Glyoxalase system

Last updated

The glyoxalase system is a set of enzymes that carry out the detoxification of methylglyoxal and the other reactive aldehydes that are produced as a normal part of metabolism. [1] [2] This system has been studied in both bacteria and eukaryotes. [2] [3] [4] This detoxification is accomplished by the sequential action of two thiol-dependent enzymes; firstly glyoxalase І, which catalyzes the isomerization of the spontaneously formed hemithioacetal adduct between glutathione and 2-oxoaldehydes (such as methylglyoxal) into S-2-hydroxyacylglutathione. [5] [6] Secondly, glyoxalase ІІ hydrolyses these thiolesters and in the case of methylglyoxal catabolism, produces D-lactate and GSH from S-D-lactoyl-glutathione. [7]

Contents

This system shows many of the typical features of the enzymes that dispose of endogenous toxins. Firstly, in contrast to the amazing substrate range of many of the enzymes involved in xenobiotic metabolism, it shows a narrow substrate specificity. [3] Secondly, intracellular thiols are required as part of its enzymatic mechanism and thirdly, the system acts to recycle reactive metabolites back to a form which may be useful to cellular metabolism.

Overview of Glyoxalase Pathway

Glyoxalase I (GLO1), glyoxalase II (GLO2), and reduced glutathione (GSH). In bacteria, there is an additional enzyme that functions if there is no GSH, it is called the third glyoxalase protein, glyoxalase 3 (GLO3). GLO3 has not been found in humans yet. [2] [8]

The 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, during which GSH is reformed to be consumed again by GLO1 with a new molecule of MG. [2] D-lactate ultimately goes on to be metabolized into pyruvate. [8]

Regulation

There are several small molecule inducers that can induce the glyoxalase pathway by either promoting GLO1 function to increase conversion of MG into D-Lactate, which are called GLO1 activators, or by directly reducing MG levels or levels of MG substrate, which are called MG scavengers. GLO1 activators include the synthetic drug candesartan or natural compounds resveratrol, fisetin, the binary combination of trans-resveratrol and hesperetin (tRES-HESP), mangiferin, allyl isothiocyanate, phenethyl isothiocyanate, sulforaphane, and bardoxolone methyl, and MG scavengers include aminoguanidine, alagebrium, and benfotiamine. There is also the small molecule pyridoxamine, which acts as both a GLO1 activator and MG scavenger. [8]

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. [8]

Medical Applications/Pharmacology

Hyperglycemia, a side effect caused by diabetes, combines with oxidative stress to create advanced glycation end-products (AGEs) that can lead to diabetic retinopathy (RD) and cause symptoms such as blindness in adults. [9]

The manipulation of the glyoxalase system in mice retina has shown there is a potential for targeting the glyoxalase system to use as a therapeutic treatment for RD by lowering the production of AGEs. [9]

Oxidative stress can lead to worsening neurological diseases such as Alzheimer's, Parkinson's, and Autism Spectrum Disorder. Flavonoids, a type of antioxidant that combats oxidative stress in the body, has been found to help decrease the production of radical oxygen species (ROS) mostly by preventing the formation of free radicals but also partially by promoting the glyoxalase pathway via increasing transcription of GSH and GSH constituent subunits to increase intracellular levels of GSH. [10]

Major metabolic pathways converging on the glyoxalase cycle

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 hydroxyacetone by aldo-keto reductases (AKRs) or into pyruvate by aldehyde dehydrogenases (ALDH). [8] Other reactions have been found to produce MG that also feeds into the glyoxalase pathway. These reactions include catabolism of threonine and acetone, peroxidation of lipids, autoxidation of glucose, and degradation of glycated proteins. [8]

See also

Related Research Articles

Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants are frequently added to industrial products, such as polymers, fuels, and lubricants, to extend their usable lifetimes. Food are also treated with antioxidants to forestall spoilage, in particular the rancidification of oils and fats. In cells, antioxidants such as glutathione, mycothiol or bacillithiol, and enzyme systems like superoxide dismutase, can prevent damage from oxidative stress.

