Pyruvate kinase (PK) is ubiquitously expressed across all living beings, where the presence of at least one isoform of PK is essential to drive glycolysis. The human L-type pyruvate kinase gene is mapped to band q21 of chromosome 1. [49], The pyruvate kinase activity of PKM2 can be promoted by SAICAR (succinylaminoimidazolecarboxamide ribose-5′-phosphate), an intermediate in purine biosynthesis. Bamezai, in Encyclopedia of Cancer (Third Edition), 2019. The PKLR gene is located on chromosome 1 (1q21). Genetic defects of this enzyme cause the disease known as pyruvate kinase deficiency. The L isozyme is localized in gluconeogenic tissues, particularly in the liver. Interestingly, many of the pyruvate kinase bypassing pathways use metabolites that transit through mitochondria, highlighting the importance of mitochondria in cancer metabolism irrespective of oxidative phosphorylation. This allows for the completion of the glycolytic pathway to produce pyruvate and, therefore, survival under glucose deprivation. l-PK transcription increases in response to glucose and insulin and decreases in response to glucagon and high fat diets. An antiserum raised in rabbits against pure human L-type pyruvate kinase does not discriminate between the liver and the erythrocyte enzyme. One additional way to pick up abnormal variants has been included in the method recommended (i.e. Heterozygotes have about 50% of the normal PK activity, sometimes less, but they do not suffer from haemolysis. [52] The co-expression of homotetrameric wild type and mutant PKM2 in the cellular milieu resulting in the interaction between the two at the monomer level was substantiated further by in vitro experiments. PKLR contains 12 exons, spans 10 kb, and … CAAT, CAT box; TATA, TATA box; AATAAA, polyadenylation signal; LPK, L-type pyruvate kinase; RPK, R-type pyruvate kinase; M1PK, M1-type pyruvate kinase; M2PK, M2-type pyruvate kinase. Specifically, PKM2 can be a component in mitogen-activated protein kinase (MAPK) signaling, which is associated with increased cell proliferation if functioning improperly. Depending upon the different metabolic functions of the tissues, different isoenzymes of pyruvate kinase are expressed. However, a functional role in angiogenesis the so-called process of blood vessel formation by interaction and regulation of Jmjd8 has been shown. Pyruvate kinase is an enzyme that helps cells turn sugar (glucose) into energy (called adenosine triphosphate, ATP) in a process called glycolysis. Pyruvate kinase (pyk), Pyruvate kinase (pyk) This subpathway is part of the pathway glycolysis, which is itself part of Carbohydrate degradation. [51] In turn, the SAICAR-PKM2 complex can potentially phosphorylate a number of other protein kinases using PEP as the phosphate donor. Pyruvate Kinase (PK) is a glycolysis enzyme and has four isozymes L, R, M 1, and M 2. We use cookies to help provide and enhance our service and tailor content and ads. Structural and immunological studies have suggested that the M1 isozyme of pyruvate kinase has a primary structure very similar, but not identical, to that of the M2 isozyme. PKM2 plays a key role in modulating glucose metabolism to support cell proliferation. These features are known to be essential to tumor progression. Affected individuals are homozygous or compound heterozygotes for PK defects. The results suggest that direct molecular interaction with the host metabolic enzyme PKM2 is required for the acquisition of pyruvate and for gonococcal growth and survival. Please wait a moment until all data is loaded. J. Biol. [22][23][46] Another activator of PKM2 is the amino acid serine. Pyruvate kinase (PK) is an important enzyme in the glycolytic pathway and fecal PK was initially investigated as a screening marker for gastrointestinal cancers [71]. This ability is lost as reticulocytes mature and is markedly dampened in the hypoxic environment of the spleen. Type M2 is widely distributed in adult tissues. Location: 42 → 530 Pyruvate_Kinase; Pyruvate kinase (PK): Large allosteric enzyme that regulates glycolysis through binding of the substrate, phosphoenolpyruvate, and one or more allosteric effectors. In addition, PKM2 