Methylglyoxal pathway

Last updated

The methylglyoxal pathway is an offshoot of glycolysis found in some prokaryotes, which converts glucose into methylglyoxal and then into pyruvate. [1] However unlike glycolysis the methylglyoxal pathway does not produce adenosine triphosphate, 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 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. [2]

Contents

The Methylglyoxal pathway

The methylglyoxal pathway, (Based on Weber Figure 4, pg. 711) Methylglyoxal pathway picture.png
The methylglyoxal pathway, (Based on Weber Figure 4, pg. 711)

The methylglyoxal pathway is activated by the increased intercellular uptake of carbon containing molecules such as glucose, glucose-6-phosphate, lactate, or glycerol. Methylglyoxal is formed from dihydroxyacetone phosphate (DHAP) by the enzyme methylglyoxal synthase, giving off a phosphate group.

Methylglyoxal is then converted into two different products, either D-lactate, and L-lactate. Methylglyoxal reductase and aldehyde dehydrogenase convert methylglyoxal into lactaldehyde 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. The pyruvate that is created most often goes on to enter the Krebs cycle (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 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 (GAP) into DHAP. The usual pathway converting GAP to pyruvate starts with the enzyme glyceraldehyde 3-phosphate dehydrogenase (Weber 711–13). Low phosphate levels inhibit GAP dehydrogenase; GAP is instead converted into DHAP by triosephosphate isomerase. 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).

Related Research Articles

<span class="mw-page-title-main">Citric acid cycle</span> Chemical reactions to release energy in cells

The citric acid cycle —also known as the Krebs cycle, Szent-Györgyi-Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. The Krebs cycle is used by organisms that respire (as opposed to organisms that ferment) to generate energy, either by anaerobic respiration or aerobic respiration. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest components of metabolism. Even though it is branded as a 'cycle', it is not necessary for metabolites to follow only one specific route; at least three alternative segments of the citric acid cycle have been recognized.

<span class="mw-page-title-main">Glycolysis</span> Catabolic pathway

Glycolysis is the metabolic pathway that converts glucose into pyruvate, and in most organisms, occurs in the liquid part of cells, the cytosol. The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.

<span class="mw-page-title-main">Cellular respiration</span> Process to convert glucose to ATP in cells

Cellular respiration is the process by which biological fuels are oxidised in the presence of an inorganic electron acceptor, such as oxygen, to drive the bulk production of adenosine triphosphate (ATP), which contains energy. Cellular respiration may be described as a set of metabolic reactions and processes that take place in the cells of organisms to convert chemical energy from nutrients into ATP, and then release waste products.

Anaerobic glycolysis is the transformation of glucose to lactate when limited amounts of oxygen (O2) are available. Anaerobic glycolysis is only an effective means of energy production during short, intense exercise, providing energy for a period ranging from 10 seconds to 2 minutes. This is much faster than aerobic metabolism. The anaerobic glycolysis (lactic acid) system is dominant from about 10–30 seconds during a maximal effort. It replenishes very quickly over this period and produces 2 ATP molecules per glucose molecule, or about 5% of glucose's energy potential (38 ATP molecules). The speed at which ATP is produced is about 100 times that of oxidative phosphorylation.

<span class="mw-page-title-main">Anabolism</span> Set of metabolic pathways that construct molecules from smaller units

Anabolism is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breaking-down aspect. Anabolism is usually synonymous with biosynthesis.

Digestion is the breakdown of carbohydrates to yield an energy-rich compound called ATP. The production of ATP is achieved through the oxidation of glucose molecules. In oxidation, the electrons are stripped from a glucose molecule to reduce NAD+ and FAD. NAD+ and FAD possess a high energy potential to drive the production of ATP in the electron transport chain. ATP production occurs in the mitochondria of the cell. There are two methods of producing ATP: aerobic and anaerobic. In aerobic respiration, oxygen is required. Using oxygen increases ATP production from 4 ATP molecules to about 30 ATP molecules. In anaerobic respiration, oxygen is not required. When oxygen is absent, the generation of ATP continues through fermentation. There are two types of fermentation: alcohol fermentation and lactic acid fermentation.

Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

<span class="mw-page-title-main">Tumor hypoxia</span> Situation where tumor cells have been deprived of oxygen

Tumor hypoxia is the situation where tumor cells have been deprived of oxygen. As a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. Hypoxic microenvironements in solid tumors are a result of available oxygen being consumed within 70 to 150 μm of tumour vasculature by rapidly proliferating tumor cells thus limiting the amount of oxygen available to diffuse further into the tumor tissue. In order to support continuous growth and proliferation in challenging hypoxic environments, cancer cells are found to alter their metabolism. Furthermore, hypoxia is known to change cell behavior and is associated with extracellular matrix remodeling and increased migratory and metastatic behavior.

<span class="mw-page-title-main">Pyruvate kinase</span> Class of enzymes

Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Pyruvate kinase was inappropriately named before it was recognized that it did not directly catalyze phosphorylation of pyruvate, which does not occur under physiological conditions. Pyruvate kinase is present in four distinct, tissue-specific isozymes in animals, each consisting of particular kinetic properties necessary to accommodate the variations in metabolic requirements of diverse tissues.

<span class="mw-page-title-main">Glucose 6-phosphate</span> Chemical compound

Glucose 6-phosphate 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 way.