<span class="mw-page-title-main">Glutathione</span> Ubiquitous antioxidant compound in living organisms

Glutathione is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, peroxides, lipid peroxides, and heavy metals. It is a tripeptide with a gamma peptide linkage between the carboxyl group of the glutamate side chain and cysteine. The carboxyl group of the cysteine residue is attached by normal peptide linkage to glycine.

Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as any drug or poison. These pathways are a form of biotransformation present in all major groups of organisms and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds. The study of drug metabolism is called pharmacokinetics.

Glycation is the covalent attachment of a sugar to a protein, lipid or nucleic acid molecule. Typical sugars that participate in glycation are glucose, fructose, and their derivatives. Glycation is the non-enzymatic process responsible for many complications in diabetes mellitus and is implicated in some diseases and in aging. Glycation end products are believed to play a causative role in the vascular complications of diabetes mellitus.

Advanced glycation end products (AGEs) are proteins or lipids that become glycated as a result of exposure to sugars. They are a bio-marker implicated in aging and the development, or worsening, of many degenerative diseases, such as diabetes, atherosclerosis, chronic kidney disease, and Alzheimer's disease.

<span class="mw-page-title-main">Glutathione disulfide</span> Chemical compound

Glutathione disulfide (GSSG) is a disulfide derived from two glutathione molecules.

<span class="mw-page-title-main">Methylglyoxal</span> Chemical compound

Methylglyoxal (MGO) is the organic compound with the formula CH3C(O)CHO. It is a reduced derivative of pyruvic acid. It is a reactive compound that is implicated in the biology of diabetes. Methylglyoxal is produced industrially by degradation of carbohydrates using overexpressed methylglyoxal synthase.

<span class="mw-page-title-main">Glutathione reductase</span> Enzyme

Glutathione reductase (GR) also known as glutathione-disulfide reductase (GSR) is an enzyme that in humans is encoded by the GSR gene. Glutathione reductase catalyzes the reduction of glutathione disulfide (GSSG) to the sulfhydryl form glutathione (GSH), which is a critical molecule in resisting oxidative stress and maintaining the reducing environment of the cell. Glutathione reductase functions as dimeric disulfide oxidoreductase and utilizes an FAD prosthetic group and NADPH to reduce one molar equivalent of GSSG to two molar equivalents of GSH:

The polyol pathway is a two-step process that converts glucose to fructose. In this pathway glucose is reduced to sorbitol, which is subsequently oxidized to fructose. It is also called the sorbitol-aldose reductase pathway.

<span class="mw-page-title-main">Sulfur assimilation</span> Incorporation of sulfur into living organisms

Sulfur assimilation is the process by which living organisms incorporate sulfur into their biological molecules. In plants, sulfate is absorbed by the roots and then be transported to the chloroplasts by the transipration stream where the sulfur are reduced to sulfide with the help of a series of enzymatic reactions. Furthermore, the reduced sulfur is incorporated into cysteine, an amino acid that is a precursor to many other sulfur-containing compounds. In animals, sulfur assimilation occurs primarily through the diet, as animals cannot produce sulfur-containing compounds directly. Sulfur is incorporated into amino acids such as cysteine and methionine, which are used to build proteins and other important molecules. Besides, With the rapid development of economy, the increase emission of sulfur results in environmental issues, such as acid rain and hydrogen sulfilde.

<span class="mw-page-title-main">Glutathione synthetase</span> Enzyme

Glutathione synthetase (GSS) is the second enzyme in the glutathione (GSH) biosynthesis pathway. It catalyses the condensation of gamma-glutamylcysteine and glycine, to form glutathione. Glutathione synthetase is also a potent antioxidant. It is found in many species including bacteria, yeast, mammals, and plants.

In enzymology, a D-lactate dehydrogenase (cytochrome) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Lactoylglutathione lyase</span> Protein-coding gene in the species Homo sapiens

The enzyme lactoylglutathione lyase (EC 4.4.1.5, also known as glyoxalase I) catalyzes the isomerization of hemithioacetal adducts, which are formed in a spontaneous reaction between a glutathionyl group and aldehydes such as methylglyoxal.

