton, S.J.; Contenti, S.; Mangiabene, C.; Rosi, G. Isolation of glyoxalase II from bovine liver mitochondria. Biochem. Int. 1990, 20, 53–58.
  72. Scire, A.; Tanfani, F.; Saccucci, F.; Bertoli, E.; Principato, G. Specific interaction of cytosolic and mitochondrial glyoxalase II with acidic phospholipids in form of liposomes results in the inhibition of the cytosolic enzyme only. Proteins 2000, 41, 33–39.
  73. Armeni, T.; Cianfruglia, L.; Piva, F.; Urbanelli, L.; Luisa Caniglia, M.; Pugnaloni, A.; Principato, G. S-D-Lactoylglutathione can be an alternative supply of mitochondrial glutathione. Free. Radic. Biol. Med. 2014, 67, 451–459.
  74. Ashour, A.; Xue, M.; Al-Motawa, M.; Thornalley, P.J.; Rabbani, N. Glycolytic overload-driven dysfunction of periodontal ligament fibroblasts in high glucose concentration, corrected by glyoxalase 1 inducer. BMJ Open Diabetes Res. Care 2020, 8, e001458.
  75. Antognelli, C.; Ferri, I.; Bellezza, G.; Siccu, P.; Love, H.D.; Talesa, V.N.; Sidoni, A. Glyoxalase 2 drives tumorigenesis in human prostate cells in a mechanism involving androgen receptor and p53–p21 axis. Mol. Carcinog. 2017, 56, 2112–2126.
  76. Schilling, O.; Wenzel, N.; Naylor, M.; Vogel, A.; Crowder, M.; Makaroff, C.; Meyer-Klaucke, W. Flexible metal binding of the metallo-beta-lactamase domain: Glyoxalase II incorporates iron, manganese, and zinc in vivo. Biochemistry 2003, 42, 11777–11786.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
ScholarVision Creations
Feedback