<span class="mw-page-title-main">Entner–Doudoroff pathway</span>

The Entner–Doudoroff pathway is a metabolic pathway that is most notable in Gram-negative bacteria, certain Gram-positive bacteria and archaea. Glucose is the substrate in the ED pathway and through a series of enzyme assisted chemical reactions it is catabolized into pyruvate. Entner and Doudoroff (1952) and MacGee and Doudoroff (1954) first reported the ED pathway in the bacterium Pseudomonas saccharophila. While originally thought to be just an alternative to glycolysis (EMP) and the pentose phosphate pathway (PPP), some studies now suggest that the original role of the EMP may have originally been about anabolism and repurposed over time to catabolism, meaning the ED pathway may be the older pathway. Recent studies have also shown the prevalence of the ED pathway may be more widespread than first predicted with evidence supporting the presence of the pathway in cyanobacteria, ferns, algae, mosses, and plants. Specifically, there is direct evidence that Hordeum vulgare uses the Entner–Doudoroff pathway.

Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes that generate energy and (2) anabolic processes where they serve as building blocks for other compounds.

<span class="mw-page-title-main">Tumor metabolome</span>

The study of the tumor metabolism, also known as tumor metabolome describes the different characteristic metabolic changes in tumor cells. The characteristic attributes of the tumor metabolome are high glycolytic enzyme activities, the expression of the pyruvate kinase isoenzyme type M2, increased channeling of glucose carbons into synthetic processes, such as nucleic acid, amino acid and phospholipid synthesis, a high rate of pyrimidine and purine de novo synthesis, a low ratio of Adenosine triphosphate and Guanosine triphosphate to Cytidine triphosphate and Uridine triphosphate, low Adenosine monophosphate levels, high glutaminolytic capacities, release of immunosuppressive substances and dependency on methionine.

<span class="mw-page-title-main">Mixed acid fermentation</span> Biochemical conversion of six-carbon sugars into acids in bacteria

In biochemistry, mixed acid fermentation is the metabolic process by which a six-carbon sugar is converted into a complex and variable mixture of acids. It is an anaerobic (non-oxygen-requiring) fermentation reaction that is common in bacteria. It is characteristic for members of the Enterobacteriaceae, a large family of Gram-negative bacteria that includes E. coli.

<span class="mw-page-title-main">Amino acid synthesis</span> The set of biochemical processes by which amino acids are produced

Amino acid synthesis is the set of biochemical processes by which the amino acids are produced. The substrates for these processes are various compounds in the organism's diet or growth media. Not all organisms are able to synthesize all amino acids. For example, humans can synthesize 11 of the 20 standard amino acids. These 11 are called the non-essential amino acids).

<span class="mw-page-title-main">Fructose-bisphosphate aldolase</span>

Fructose-bisphosphate aldolase, often just aldolase, is an enzyme catalyzing a reversible reaction that splits the aldol, fructose 1,6-bisphosphate, into the triose phosphates dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (G3P). Aldolase can also produce DHAP from other (3S,4R)-ketose 1-phosphates such as fructose 1-phosphate and sedoheptulose 1,7-bisphosphate. Gluconeogenesis and the Calvin cycle, which are anabolic pathways, use the reverse reaction. Glycolysis, a catabolic pathway, uses the forward reaction. Aldolase is divided into two classes by mechanism.

Glucose-1,6-bisphosphate synthase is a type of enzyme called a phosphotransferase and is involved in mammalian starch and sucrose metabolism. It catalyzes the transfer of a phosphate group from 1,3-bisphosphoglycerate to glucose-1-phosphate, yielding 3-phosphoglycerate and glucose-1,6-bisphosphate.

The enzyme methylglyoxal synthase catalyzes the chemical reaction

<span class="mw-page-title-main">Inborn errors of carbohydrate metabolism</span> Medical condition

Inborn errors of carbohydrate metabolism are inborn error of metabolism that affect the catabolism and anabolism of carbohydrates.

Fructolysis refers to the metabolism of fructose from dietary sources. Though the metabolism of glucose through glycolysis uses many of the same enzymes and intermediate structures as those in fructolysis, the two sugars have very different metabolic fates in human metabolism. Unlike glucose, which is directly metabolized widely in the body, fructose is almost entirely metabolized in the liver in humans, where it is directed toward replenishment of liver glycogen and triglyceride synthesis. Under one percent of ingested fructose is directly converted to plasma triglyceride. 29% - 54% of fructose is converted in liver to glucose, and about a quarter of fructose is converted to lactate. 15% - 18% is converted to glycogen. Glucose and lactate are then used normally as energy to fuel cells all over the body.

References

  1. Alfarouk, Khalid O.; Alqahtani, Saad S.; Alshahrani, Saeed; Morgenstern, Jakob; Supuran, Claudiu T.; Reshkin, Stephan J. (1 January 2021). "The possible role of methylglyoxal metabolism in cancer". Journal of Enzyme Inhibition and Medicinal Chemistry. 36 (1): 2010–2015. doi: 10.1080/14756366.2021.1972994 . PMC   8451662 . PMID   34517737.
  2. Alfarouk, Khalid O.; Alqahtani, Saad S.; Alshahrani, Saeed; Morgenstern, Jakob; Supuran, Claudiu T.; Reshkin, Stephan J. (1 January 2021). "The possible role of methylglyoxal metabolism in cancer". Journal of Enzyme Inhibition and Medicinal Chemistry. 36 (1): 2010–2015. doi: 10.1080/14756366.2021.1972994 . PMC   8451662 . PMID   34517737.

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 <http://mic.sgmjournals.org/cgi/reprint/151/3/707>.

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 <http://www.pdb.org/pdb/explore.do?structureId=1B93>.

"Methylglyoxal Synthase From Escherichia Coli." RCSB Protein Data Base. 24 Apr. 2007. RCSB Protein Data Base. 25 Apr. 2007 <http://www.pdb.org/pdb/explore.do?structureId=1B93>.

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 <http://www.pdb.org/pdb/explore.do?structureId=1DC4>.