User:Iva Vucic/Glyoxalase system

New Sections to Add (Notes/Rough Outline)

Overview of Glyoxalase Pathway

 * List of enzymes involved
 * glyoxalase 1 (GLO1), glyoxalase 2 (GLO2), and reduced glutathione (GSH) (add “glutathione” to abbreviation “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.
 * GLO2 acts to hydrolyze
 * GSH works as a catalytic component that is used up by GLO1
 * Other potential/example enzymes
 * They affect: methylglyoxal (MG) and metabolites to make them not harmful to the body
 * MG is made by through the methylglyoxal pathway and as a result of glycolysis
 * Too much MG can lead to the degradation of proteins/DNA and cause health problems.
 * Another pathway to remove MG is

Pathway

 * 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. D-lactate ultimately goes on to be metabolized into pyruvate.
 * A little more chemistry behind the pathway: To begin the pathway, a cactalytic amount of GSH spontaneously reacts with the aldehyde component of An alpha-dicarbonyl, such as MG, to form a hemithioacetal. In the next step, the formed hemithioacetal undergoes a catalyzed reaction with GLO1 to be formed into S-D-lactoylglutathione. Then, the formed S-D-lactoglutathione undergoes a reaction catalyzed by GLO2 to be transformed into D-lactate, during which GSH is also regenerated to restart the pathway.

Medical Applications/Pharmacology

 * Research on pharmacological/medical applications to this pathway
 * Diabetes, cardiovascular disease, neurodegenerative disorders, and cancer
 * Hyperglycemia, a side effect caused by diabetes, combines with oxidative stress to create advanced glycation end-products (AGEs) that, when combined with oxidative stress, can lead to diabetic retinopathy (RD) and cause symptoms such as blindness in adults.
 * 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.
 * Oxidative stress can lead to worsening neurological diseases such as Alzheimer’s, Parkinson’s, Aging, 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.

Regulation

 * Any inhibitors, promoters, feedback loops, etc?
 * Mentioned earlier: Flavonoids can promote the glyoxalase pathway by increasing intracellular levels of GSH.
 * There are several small molecule inducers that can induce the glyoxalase pathway by either 1) promoting GLO1 function to increase conversion of MG into D-Lactate, which are called GLO1 actvators, or 2) by directly reducing MG levels or levels of MG substrate, which are called MG scavengers. GLO1 activators include the synthetic drug candesaryan or natural compounds resveratrol, fisetin, the binary combination of trans-resveratrol and hesperetin (tRES-HESP), mangiferin, allyl isothiocyanate, phenethyl iosthiocyanate, sulforaphane, and bardoxolone methyl, and MG scavengers include aminguanidine, alagebrium, and benfotiamine. There is also the small molecule pyridoxamine, which acts as both a GLO1 activator and MG scavenger.
 * Many inhibitors have of GLO1 have been discovered since GLO1 activity tends to be promoted in cancer cells, thus GLO1 serves as a potential therapuetic target for anti-cancer drug treatment and has been the focus of many research studies regarding its regulation in tumor cells. (Continue this section!).
 * A lot is known about the regulation of GLO1, but not as much on GLO2
 * GLO1 can be induced by nuclear factor erythroid 2-related factor 2 (Nrf2)
 * Specific Research source:
 * Rabbani, Naila; Xue, Mingzhan; Thornalley, Paul J. (March 20, 2014). "Activity, regulation, copy number and function in the glyoxalase system". Biochemical Society Transactions. 42 (2): 419–424. doi:10.1042/BST20140008. ISSN 0300-5127.

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 aldoketoreductases (AKRs) or into pyruvate by aldehyde dehydrogenases (ALDH).
 * 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.

Differences in cycles between organisms

 * Subsections: Eukaryotes, prokaryotes, etc.