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34-439: 2PSN , 3B97 2023 13806 ENSG00000074800 ENSMUSG00000063524 P06733 P17182 NM_001201483 NM_001428 NM_001353346 NM_023119 NM_001379127 NM_001379128 NP_001188412 NP_001419 NP_001340275 NP_001366056 NP_001366057 NP_075608 NP_001020559 Enolase 1 (ENO1), more commonly known as alpha-enolase , is a glycolytic enzyme expressed in most tissues, one of

68-526: A TATA box while possessing multiple transcription start sites . A hypoxia -responsive element can be found in the ENO1 promoter and allows the enzyme to function in aerobic glycolysis and contribute to the Warburg effect in tumor cells. The mRNA transcript of the ENO1 gene can be alternatively translated into a cytoplasmic protein, with a molecular weight of 48 kDa , or a nuclear protein, with

102-415: A tumor suppressor by binding and inhibiting the c-myc protooncogene promoter, and lacks the glycolytic enzyme activity of the cytoplasmic form. ENO1 also plays a role in other functions, including a cell surface receptor for plasminogen on pathogens , such as streptococci , and activated immune cells, leading to systemic infection or tissue invasion; an oxidative stress protein in endothelial cells;

136-506: A tumor suppressor . Several pseudogenes have been identified, including one on the long arm of chromosome 1. Alpha-enolase has also been identified as an autoantigen in Hashimoto encephalopathy . ENO1 is one of three enolase isoforms, the other two being ENO2 (ENO-γ) and ENO3 (ENO-β). Each isoform is a protein subunit that can hetero- or homodimerize to form αα, αβ, αγ, ββ, and γγ dimers. The ENO1 gene spans 18 kb and lacks

170-484: A lens crystalline ; a heat shock protein ; and a binding partner of cytoskeletal and chromatin structures to aid in transcription . ENO1 overexpression has been associated with multiple tumors, including glioma , neuroendocrine tumors, neuroblastoma , pancreatic cancer , prostate cancer , cholangiocarcinoma , thyroid carcinoma , lung cancer , hepatocellular carcinoma , and breast cancer . In many of these tumors, ENO1 promoted cell proliferation by regulating

204-575: A molecular weight of a 37 kDa. The nuclear form was previously identified as Myc-binding protein-1 (MBP1), which downregulates the protein level of the c-myc protooncogene . A start codon at codon 97 of ENO1 and a Kozak consensus sequence were found preceding the 3' region of ENO1 encoding the MBP1 protein. In addition, the N-terminal region of the MBP1 protein it critical to DNA binding and, thus, its inhibitory function. As an enolase, ENO1

238-470: A possible intermediate in glycolysis. With all of these pieces available by the 1930s, Gustav Embden proposed a detailed, step-by-step outline of that pathway we now know as glycolysis. The biggest difficulties in determining the intricacies of the pathway were due to the very short lifetime and low steady-state concentrations of the intermediates of the fast glycolytic reactions. By the 1940s, Meyerhof, Embden and many other biochemists had finally completed

272-739: A putative target antigen of anti-endothelial cell antibody in Behçet's disease . Reduced expression of the enzyme has been found in the corneal epithelium of people suffering from keratoconus . CagA protein was found to activate ENO1 expression through activating the Src and MEK / ERK pathways as a mechanism for H. pylori -mediated gastric diseases. Enolase deficiency is a rare inborn error of metabolism disease, leads to hemolytic anemia in affected homozygous carriers of loss of function mutations in ENO1. As with other glycolysis enzyme deficiency diseases,

306-409: A second experiment, that a heat-sensitive high-molecular-weight subcellular fraction (the enzymes) and a heat-insensitive low-molecular-weight cytoplasm fraction (ADP, ATP and NAD and other cofactors ) are required together for fermentation to proceed. This experiment begun by observing that dialyzed (purified) yeast juice could not ferment or even create a sugar phosphate. This mixture was rescued with

340-441: A series of experiments (1905–1911), scientists Arthur Harden and William Young discovered more pieces of glycolysis. They discovered the regulatory effects of ATP on glucose consumption during alcohol fermentation. They also shed light on the role of one compound as a glycolysis intermediate: fructose 1,6-bisphosphate. The elucidation of fructose 1,6-bisphosphate was accomplished by measuring CO 2 levels when yeast juice

374-466: Is catalyzed by the enzyme phosphoenolpyruvate carboxykinase (PEPCK). This reaction is a rate-limiting step in gluconeogenesis: Click on genes, proteins and metabolites below to link to respective articles. PEP may be used for the synthesis of chorismate through the shikimate pathway . Chorismate may then be metabolized into the aromatic amino acids ( phenylalanine , tryptophan and tyrosine ) and other aromatic compounds. The first step

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408-410: Is a glycolytic enzyme the catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate . This isozyme is ubiquitously expressed in adult human tissues, including liver , brain , kidney , and spleen . Within cells, ENO1 predominantly localizes to the cytoplasm , though an alternatively translated form is localized to the nucleus . Its nuclear form, also known as MBP1, functions solely as

