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Glyoxalase system
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<h2 id="overview-of-glyoxalase-pathway">Overview of Glyoxalase Pathway</h2> <p>The glyoxalase system includes g<a href="/facts/Lactoylglutathione_lyase/De5smz6Q">lyoxalase I</a> (GLO1), <a href="/facts/Hydroxyacylglutathione_hydrolase/fm6WYVkS">glyoxalase II</a> (GLO2), and reduced <a href="/facts/Glutathione/5bSxjusL">glutathione</a> (GSH). In bacteria, there is an additional enzyme known as glyoxalase III (GLO3), that can function in the absence of GSH. GLO3 has not been found in humans yet.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a><a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> The system pathway begins with methylglyoxal (MG), which is produced from non-enzymatic reactions with DHAP or G3P produced in glycolysis. Methylglyoxal is then converted into S-d-lactoylglutathione by enzyme GLO1 with a catalytic amount of GSH, of which is hydrolyzed into non-toxic D-lactate via GLO2, with liberation of GSH that can be consumed by GLO1 with a new molecule of MG.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a><a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> D-lactate ultimately goes on to be metabolized into <a href="/facts/Pyruvic_acid/qJTgl4J9">pyruvate</a>.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p> <h2 id="regulation">Regulation</h2> <p>Several small molecule inducers that can activate the glyoxalase pathway by either by promoting GLO1 activity to increase conversion of MG into D-Lactate (GLO1 activators), or by directly reducing MG levels or levels of MG substrate (MG scavengers). GLO1 activators include the synthetic drug <a href="/facts/Candesartan/ogdHFCJG">candesartan</a> or natural compounds <a href="/facts/Resveratrol/5sF3fvl7">resveratrol</a>, <a href="/facts/Fisetin/2P31nfTU">fisetin</a>, the binary combination of trans-resveratrol and <a href="/facts/Hesperetin/Evv28WfB">hesperetin</a> (tRES-HESP), <a href="/facts/Mangiferin/qGS9QLsp">mangiferin</a>, <a href="/facts/Allyl_isothiocyanate/5b0SaJHF">allyl isothiocyanate</a>, <a href="/facts/Phenethyl_isothiocyanate/m8yhuhDY">phenethyl isothiocyanate</a>, <a href="/facts/Sulforaphane/8b0gAE7y">sulforaphane</a>, and <a href="/facts/Bardoxolone_methyl/78a3lk4V">bardoxolone methyl</a>, and MG scavengers including <a href="/facts/Aminoguanidine/xRuAt4KG">aminoguanidine</a>, <a href="/facts/Alagebrium/AbrcPAYv">alagebrium</a>, and <a href="/facts/Benfotiamine/tRb2xyC4">benfotiamine</a>. There is also the small molecule <a href="/facts/Pyridoxamine/ntHlzLwv">pyridoxamine</a>, which acts as both a GLO1 activator and MG scavenger.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> </p><p>Many inhibitors of GLO1 have been discovered since GLO1 activity tends to be promoted in cancer cells, thus GLO1 serves as a potential therapeutic target for anti-cancer drug treatment and has been the focus of many research studies regarding its regulation in tumor cells.<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p> <h2 id="medical-applicationspharmacology">Medical Applications/Pharmacology</h2> <p><a href="/facts/Hyperglycemia/HM8eNqfX">Hyperglycemia</a>, a side effect caused by diabetes, combines with <a href="/facts/Oxidative_stress/HX7dfUUb">oxidative stress</a> to create <a href="/facts/Advanced_glycation_end-product/Xv9BaHTf">advanced glycation end-products</a> (AGEs) that can lead to <a href="/facts/Diabetic_retinopathy/qjtejArl">diabetic retinopathy</a> (DR), age related macular degeneration (AMD) and cataracts.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a><a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> </p><p>Enhancing the glyoxalase system has been shown to delay accumulation of AGEs and associated retinal damage in animals that consume higher glycemic index diets. This was corroborated upon over-expression of GLO1, which in <i>C. elegans</i> reduced basal MG concentration, prevented mitochondrial protein modification and enhanced lifespan. Similarly, in mice, GLO1 over-expression reduced baseline MG concentrations in the brain. In diabetic mice, it prevented diabetes-induced increases in MG modification of glomerular proteins, reduced oxidative stress, and prevented development if diabetic kidney pathology, despite unchanged levels of hyperglycemia.