# GLO1

## Overview
The GLO1 gene encodes the enzyme glyoxalase I, a zinc-dependent metalloenzyme that plays a pivotal role in cellular detoxification processes. Glyoxalase I is part of the glyoxalase system, which is crucial for the conversion of methylglyoxal, a cytotoxic byproduct of glycolysis, into less harmful compounds. This enzyme is categorized as a dimeric protein and belongs to the βαβββ structural superfamily, characterized by its beta-alpha-beta fold (Honek2015Glyoxalase; Thornalley2003Glyoxalase). The GLO1 gene is ubiquitously expressed across human tissues and exhibits polymorphism, resulting in different phenotypes that may influence its enzymatic activity (Gale2004The; Thornalley2003Glyoxalase). Glyoxalase I's activity is essential for maintaining cellular homeostasis by preventing the accumulation of advanced glycation end-products, which are associated with various pathological conditions, including cancer, cardiovascular diseases, and neurological disorders (Wortmann2014Glyoxalase; Rabbani2010Methylglyoxal).

## Structure
The human glyoxalase I (GLO1) protein is a dimeric Zn2+ metalloenzyme with a molecular mass of 42 kDa. It consists of 184 amino acids, with the N-terminal methionine removed during post-translational processing, and the N-terminal alanine is modified by an unknown process (Thornalley2003Glyoxalase). The enzyme's active site is located at the dimer interface, where it coordinates an essential zinc ion through residues Gln-33A, Glu-99A, His-126B, Glu-172B, and two water molecules in an octahedral geometry (Thornalley2003Glyoxalase). 

GLO1 belongs to the βαβββ structural superfamily, which is characterized by a beta-alpha-beta fold, a common motif in proteins with diverse biological activities (Honek2015Glyoxalase). The enzyme's tertiary structure is defined by two structurally equivalent domains in each monomer, contributing to its dimeric quaternary structure (Thornalley2003Glyoxalase). 

The GLO1 gene exhibits polymorphism, resulting in three phenotypes (GLO 1-1, GLO 1-2, and GLO 2-2) due to a diallelic gene, and it is expressed ubiquitously across human tissues (Gale2004The; Thornalley2003Glyoxalase). The protein has at least four potential phosphorylation sites, which may influence its activity and stability (Thornalley2003Glyoxalase).

## Function
Glyoxalase I (GLO1) is a crucial enzyme in the glyoxalase system, primarily active in the cytosol of most human cells. It plays a significant role in detoxifying methylglyoxal (MG), a reactive byproduct of glycolysis, by catalyzing its conversion to S-D-lactoylglutathione using glutathione (GSH) as a cofactor. This detoxification process is essential for preventing the accumulation of MG, which can lead to the formation of advanced glycation end-products (AGEs) and subsequent cellular dysfunction (Wortmann2014Glyoxalase; Rabbani2010Methylglyoxal).

GLO1 activity is directly proportional to the cellular concentration of GSH, and its function is vital in maintaining cellular homeostasis by suppressing dicarbonyl-mediated glycation reactions. This enzymatic activity helps prevent apoptosis and cytotoxicity associated with MG accumulation, thereby protecting cells from oxidative stress and inflammation (Stratmann2016Glyoxalase; Rabbani2010Methylglyoxal).

In healthy human cells, GLO1 contributes to vascular health by regulating endothelial function and reducing the formation of AGEs, which are linked to various cardiovascular diseases. Its activity is crucial in preventing endothelial dysfunction and inflammation, which are associated with increased MG levels and vascular damage (Wortmann2014Glyoxalase; Stratmann2016Glyoxalase).

## Clinical Significance
Alterations in the expression of the GLO1 gene have been implicated in various diseases and conditions. In cancer, GLO1 is frequently amplified and overexpressed, contributing to tumor cell survival, proliferation, and multidrug resistance. This overexpression is particularly noted in breast, sarcomas, non-small cell lung, bladder, renal, and gastric cancers, where it supports tumor growth by enhancing methylglyoxal detoxification, a byproduct of glycolysis (Santarius2010GLO1—A; Thornalley2011Glyoxalase). Inhibiting GLO1 can increase sensitivity to chemotherapy, suggesting its potential as a therapeutic target (Thornalley2011Glyoxalase).