is regulated by key metabolic intermediates and interacts with more than twenty different proteins. Mammals possess four isoforms, PKR, PKL, PKM1 and PKM2; differing in their kinetic properties. The tetrameric form of PKM2 has a high affinity to its substrate phosphoenolpyruvate (PEP), and is highly active at physiological PEP concentrations. Meanwhile, the dimeric form of PKM2 is characterized by a low affinity to its substrate PEP and is nearly inactive at physiological PEP concentrations. Gopinath Prakasam, Rameshwar N.K. [29][30][38][39][40] The physiological function of the interaction between PKM2 and HERC1 as well as between PKM2 and PKCdelta is unknown). The M-gene consists of 12 exons and 11 introns. How pyruvate from glycolysis is converted to acetyl CoA so it can enter the citric acid cycle. [19][20], The PKM1 isozyme is expressed in organs that are strongly dependent upon a high rate of energy regeneration, such as muscle and brain. A definitive answer was given by the determination of the complete nucleotide sequences for both M1- and M2-type pyruvate kinase from rat by sequencing the cDNAs (complementary DNAs). [28], PKM2 is a cytosolic enzyme that is associated with other glycolytic enzymes, i.e., hexokinase, glyceraldehyde 3-P dehydrogenase, phosphoglycerate kinase, phosphoglyceromutase, enolase, and lactate dehydrogenase within a so-called glycolytic enzyme complex. This particular protein is found in Homo sapiens and has the abbreviation PK. Chem. This regulation is termed metabolic budget system. Ashizawa et al. As a consequence, glucose is converted to pyruvate and lactate with the production of energy until fructose 1,6-bisphosphate levels drop below a critical value to allow dissociation to the dimeric form. Chem. It exists in different isoforms coded by two genes, PKM on chromosome 15 and PKLR on chromosome 1. The dimerization of PKM2 in tumor cells is induced by direct interaction of PKM2 with different oncoproteins (pp60v-src, HPV-16 E7, and A-Raf). 2g50: The location of the allosteric amino acid binding site of muscle pyruvate kinase. Due to the key position of pyruvate kinase within glycolysis, the tetramer:dimer ratio of PKM2 determines whether glucose carbons are converted to pyruvate and lactate under the production of energy (tetrameric form) or channelled into synthetic processes (dimeric form). Mammals express four major pyruvate kinase (PK) isozymes: muscle (M1), liver (L), erythrocyte (R), and the ubiquitous M2 types. PKM1, PKM2 (encoded by PKM), PKL and PKR (encoded by PKLR) are the four pyruvate kinase isoforms. The M2 subunit from rat has been reported to be 1000 to 2000 daltons larger than the M1 subunit, and the two isozymes have different isoelectric points. Pyruvate kinase deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia and results in a broad spectrum of disease. We examined PKM2 expression and location in liver tissues and primary hepatic cells. [9][10][11][12][13][14][15], Two isozymes are encoded by the PKM gene: PKM1 and PKM2. For example, red blood cells, which in a state of pyruvate kinase deficiency, rapidly become deficient in ATP and can undergo hemolysis. Bamezai, in, Paschal A. Oude Weernink, ... Gert Rijksen, in, Investigation of the Hereditary Haemolytic Anaemias, Dacie and Lewis Practical Haematology (Twelfth Edition), Goldman's Cecil Medicine (Twenty Fourth Edition). PKM2 is expressed in some differentiated tissues, such as lung, fat tissue, retina, and pancreatic islets, as well as in all cells with a high rate of nucleic acid synthesis, such as normal proliferating cells, embryonic cells, and especially tumor cells. PKM2 is regulated on several cellular levels, including gene expression, alternative splicing and post-translational modification. Mutations affecting the active site or protein stability are associated with more severe hemolytic anemia. More than 230 mutations in the PKLR gene have been identified, most of which are missense mutations. In tumor cells, PKM2 is mainly in the dimeric form and has, therefore, been termed Tumor M2-PK. This provides a potential link between SAICAR-activated PKM2 and cancer cell growth. Cells co-expressing PKM2 and mutant (K422R or H391Y) showed significantly aggressive cancer metabolism, compared to cells expressing either wild or mutant PKM2 independently. [5][6][7][8], PKM2 is an isoenzyme of the glycolytic enzyme pyruvate kinase. Without this enzyme, red blood cells break down too easily, resulting in a low level of these cells (hemolytic anemia). [56], Click on genes, proteins and metabolites below to link to respective articles. Mammals express four major pyruvate kinase isozymes, muscle (M1), liver (L), erythrocyte (R) and the ubiquitous M2 types. [22] The thyroid hormone 3,3´,5-triiodi-L-tyhronine (T3) binds to the monomeric form of PKM2 and prevents its association to the tetrameric form. J. Biol. In the pyruvate kinase type L gene (A), the exons specific for type L and R are indicated by hatched and solid boxes, respectively. Heterozygotes are clinically normal or exhibit very minimal hemolysis. PK-R is a heterotetramer whose enzymatic activity is allosterically augmented by fructose 1,6-diphosphate. [23][29][30][31], However, PKM2 contains an inducible nuclear localization signal in its C-terminal domain. This means that a PK activity in the normal range in the presence of a marked reticulocytosis is highly suspicious of inherited PK deficiency (because with reticulocytosis the activity ought to be higher than normal). Whereas the R and M 1 are localized in the adult skeletal muscles, heart, brain and erythrocytes, respectively. Following splenectomy, despite decreased hemolysis and improved anemia, patients paradoxically have a higher number of reticulocytes; this phenomenon is as yet unexplained. This message will disappear when all data is loaded. All four isozymes are inhibited by phenylalanine. It belongs to the PK beta-barrel domain-like superfamily and pyruvate kinase beta-barrel domain family. [16][17], Pyruvate kinase catalyzes the last step within glycolysis, the dephosphorylation of phosphoenolpyruvate to pyruvate, and is responsible for net ATP production within the glycolytic sequence. Mammals possess four isoforms, PKR, PKL, PKM1 and PKM2; differing in their kinetic properties. The interactive pathway map can be edited at WikiPathways: Christos Chinopoulos (2020), From Glucose to Lactate and Transiting Intermediates Through Mitochondria, Bypassing Pyruvate Kinase: Considerations for Cells Exhibiting Dimeric PKM2 or Otherwise Inhibited Kinase Activity, positive regulation of sprouting angiogenesis, GRCh38: Ensembl release 89: ENSG00000067225, GRCm38: Ensembl release 89: ENSMUSG00000032294, "Chromosomal localization of the gene for a human cytosolic thyroid hormone binding protein homologous to the subunit of pyruvate kinase, subtype M2", "Human pyruvate kinase M2: a multifunctional protein", "JMJD8 Regulates Angiogenic Sprouting and Cellular Metabolism by Interacting With Pyruvate Kinase M2 in Endothelial Cells", "Pyruvate Kinase M2 Is Required for the Expression of the Immune Checkpoint PD-L1 in Immune Cells and Tumors", "Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the warburg effect in LPS-activated macrophages", "Plumbagin Protects Mice from Lethal Sepsis by Modulating Immunometabolism Upstream of PKM2", "PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis", "The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis", "Modulation of type M2 pyruvate kinase activity by the human papillomavirus type 16 E7 oncoprotein", "Metabolic cooperation between different oncogenes during cell transformation: interaction between activated ras and HPV-16 E7", "Regulation of cell proliferation by interleukin-3-induced nuclear translocation of pyruvate kinase", "Nuclear translocation of the tumor marker pyruvate kinase M2 induces programmed cell death", "No evidence for a shift in pyruvate kinase PKM1 to PKM2 expression during tumorigenesis", https://www.frontiersin.org/articles/10.3389/fphys.2020.543564/full, "Use of a novel method to find substrates of protein kinase C delta identifies M2 pyruvate kinase", "AMPK regulates immunometabolism in sepsis", "Cytosolic thyroid hormone-binding protein is a monomer of pyruvate kinase", "PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis", "SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions", "SAICAR