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> Western diets, typically high in glycemic index, exacerbate AGE accumulation and amplify aging-related damage. Enhancing the glyoxalase system may offer a promising therapeutic strategy to prevent the onset and progression of AGEs-related diseases.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a><a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> </p><p>Oxidative stress can lead to worsening neurological diseases such as <a href="/facts/Alzheimer%2527s_disease/w7Ad6tdg">Alzheimer's</a>, <a href="/facts/Parkinson%2527s_disease/xpekKj6x">Parkinson's</a>, and <a href="/facts/Autism_spectrum/bzouRyMI">Autism Spectrum Disorder</a>. <a href="/facts/Flavonoid/J7FEAtLE">Flavonoids</a>, a type of antioxidant that combats oxidative stress in the body, has been found to help decrease the production of <a href="/facts/Reactive_oxygen_species/GpwSRugH">radical oxygen species</a> (ROS) mostly by preventing the formation of free radicals, additionally they partially enhance the transcription of glyoxalase.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> </p><p>Retinal pigmented epithelial cells (RPE) and retina have among the highest glyoxalase activities in the body, however, glyoxalase activity is depressed upon aging. This is consistent with observed increases in AGEs associated with aging.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a><a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> Enhancing the glyoxalase system has been shown to delay accumulation of AGEs and associated retinal damage in animals that consume higher glycemic index diets. </p> <h2 id="major-metabolic-pathways-converging-on-the-glyoxalase-cycle">Major metabolic pathways converging on the glyoxalase cycle</h2> <p>Although the glyoxalase pathway is the main metabolic system that reduces methylglyoxal levels in the cell, other enzymes have also been found to convert methylglyoxal into non-AGE producing species. Specifically, 99% of MG is processed by glyoxalase metabolism, while less than 1% is metabolized into <a href="/facts/Hydroxyacetone/xhb40AUx">hydroxyacetone</a> by <a href="/facts/Aldo-keto_reductase/gN6bBqGm">aldo-keto reductases</a> (AKRs) or into pyruvate by aldehyde dehydrogenases (ALDH).<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> Other reactions have been found to produce MG that also feeds into the glyoxalase pathway. These reactions include catabolism of <a href="/facts/Threonine/7zffFQ6W">threonine</a> and <a href="/facts/Acetone/cVyJxKqw">acetone</a>, <a href="/facts/Lipid_peroxidation/NpvyVrEw">peroxidation</a> of <a href="/facts/Lipid/TdQR87HX">lipids</a>, <a href="/facts/Autoxidation/2mY5fjvj">autoxidation</a> of <a href="/facts/Glucose/oUSkoLCD">glucose</a>, and degradation of glycated proteins.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Antioxidant/4TG4MQ83">Antioxidant</a> – Compound that inhibits the oxidation of other molecules</li> <li><a href="/facts/Advanced_glycation_endproduct/Xv9BaHTf">Advanced glycation endproduct</a> – Proteins or lipids chemically altered by sugar exposurePages displaying short descriptions of redirect targets</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Vander Jagt DL (1989). "15. The glyoxalase system". In Dolphin D, Poulson R, Avramovic O (eds.). Glutathione: Chemical, Biochemical and Medical Aspects. Part A. Coenzymes and cofactors. Wiley. pp. 597–641. ISBN 9780471097846. OCLC 18222786. <a href="9780471097846" target="_blank">9780471097846</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Farrera, Dominique; Galligan, James (September 2022). "The Human Glyoxalase Gene Family in Health and Disease". Chemical Research in Toxicology. 35 (10): 1766–1776. doi:10.1021/acs.chemrestox.2c00182. PMC 10013676. PMID 36048613. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10013676" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10013676</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Farrera, Dominique; Galligan, James (September 2022). "The Human Glyoxalase Gene Family in Health and Disease". Chemical Research in Toxicology. 35 (10): 1766–1776. doi:10.1021/acs.chemrestox.2c00182. PMC 10013676. PMID 36048613. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10013676" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10013676</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Dixon DP, Cummins L, Cole DJ, Edwards R (June 1998). "Glutathione-mediated detoxification systems in plants". Current Opinion in Plant Biology. 