Glutamate–cysteine ligase (GCL) EC 6.3.2.2), previously known as γ-glutamylcysteine synthetase (GCS), is the first enzyme of the cellular glutathione (GSH) biosynthetic pathway that catalyzes the chemical reaction:

<span class="mw-page-title-main">GSTZ1</span> Protein-coding gene in the species Homo sapiens

Glutathione S-transferase Zeta 1 is an enzyme that in humans is encoded by the GSTZ1 gene on chromosome 14.

The ascorbate-glutathione cycle, sometimes Foyer-Halliwell-Asada pathway, is a metabolic pathway that detoxifies hydrogen peroxide (H2O2), a reactive oxygen species that is produced as a waste product in metabolism. The cycle involves the antioxidant metabolites: ascorbate, glutathione and NADPH and the enzymes linking these metabolites.

<span class="mw-page-title-main">Bacterial glutathione transferase</span>

Bacterial glutathione transferases are part of a superfamily of enzymes that play a crucial role in cellular detoxification. The primary role of GSTs is to catalyze the conjugation of glutathione (GSH) with the electrophilic centers of a wide variety of molecules. The most commonly known substrates of GSTs are xenobiotic synthetic chemicals. There are also classes of GSTs that utilize glutathione as a cofactor rather than a substrate. Often these GSTs are involved in reduction of reactive oxidative species toxic to the bacterium. Conjugation with glutathione receptors renders toxic substances more soluble, and therefore more readily exocytosed from the cell.

<span class="mw-page-title-main">3-Deoxyglucosone</span> Chemical compound

3-Deoxyglucosone (3DG) is a sugar that is notable because it is a marker for diabetes. 3DG reacts with protein to form advanced glycation end-products (AGEs), which contribute to diseases such as the vascular complications of diabetes, atherosclerosis, hypertension, Alzheimer's disease, inflammation, and aging.

D-lactate dehydratase (EC 4.2.1.130, glyoxylase III) is an enzyme with systematic name (R)-lactate hydro-lyase. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Argpyrimidine</span> Chemical compound

Argpyrimidine is an organic compound with the chemical formula C11H18N4O3. It is an advanced glycation end-product formed from arginine and methylglyoxal through the Maillard reaction. Argpyrimidine has been studied for its food chemistry purposes and its potential involvement in aging diseases and Diabetes Mellius.

References

  1. ↑ 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.
  2. 1 2 3 4 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.
  3. 1 2 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. doi:10.1016/S1369-5266(98)80114-3. PMID   10066594.
  4. ↑ 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. PMID   8540421.
  5. ↑ Thornalley PJ (December 2003). "Glyoxalase I--structure, function and a critical role in the enzymatic defence against glycation". Biochemical Society Transactions. 31 (Pt 6): 1343–8. doi:10.1042/BST0311343. PMID   14641060.
  6. ↑ Creighton DJ, Hamilton DS (March 2001). "Brief history of glyoxalase I and what we have learned about metal ion-dependent, enzyme-catalyzed isomerizations". Archives of Biochemistry and Biophysics. 387 (1): 1–10. doi:10.1006/abbi.2000.2253. PMID   11368170.
  7. ↑ Vander Jagt DL (May 1993). "Glyoxalase II: molecular characteristics, kinetics and mechanism". Biochemical Society Transactions. 21 (2): 522–7. doi:10.1042/bst0210522. PMID   8359524.
  8. 1 2 3 4 5 6 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.
  9. 1 2 Aragonès G, Rowan S, G Francisco S, Yang W, Weinberg J, Taylor A, Bejarano E (October 2020). "Glyoxalase System as a Therapeutic Target against Diabetic Retinopathy". Antioxidants. 9 (11): 1062. doi: 10.3390/antiox9111062 . PMC   7692619 . PMID   33143048.
  10. ↑ Frandsen JR, Narayanasamy P (April 2018). "Neuroprotection through flavonoid: Enhancement of the glyoxalase pathway". Redox Biology. 14: 465–473. doi:10.1016/j.redox.2017.10.015. PMC   5680520 . PMID   29080525.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.