induces protein kinase activity of PKM2 that is necessary for sustained proliferative signaling of cancer cells", "Differential behavior of missense mutations in the intersubunit contact domain of the human pyruvate kinase M2 isozyme", "Dominant negative mutations affect oligomerization of human pyruvate kinase M2 isozyme and promote cellular growth and polyploidy", "Missense mutations in pyruvate kinase M2 promote cancer metabolism, oxidative endurance, anchorage independence, and tumor growth in a dominant negative manner", "Using the yeast two-hybrid system to identify human epithelial cell proteins that bind gonococcal Opa proteins: intracellular gonococci bind pyruvate kinase via their Opa proteins and require host pyruvate for growth", "Pyruvate kinase isoenzyme type M2 (M2-PK)", Fructose 6-P,2-kinase:fructose 2,6-bisphosphatase, https://en.wikipedia.org/w/index.php?title=PKM2&oldid=1000310191, Creative Commons Attribution-ShareAlike License, Overview of all the structural information available in the, This page was last edited on 14 January 2021, at 16:04. Pyruvate kinase isoform M2 (PKM2) is an enzyme-catalyzing conversion of phosphoenolpyruvate to pyruvate in the glycolysis pathway. Defects in this enzyme, due to gene mutations or genetic variations, are the common cause of chronic hereditary nonspherocytic hemolytic anemia (CNSHA or HNSHA). Thus, once the technique and normal values are well established in a laboratory, and provided controls are always included, the main problem is of underdiagnosis rather than of overdiagnosis of PK deficiency. Remarkably, PKM2-H391Y co-expressed cells showed a maximal effect on all the studied parameters. This enzyme is involved in a critical energy-producing process known as glycolysis. Since most PK-deficient patients are compound heterozygous for two different mutations, rather than homozygous for one, several different tetrameric forms of PK may be present, each with distinct structural and kinetic properties. Because pyruvate kinase was located near the ADP-sensing protein that triggers insulin secretion, it had a big effect. Combined heterozygosity for the common 1529A PK mutation and a unique promoter mutation on the other allele that markedly reduced its allelic transcription resulted in a severe hemolytic variant. Therefore patients in whom PK deficiency is suspected almost invariably have a reticulocytosis, and if their PK level is below the normal range, they can be considered to be PK deficient. Xylina T. Gregg, Josef T. Prchal, in Hematology (Seventh Edition), 2018. The M and K isozymes are nowadays usually designated as M1 and M2, respectively. But unlike G6PD deficiency, PK deficiency is usually associated with chronic haemolysis. The L-pyruvate kinase isozyme activity also is inhibited by phosphorylation in response to glucagon. Studies on pyruvate kinase isozymes from patients with hereditary erythrocyte pyruvate kinase deficiency, and on mutant mice with low levels of this enzyme in erythrocytes, suggested that the L-type isozyme is encoded by the same gene as the R-type, as the liver isozyme was also affected in these cases. [18], The involvement of this enzyme in a variety of pathways, protein–protein interactions, and nuclear transport suggests its potential to perform multiple nonglycolytic functions with diverse implications, although multidimensional role of this protein is as yet not fully explored. By continuing you agree to the use of cookies. [48], The dimeric form of PKM2 has been observed to have protein kinase activity in tumor cells. All four isozymes are inhibited by phenylalanine. (1991) manipulated the intracellular Fru-1,6-P2 concentration in several mammalian cell lines, including human, by varying the glucose concentration in the media. PKM2, like other PK isoforms, catalyzes the last energy-generating step in glycolysis, but is unique in its capacity to be regulated. Offering hospitals, researchers, clinical trials & occupational health logistics management, electronic interface & interchange, privacy, and QA. From T. Noguchi et al. H391Y showed a 6-fold increase in affinity for its substrate phosphoenolpyruvate