1 (3): 258–66. Bibcode:1998COPB....1..258D. doi:10.1016/S1369-5266(98)80114-3. PMID 10066594. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Inoue Y, Kimura A (1995). "Methylglyoxal and regulation of its metabolism in microorganisms". Advances in Microbial Physiology. 37: 177–227. doi:10.1016/S0065-2911(08)60146-0. ISBN 9780120277377. 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"Glyoxalase II: molecular characteristics, kinetics and mechanism". Biochemical Society Transactions. 21 (2): 522–7. doi:10.1042/bst0210522. PMID 8359524. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Dixon DP, Cummins L, Cole DJ, Edwards R (June 1998). "Glutathione-mediated detoxification systems in plants". Current Opinion in Plant Biology. 1 (3): 258–66. Bibcode:1998COPB....1..258D. doi:10.1016/S1369-5266(98)80114-3. PMID 10066594. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Farrera, Dominique; Galligan, James (September 2022). "The Human Glyoxalase Gene Family in Health and Disease". Chemical Research in Toxicology. 35 (10): 1766–1776. doi:10.1021/acs.chemrestox.2c00182. PMC 10013676. PMID 36048613. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10013676" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10013676</a> <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>He Y, Zhou C, Huang M, Tang C, Liu X, Yue Y, et al. (November 2020). "Glyoxalase system: A systematic review of its biological activity, related-diseases, screening methods and small molecule regulators". Biomedicine & Pharmacotherapy. 131: 110663. doi:10.1016/j.biopha.2020.110663. PMID 32858501. <a href="https://doi.org/10.1016%2Fj.biopha.2020.110663" target="_blank">https://doi.org/10.1016%2Fj.biopha.2020.110663</a> <a href="#fnref:11" class="footnote-back-ref">↩</a></p></li> <li id="fn:12"><p>Farrera, Dominique; Galligan, James (September 2022). "The Human Glyoxalase Gene Family in Health and Disease". Chemical Research in Toxicology. 35 (10): 1766–1776. doi:10.1021/acs.chemrestox.2c00182. PMC 10013676. 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"Glyoxalase system: A systematic review of its biological activity, related-diseases, screening methods and small molecule regulators". Biomedicine & Pharmacotherapy. 131: 110663. doi:10.1016/j.biopha.2020.110663. PMID 32858501. <a href="https://doi.org/10.1016%2Fj.biopha.2020.110663" target="_blank">https://doi.org/10.1016%2Fj.biopha.2020.110663</a> <a href="#fnref:14" class="footnote-back-ref">↩</a></p></li> <li id="fn:15"><p>He Y, Zhou C, Huang M, Tang C, Liu X, Yue Y, et al. (November 2020). "Glyoxalase system: A systematic review of its biological activity, related-diseases, screening methods and small molecule regulators". Biomedicine & Pharmacotherapy. 131: 110663. doi:10.1016/j.biopha.2020.110663. PMID 32858501. <a href="https://doi.org/10.1016%2Fj.biopha.2020.110663" target="_blank">https://doi.org/10.1016%2Fj.biopha.2020.110663</a> <a href="#fnref:15" class="footnote-back-ref">↩</a></p></li> <li id="fn:16"><p>He Y, Zhou C, Huang M, Tang C, Liu X, Yue Y, et al. 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PMID 38521386. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699537" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699537</a> <a href="#fnref:25" class="footnote-back-ref">↩</a></p></li> <li id="fn:26"><p>He Y, Zhou C, Huang M, Tang C, Liu X, Yue Y, et al. (November 2020). "Glyoxalase system: A systematic review of its biological activity, related-diseases, screening methods and small molecule regulators". Biomedicine & Pharmacotherapy. 131: 110663. doi:10.1016/j.biopha.2020.110663. PMID 32858501. <a href="https://doi.org/10.1016%2Fj.biopha.2020.110663" target="_blank">https://doi.org/10.1016%2Fj.biopha.2020.110663</a> <a href="#fnref:26" class="footnote-back-ref">↩</a></p></li> <li id="fn:27"><p>He Y, Zhou C, Huang M, Tang C, Liu X, Yue Y, et al. (November 2020). "Glyoxalase system: A systematic review of its biological activity, related-diseases, screening methods and small molecule regulators". Biomedicine & Pharmacotherapy. 131: 110663. doi:10.1016/j.biopha.2020.110663. PMID 32858501. <a href="https://doi.org/10.1016%2Fj.biopha.2020.110663" target="_blank">https://doi.org/10.1016%2Fj.biopha.2020.110663</a> <a href="#fnref:27" class="footnote-back-ref">↩</a></p></li> </ol>