442-420: Is also involved in the biosynthesis of various aromatic compounds, and in carbon fixation ; in bacteria, it is also used as the source of energy for the phosphotransferase system . PEP is formed by the action of the enzyme enolase on 2-phosphoglyceric acid . Metabolism of PEP to pyruvic acid by pyruvate kinase (PK) generates adenosine triphosphate (ATP) via substrate-level phosphorylation . ATP

476-441: Is also used in the liver, which has a much lower affinity for glucose (K m in the vicinity of normal glycemia), and differs in regulatory properties. The different substrate affinity and alternate regulation of this enzyme are a reflection of the role of the liver in maintaining blood sugar levels. Cofactors: Mg G6P is then rearranged into fructose 6-phosphate (F6P) by glucose phosphate isomerase . Fructose can also enter

510-536: Is an ancient metabolic pathway. Indeed, the reactions that make up glycolysis and its parallel pathway, the pentose phosphate pathway , can occur in the oxygen-free conditions of the Archean oceans, also in the absence of enzymes, catalyzed by metal ions, meaning this is a plausible prebiotic pathway for abiogenesis . The most common type of glycolysis is the Embden–Meyerhof–Parnas (EMP) pathway , which

544-938: Is located on the 1p36 tumor suppressor locus near MIR34A which is homozygously deleted in Glioblastoma , Hepatocellular carcinoma and Cholangiocarcinoma . The co-deletion of ENO1 is a passenger event with the resultant tumor cells being entirely dependent on ENO2 for the execution of glycolysis . Tumor cells with such deletions are exceptionally sensitive towards ablation of ENO2. Inhibition of ENO2 in ENO1-homozygously deleted cancer cells constitutes an example of synthetic lethality treatment for cancer. ENO1 has been detected in serum drawn from children diagnosed with juvenile idiopathic arthritis . Alpha-enolase has been identified as an autoantigen in Hashimoto's encephalopathy . Single studies have also identified it as an autoantigen associated with severe asthma and

578-404: Is maintained by the two phosphate (P i ) groups: Charges are balanced by the difference between ADP and ATP. In the cellular environment, all three hydroxyl groups of ADP dissociate into −O and H , giving ADP , and this ion tends to exist in an ionic bond with Mg , giving ADPMg . ATP behaves identically except that it has four hydroxyl groups, giving ATPMg . When these differences along with

612-442: Is one of the major currencies of chemical energy within cells . Compound C00631 at KEGG Pathway Database. Enzyme 4.2.1.11 at KEGG Pathway Database. Compound C00074 at KEGG Pathway Database. Enzyme 2.7.1.40 at KEGG Pathway Database. Compound C00022 at KEGG Pathway Database. PEP is formed from the decarboxylation of oxaloacetate and hydrolysis of one guanosine triphosphate molecule. This reaction

646-530: Is the only biochemical pathway in eukaryotes that can generate ATP, and, for many anaerobic respiring organisms the most important producer of ATP. Therefore, many organisms have evolved fermentation pathways to recycle NAD to continue glycolysis to produce ATP for survival. These pathways include ethanol fermentation and lactic acid fermentation . The modern understanding of the pathway of glycolysis took almost 100 years to fully learn. The combined results of many smaller experiments were required to understand

680-493: The PI3K / AKT signaling pathway and induced tumorigenesis by activating plasminogen. Moreover, ENO1 is expressed on the tumor cell surface during pathological conditions such as inflammation , autoimmunity , and malignancy . Its role as a plasminogen receptor leads to extracellular matrix degradation and cancer invasion. Due to its surface expression, targeting surface ENO1 enables selective targeting of tumor cells while leaving

714-400: The isozymes of enolase . Each isoenzyme is a homodimer composed of 2 alpha, 2 gamma, or 2 beta subunits , and functions as a glycolytic enzyme. Alpha-enolase, in addition, functions as a structural lens protein ( tau - crystallin ) in the monomeric form. Alternative splicing of this gene results in a shorter isoform that has been shown to bind to the c-myc promoter and function as

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748-446: The ENO1 inside normal cells functional. Moreover, in tumors such as non-Hodgkin lymphomas (NHLs) and breast cancer, inhibition of ENO1 expression decreased tolerance to hypoxia while increasing sensitivity to radiation therapy , thus indicating that ENO1 may have aided chemoresistance . Considering these factors, ENO1 holds great potential to serve as an effective therapeutic target for treating many types of tumors in patients. ENO1

782-559: The addition of undialyzed yeast extract that had been boiled. Boiling the yeast extract renders all proteins inactive (as it denatures them). The ability of boiled extract plus dialyzed juice to complete fermentation suggests that the cofactors were non-protein in character. In the 1920s Otto Meyerhof was able to link together some of the many individual pieces of glycolysis discovered by Buchner, Harden, and Young. Meyerhof and his team were able to extract different glycolytic enzymes from muscle tissue , and combine them to artificially create

