Methylglyoxal Pathway
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The methylglyoxal pathway is an offshoot of
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The Thermodynamic free energy, free energy released in this process is used to form ...
found in some
prokaryote A prokaryote (; less commonly spelled procaryote) is a unicellular organism, single-celled organism whose cell (biology), cell lacks a cell nucleus, nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Ancient Gree ...
s, which converts
glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
into
methylglyoxal 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 ...
and then into
pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic ...
. However unlike glycolysis the methylglyoxal pathway does not produce
adenosine triphosphate Adenosine triphosphate (ATP) is a nucleoside triphosphate that provides energy to drive and support many processes in living cell (biology), cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known ...
, ATP. The pathway is named after the substrate methylglyoxal which has three carbons and two carbonyl groups located on the 1st carbon and one on the 2nd carbon. Methylglyoxal is, however, a reactive
aldehyde In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...
that is very toxic to cells, it can inhibit growth in ''E. coli'' at milimolar concentrations. The excessive intake of glucose by a cell is the most important process for the activation of the methylglyoxal pathway.


The Methylglyoxal pathway

The methylglyoxal pathway is activated by the increased intercellular uptake of carbon containing molecules such as
glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
,
glucose-6-phosphate Glucose 6-phosphate (G6P, sometimes called the Robison ester) is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cells as the majority of glucose entering a cell will become phosphorylated in this wa ...
, lactate, or
glycerol Glycerol () is a simple triol compound. It is a colorless, odorless, sweet-tasting, viscous liquid. The glycerol backbone is found in lipids known as glycerides. It is also widely used as a sweetener in the food industry and as a humectant in pha ...
. Methylglyoxal is formed from
dihydroxyacetone phosphate Dihydroxyacetone phosphate (DHAP, also glycerone phosphate in older texts) is the anion with the formula HOCH2C(O)CH2OPO32-. This anion is involved in many metabolic pathways, including the Calvin cycle in plants and glycolysis.Nelson, D. L.; Co ...
(DHAP) by the enzyme
methylglyoxal synthase The enzyme methylglyoxal synthase () catalysis, catalyzes the chemical reaction :glycerone phosphate \rightleftharpoons 2-oxopropanalCommonly known as methylglyoxal + phosphate Attempts to observe Reversible reaction, reversibility of this react ...
, giving off a phosphate group. Methylglyoxal is then converted into two different products, either D-lactate, and L-lactate. Methylglyoxal reductase and
aldehyde dehydrogenase Aldehyde dehydrogenases () are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes (R–C(=O)) to carboxylic acids (R–C(=O)). The oxygen comes from a water molecule. To date, nineteen ALDH genes have ...
convert methylglyoxal into
lactaldehyde Lactaldehyde is an intermediate in the methylglyoxal metabolic pathway. Methylglyoxal is converted to D-lactaldehyde by glycerol dehydrogenase (gldA). Lactaldehyde is then oxidized to lactic acid by aldehyde dehydrogenase. Structure Lactalde ...
and, eventually, L-lactate. If methylglyoxal enters the glyoxylase pathway, it is converted into lactoylguatathione and eventually D-lactate. Both D-lactate, and L-lactate are then converted into
pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic ...
. The pyruvate that is created most often goes on to enter the
Krebs cycle The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of biochemical reactions that release the energy stored in nutrients through acetyl-CoA oxidation. The e ...

Weber
711–13).


Enzymes and regulation

The potentially hazardous effects of methylglyoxal require regulation of the reactions with this substrate. Synthesis of methylglyoxal is regulated by levels of DHAP and phosphate concentrations. High concentrations of DHAP encourage
methylglyoxal synthase The enzyme methylglyoxal synthase () catalysis, catalyzes the chemical reaction :glycerone phosphate \rightleftharpoons 2-oxopropanalCommonly known as methylglyoxal + phosphate Attempts to observe Reversible reaction, reversibility of this react ...
to produce methylglyoxal, while high phosphate concentrations inhibit the enzyme, and therefore the production of more methylglyoxal. The enzyme triose phosphate isomerase affects the levels of DHAP by converting
glyceraldehyde 3-phosphate Glyceraldehyde 3-phosphate, also known as triose phosphate or 3-phosphoglyceraldehyde and abbreviated as G3P, GA3P, GADP, GAP, TP, GALP or PGAL, is a metabolite that occurs as an intermediate in several central pathways of all organisms.Nelson, D ...
(GAP) into DHAP. The usual pathway converting GAP to pyruvate starts with the enzyme
glyceraldehyde 3-phosphate dehydrogenase Glyceraldehyde 3-phosphate dehydrogenase (abbreviated GAPDH) () is an enzyme of about 37kDa that catalyzes the sixth step of glycolysis and thus serves to break down glucose for energy and carbon molecules. In addition to this long establis ...

Weber
711–13). Low phosphate levels inhibit GAP dehydrogenase; GAP is instead converted into DHAP by
triosephosphate isomerase Triose-phosphate isomerase (TPI or TIM) is an enzyme () that catalyzes the reversible interconversion of the triose phosphate isomers dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate. TPI plays an important role in glycolysis and i ...
. Again, increased levels of DHAP activate methylglyoxal synthase and methylglyoxal production
Weber
711–13).


The oscillation of Methylglyoxal concentration in feast concentrations

Jan Weber, Anke Kayser, and Ursula Rinas, performed an experiment to test what happened to the methylglyoxal pathway when ''E. coli'' was in the presence of a constantly high concentration of glucose. The concentration of methylglyoxal increased until it reached 20 μmol. Methylglyoxal concentration then began to decrease, once it reached this level. The decrease in the concentration of methylglyoxal was connected to the drop in respiratory activity. When respiration activity increased the concentration of methylglyoxal increased again, until it reached the 20 μmol concentration
Weber
714–15).


Why does the Methylglyoxal pathway exist?

This pathway does not produce any ATP, this pathway does not replace glycolysis, it runs simultaneously to glycolysis and is only initiated with an increased concentration of sugar phosphates. One believed purpose of the methylglyoxal pathway is to help release the stress of elevated sugar phosphate concentration. Also when methylglyoxal is formed from DHAP, an inorganic phosphate is given off which can be used to replenish a low concentration of needed inorganic phosphate. The methylglyoxal pathway is a rather dangerous tactic, both because less energy is produced and a toxic compound, methylglyoxal is formed.
Weber
715).


References

{{Reflist Weber, Jan, Anke Kayser, and Ursula Rinas. Metabolic Flux Analysis of Escherichia Coli In. Vers. 151: 707-716. 6 Dec. 2004. Microbiology. 10 Apr. 2007 . Saadat, D., Harrison, D.H.T. "Methylglyoxal Synthase From ''Escherichia Coli''." RCSB Protein Data Base. 24 Apr. 2007. RCSB Protein Data Base. 25 Apr. 2007 . "Methylglyoxal Synthase From Escherichia Coli." RCSB Protein Data Base. 24 Apr. 2007. RCSB Protein Data Base. 25 Apr. 2007 . Yun, M., C.-G. Park, J.-Y Kim, and H.-W. Park. "Structural Anayysis of Glyeraldehyde 3-Phosphate Dehydrogenase from ''Escherichia coli: Direct Evidence for Substrate Binding and Cofactor-Induced Confromational Changes.'' RCSB Protein Data Base. 24 Apr. 2007. RCSB Protein Data Base. 30 Apr. 2007 . Cellular respiration