In neurological disorders, GLO1 polymorphisms are associated with increased risk of schizophrenia, with specific mutations linked to reduced promoter activity and expression levels. This reduction contributes to carbonyl stress and the accumulation of advanced glycation end-products, which are implicated in the disease's etiology (Yin2021Glyoxalase). In autism, the C332 (Ala111) allele of GLO1 is associated with increased vulnerability, potentially due to reduced glyoxalase activity and increased AGE levels in the brain (Gabriele2014The).

In prostate cancer, the GLO1 2419C.A polymorphism is linked to oxidative stress and disease progression, highlighting its role in cancer pathogenesis (Antognelli2013Glyoxalase).

## Interactions
Glyoxalase I (GLO1) is a key enzyme in the glyoxalase system, primarily involved in the detoxification of methylglyoxal. It functions in conjunction with glyoxalase II (GLO2) and reduced glutathione (GSH) to convert methylglyoxal into non-toxic D-lactate. GLO1 is a metal-dependent enzyme that contains zinc ions and forms a dimeric protein structure in humans (He2020Glyoxalase).

GLO1 interacts with various proteins and regulatory elements. Its promoter region includes binding sites for transcription factors such as AP-2α, E2F4, NF-κB, AP-1, ARE, MRE, and IRE, which regulate its expression. The transcription factor Nrf2 is particularly significant, as it binds to an antioxidant response element in the GLO1 gene, enhancing its expression and providing a defense against oxidative stress and dicarbonyl glycation (Xue2012Transcriptional).

GLO1 can undergo post-translational modifications, including phosphorylation by protein kinase A (PKA), which can influence its activity and lead to cellular responses such as caspase-dependent cell death and reactive oxygen species production (He2020Glyoxalase). These interactions highlight the enzyme's role in cellular stress responses and its potential as a therapeutic target in various diseases.


## References


[1. (He2020Glyoxalase) Yujiao He, Chunyan Zhou, Maolin Huang, Chunyan Tang, Xiao Liu, Yan Yue, Qingchun Diao, Zhebin Zheng, and Deming Liu. Glyoxalase system: a systematic review of its biological activity, related-diseases, screening methods and small molecule regulators. Biomedicine & Pharmacotherapy, 131:110663, November 2020. URL: http://dx.doi.org/10.1016/j.biopha.2020.110663, doi:10.1016/j.biopha.2020.110663. This article has 85 citations.](https://doi.org/10.1016/j.biopha.2020.110663)

[2. (Gale2004The) Christopher P. Gale and Peter J. Grant. The characterisation and functional analysis of the human glyoxalase-1 gene using methods of bioinformatics. Gene, 340(2):251–260, October 2004. URL: http://dx.doi.org/10.1016/j.gene.2004.07.009, doi:10.1016/j.gene.2004.07.009. This article has 19 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.gene.2004.07.009)

[3. (Honek2015Glyoxalase) John F. Honek. Glyoxalase biochemistry. Biomolecular Concepts, 6(5–6):401–414, December 2015. URL: http://dx.doi.org/10.1515/bmc-2015-0025, doi:10.1515/bmc-2015-0025. This article has 31 citations and is from a peer-reviewed journal.](https://doi.org/10.1515/bmc-2015-0025)

[4. (Santarius2010GLO1—A) Thomas Santarius, Graham R. Bignell, Chris D. Greenman, Sara Widaa, Lina Chen, Claire L. Mahoney, Adam Butler, Sarah Edkins, Sahar Waris, Paul J. Thornalley, P. Andrew Futreal, and Michael R. Stratton. Glo1—a novel amplified gene in human cancer. Genes, Chromosomes and Cancer, 49(8):711–725, May 2010. URL: http://dx.doi.org/10.1002/gcc.20784, doi:10.1002/gcc.20784. This article has 93 citations.](https://doi.org/10.1002/gcc.20784)

[5. (Thornalley2011Glyoxalase) Paul J. Thornalley and Naila Rabbani. Glyoxalase in tumourigenesis and multidrug resistance. Seminars in Cell & Developmental Biology, 22(3):318–325, May 2011. URL: http://dx.doi.org/10.1016/j.semcdb.2011.02.006, doi:10.1016/j.semcdb.2011.02.006. This article has 191 citations.](https://doi.org/10.1016/j.semcdb.2011.02.006)