816-414: The cell through the plasma membrane transporters. In addition, phosphorylation blocks the glucose from leaking out – the cell lacks transporters for G6P, and free diffusion out of the cell is prevented due to the charged nature of G6P. Glucose may alternatively be formed from the phosphorolysis or hydrolysis of intracellular starch or glycogen. In animals , an isozyme of hexokinase called glucokinase

850-521: The condition is aggravated by redox-cycling agents such as nitrofurantoin . Click on genes, proteins and metabolites below to link to respective articles. Alpha-enolase has been shown to interact with TRAPPC2 . This article incorporates text from the United States National Library of Medicine , which is in the public domain . Glycolysis The wide occurrence of glycolysis in other species indicates that it

884-675: The entire pathway. The first steps in understanding glycolysis began in the 19th century. For economic reasons, the French wine industry sought to investigate why wine sometimes turned distasteful, instead of fermenting into alcohol. The French scientist Louis Pasteur researched this issue during the 1850s. His experiments showed that alcohol fermentation occurs by the action of living microorganisms , yeasts, and that glucose consumption decreased under aerobic conditions (the Pasteur effect ). The component steps of glycolysis were first analysed by

918-448: The glycolytic pathway by phosphorylation at this point. Phosphoenolpyruvate Phosphoenolpyruvate ( 2-phosphoenolpyruvate , PEP ) is the carboxylic acid derived from the enol of pyruvate and phosphate . It exists as an anion . PEP is an important intermediate in biochemistry . It has the highest-energy phosphate bond found (−61.9 kJ/mol) in organisms, and is involved in glycolysis and gluconeogenesis . In plants, it

952-399: The non-cellular fermentation experiments of Eduard Buchner during the 1890s. Buchner demonstrated that the conversion of glucose to ethanol was possible using a non-living extract of yeast, due to the action of enzymes in the extract. This experiment not only revolutionized biochemistry, but also allowed later scientists to analyze this pathway in a more controlled laboratory setting. In

986-553: The pathway from glycogen to lactic acid. In one paper, Meyerhof and scientist Renate Junowicz-Kockolaty investigated the reaction that splits fructose 1,6-diphosphate into the two triose phosphates. Previous work proposed that the split occurred via 1,3-diphosphoglyceraldehyde plus an oxidizing enzyme and cozymase. Meyerhoff and Junowicz found that the equilibrium constant for the isomerase and aldoses reaction were not affected by inorganic phosphates or any other cozymase or oxidizing enzymes. They further removed diphosphoglyceraldehyde as

1020-440: The preparatory (or investment) phase, since they consume energy to convert the glucose into two three-carbon sugar phosphates ( G3P ). Once glucose enters the cell, the first step is phosphorylation of glucose by a family of enzymes called hexokinases to form glucose 6-phosphate (G6P). This reaction consumes ATP, but it acts to keep the glucose concentration inside the cell low, promoting continuous transport of blood glucose into

1054-935: The puzzle of glycolysis. The understanding of the isolated pathway has been expanded in the subsequent decades, to include further details of its regulation and integration with other metabolic pathways. Glucose Hexokinase Glucose 6-phosphate Glucose-6-phosphate isomerase Fructose 6-phosphate Phosphofructokinase-1 Fructose 1,6-bisphosphate Fructose-bisphosphate aldolase Dihydroxyacetone phosphate + Glyceraldehyde 3-phosphate Triosephosphate isomerase 2 × Glyceraldehyde 3-phosphate Glyceraldehyde-3-phosphate dehydrogenase 2 × 1,3-Bisphosphoglycerate Phosphoglycerate kinase 2 × 3-Phosphoglycerate Phosphoglycerate mutase 2 × 2-Phosphoglycerate Phosphopyruvate hydratase ( enolase ) 2 × Phosphoenolpyruvate Pyruvate kinase 2 × Pyruvate The first five steps of Glycolysis are regarded as

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1088-400: The true charges on the two phosphate groups are considered together, the net charges of −4 on each side are balanced. In high-oxygen (aerobic) conditions, eukaryotic cells can continue from glycolysis to metabolise the pyruvate through the citric acid cycle or the electron transport chain to produce significantly more ATP. Importantly, under low-oxygen (anaerobic) conditions, glycolysis

1122-737: Was discovered by Gustav Embden , Otto Meyerhof , and Jakub Karol Parnas . Glycolysis also refers to other pathways, such as the Entner–Doudoroff pathway and various heterofermentative and homofermentative pathways. However, the discussion here will be limited to the Embden–Meyerhof–Parnas pathway. The glycolysis pathway can be separated into two phases: The overall reaction of glycolysis is: d -Glucose     2 × Pyruvate   The use of symbols in this equation makes it appear unbalanced with respect to oxygen atoms, hydrogen atoms, and charges. Atom balance

1156-435: Was incubated with glucose. CO 2 production increased rapidly then slowed down. Harden and Young noted that this process would restart if an inorganic phosphate (Pi) was added to the mixture. Harden and Young deduced that this process produced organic phosphate esters, and further experiments allowed them to extract fructose diphosphate (F-1,6-DP). Arthur Harden and William Young along with Nick Sheppard determined, in

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