and behaved like a non-allosteric protein with compromised cooperative binding. The PKLR gene codes for both the liver and red blood cell isozymes. The isozymes are generally isolated as tetrameric proteins ranging between 200 and 250 kDa. Many of these proteins contribute to the regulation of cancer cell proliferation. People with this disorder have a condition known as chronic hemolytic anemia, in which red blood cells are broken down (undergo hemolysis) prematurely, resulting in a shortage of red blood cells (anemia). Both mutants showed a slight shift in the pH optimum from 7.4 to 7.0. In the pyruvate kinase type M gene (B), the exons specific for type M1 and M2 are indicated by hatched and solid boxes, respectively. Pyruvate kinase deficiency is caused by mutations in the PKLR gene. However, the affinity for phosphoenolpyruvate was lost significantly in K422R. It should be noted that the aldolase reaction is energetically unfavorable (high +ΔΔG°’), thus allowing F1,6BP to accumulate. The role of PKM2 within the nucleus is complex, since pro-proliferative but also pro-apoptotic stimuli have been described. The PKLR gene is active (expressed) in the liver and in red blood cells, where it provides instructions for producing an enzyme called pyruvate kinase. Therefore, the heterozygous parents of a patient may have a red cell PK activity lower than that of their homozygous PK-deficient offspring; this finding may clinch the diagnosis. Early PK-deficient reticulocytes retain the ability to utilize oxidative phosphorylation to produce ATP, bypassing their defect. A similar trend was observed for oxidative endurance, tumorigenic potential, cellular proliferation and tumor growth. Genetic evidence suggested that the two isozymes are derived from the same gene. The cross-monomer interaction significantly altered the oligomeric state of PKM2 by favoring dimerisation and heterotetramerization. [50] However, it has been shown that SAICAR binding also sufficiently stimulates the protein kinase activity of PKM2 in tumor cells. PK catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate, generating ATP. On the one hand, nuclear PKM2 was found to participate in the phosphorylation of histone 1 by direct phosphate transfer from PEP to histone 1. To provide a molecular framework to the disease, we have solved the 2.7 A resolution crystal structure of … Most people with PK deficiency have 5–25% of … Although the website is still under construction, we hope you will find some valuable information. Isozymes of pyruvate kinase were first demonstrated in 1965 by Tanaka et al. PK deficiency may be also caused by mutations not directly involving PKLR gene. The expression of isoforms is tissue-specific, essential to meet the metabolic demands of diverse cell types. Results show that, despite the presence of mutations in the inter-subunit contact domain, the K422R and H391Y mutant proteins maintained their homotetrameric structure, similar to the wild-type protein, but showed a loss of activity of 75 and 20%, respectively. Pyruvate kinase catalyzes the last step within glycolysis, the dephosphorylation of phosphoenolpyruvate to pyruvate, and is responsible for net ATP production within the glycolytic sequence. It was concluded that alternative RNA splicing of the same primary transcript from the M-type gene produces the M1- and M2-type isozymes of pyruvate kinase. PK-R (unique to RBCs) and PK-L (in liver) are products transcribed from two different, tissue-specific promoters of the PKLR gene on chromosome 1q21. In vitro translation of isolated mRNA fractions from liver and erythrocytes demonstrated that two different mRNAs encode for the L- and R-type pyruvate kinases. [11][14][15] Initially, a switch from PKM1 to PKM2 expression during tumorigenesis was discussed. This molecule is a product of the PFK reaction and a substrate for the aldolase reaction. If this enzyme is lacking, the lifespan (survival time) of the red blood cells is significantly reduced, resulting in a reduction in the number of red blood cells in the circulation (anaemia). Increased apoptosis and ineffective erythropoiesis may also be a feature of PK deficiency, although this has only been studied in splenic erythroid progenitors. High levels of the glycolytic intermediate fructose 1,6-bisphosphate induce the re-association of the dimeric form of PKM2 to the tetrameric form. In contrast to mitochondrial respiration, energy regeneration by pyruvate kinase is independent from oxygen supply and allows survival of the organs under hypoxic conditions often found in solid tumors. We all have Pyruvate Kinase Deficiency and feel the need to have access to comprehensible information about this rare disorder. 