[6. (Wortmann2014Glyoxalase) Markus Wortmann, Andreas S. Peters, Maani Hakimi, Dittmar Böckler, and Susanne Dihlmann. Glyoxalase i (glo1) and its metabolites in vascular disease. Biochemical Society Transactions, 42(2):528–533, March 2014. URL: http://dx.doi.org/10.1042/bst20140003, doi:10.1042/bst20140003. This article has 12 citations and is from a peer-reviewed journal.](https://doi.org/10.1042/bst20140003)

[7. (Gabriele2014The) Stefano Gabriele, Federica Lombardi, Roberto Sacco, Valerio Napolioni, Laura Altieri, Maria Cristina Tirindelli, Chiara Gregorj, Carmela Bravaccio, Francis Rousseau, and Antonio M. Persico. The glo1 c332 (ala111) allele confers autism vulnerability: family-based genetic association and functional correlates. Journal of Psychiatric Research, 59:108–116, December 2014. URL: http://dx.doi.org/10.1016/j.jpsychires.2014.07.021, doi:10.1016/j.jpsychires.2014.07.021. This article has 19 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.jpsychires.2014.07.021)

[8. (Xue2012Transcriptional) Mingzhan Xue, Naila Rabbani, Hiroshi Momiji, Precious Imbasi, M. Maqsud Anwar, Neil Kitteringham, B. Kevin Park, Tomokazu Souma, Takashi Moriguchi, Masayuki Yamamoto, and Paul J. Thornalley. Transcriptional control of glyoxalase 1 by nrf2 provides a stress-responsive defence against dicarbonyl glycation. Biochemical Journal, 443(1):213–222, March 2012. URL: http://dx.doi.org/10.1042/bj20111648, doi:10.1042/bj20111648. This article has 243 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1042/bj20111648)

[9. (Yin2021Glyoxalase) Jingwen Yin, Guoda Ma, Shucun Luo, Xudong Luo, Bin He, Chunmei Liang, Xiang Zuo, Xusan Xu, Qing Chen, Susu Xiong, Zhi Tan, Jiawu Fu, Dong Lv, Zhun Dai, Xia Wen, Dongjian Zhu, Xiaoqing Ye, Zhixiong Lin, Juda Lin, You Li, Wubiao Chen, Zebin Luo, Keshen Li, and Yajun Wang. Glyoxalase 1 confers susceptibility to schizophrenia: from genetic variants to phenotypes of neural function. Frontiers in Molecular Neuroscience, November 2021. URL: http://dx.doi.org/10.3389/fnmol.2021.739526, doi:10.3389/fnmol.2021.739526. This article has 9 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fnmol.2021.739526)

[10. (Thornalley2003Glyoxalase) P.J. Thornalley. Glyoxalase i – structure, function and a critical role in the enzymatic defence against glycation. Biochemical Society Transactions, 31(6):1343–1348, December 2003. URL: http://dx.doi.org/10.1042/bst0311343, doi:10.1042/bst0311343. This article has 771 citations and is from a peer-reviewed journal.](https://doi.org/10.1042/bst0311343)

[11. (Rabbani2010Methylglyoxal) Naila Rabbani and Paul J. Thornalley. Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome. Amino Acids, 42(4):1133–1142, October 2010. URL: http://dx.doi.org/10.1007/s00726-010-0783-0, doi:10.1007/s00726-010-0783-0. This article has 320 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s00726-010-0783-0)

[12. (Antognelli2013Glyoxalase) Cinzia Antognelli, Letizia Mezzasoma, Ettore Mearini, and Vincenzo Nicola Talesa. Glyoxalase 1−419c>a variant is associated with oxidative stress: implications in prostate cancer progression. PLoS ONE, 8(9):e74014, September 2013. URL: http://dx.doi.org/10.1371/journal.pone.0074014, doi:10.1371/journal.pone.0074014. This article has 33 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0074014)

[13. (Stratmann2016Glyoxalase) Bernd Stratmann, Britta Engelbrecht, Britta C. Espelage, Nadine Klusmeier, Janina Tiemann, Thomas Gawlowski, Yvonne Mattern, Martin Eisenacher, Helmut E. Meyer, Naila Rabbani, Paul J. Thornalley, Diethelm Tschoepe, Gereon Poschmann, and Kai Stühler. Glyoxalase 1-knockdown in human aortic endothelial cells – effect on the proteome and endothelial function estimates. Scientific Reports, November 2016. URL: http://dx.doi.org/10.1038/srep37737, doi:10.1038/srep37737. This article has 37 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/srep37737)