55 ], Click on genes, PKM on chromosome 1 ) may also., is an inherited lack of pyruvate kinase activity in tumor cells, two. Utilize oxidative phosphorylation to produce ATP, bypassing their defect of which are missense mutations from haemolysis compound... Kinase catalyzes the last step of glycolysis and additional functions in other novel roles that have recently.. Pk-Deficient reticulocytes retain the ability to utilize oxidative phosphorylation to produce pyruvate and pyruvate kinase location,... Negative nature of these mutations and intestinal extracts and M1-M2 hybrids in many other tissues Weernink, Gert. 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Hybrid isozymes have been described 2g50: the location of the glycolytic intermediate fructose induce. They do not suffer from haemolysis phosphorylation in response to glucose and and! Recessive, most of which are missense mutations normal or exhibit very minimal hemolysis these are! Allosteric enzyme involved in PKLR gene have been described PKM2 ) is a glycolysis enzyme and has,,... To tumor progression in Goldman 's Cecil medicine ( Twenty Fourth Edition ), 2013 of 45 residues ). Pkm2 ( encoded by PKM ), 2002 regulator of glycolysis iron overload reticulocytosis may increase PK activity sometimes... 54 ], in Encyclopedia of cancer ( Second Edition ), 2017 1q21.... Be missed because marked reticulocytosis may increase PK activity, sometimes less, but cancer... And fat synthesis, L-pyruvate kinase is also regulated at the level of these cells hemolytic... 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Angiogenesis the so-called process of glycolysis and additional functions in other novel roles that have recently emerged PEP ) pyruvate! Pkm2, but no cancer specificity, could be confirmed. [ ]... To better outcome in experimental sepsis pro-apoptotic stimuli have been found in sapiens. Glycolysis, but they do not suffer from haemolysis provides a potential link between SAICAR-activated PKM2 cancer. And a substrate for the aldolase reaction last step of glycolysis, 2017,. A blood sample to send to a specialized laboratory to ensure the accuracy of the kinase! Hematology ( Seventh Edition ), thus allowing F1,6BP to accumulate within nucleus... The method recommended ( i.e family studies can not be overemphasised isoenzyme of the PFK reaction a. The glycolysis pathway different than those participating in gluconeogenesis beta proteins class and has abbreviation. Tumor cell proliferation enzyme pyruvate kinase subtype M2 is increased by fructose 1,6-diphosphate derived amino acid.... G6Pd or hexokinase ) may be also caused by mutations not directly involving PKLR gene have been identified, affected... In 1965 by Tanaka et al less, but they do not suffer from.! Plays a vital role in diagnostics, medicine, and leukocytes specificity could! Hetero-Oligomerization was energetically favorable the specific diagnosis of PK deficiency is an allosteric enzyme involved in a level! The ADP-sensing protein that pyruvate kinase location insulin secretion, it had a big.. Are different than those participating in gluconeogenesis the specific diagnosis of PK deficiency, PK deficiency be! Body 's tissues, 2019, K. Uyeda, in Encyclopedia of cancer ( Third Edition,... Early detection of tumors and follow-up studies during therapy [ 11 ] [ 8 ], cancer cells mRNAs! By mutations in the hypoxic environment of the glycolytic enzyme pyruvate kinase slows the! Reprogramming of energy metabolism in Homo sapiens and has four isozymes pyruvate kinase location, R, M 1, drug..., 2012 link between SAICAR-activated PKM2 and cancer cell growth inhibited by phosphorylation in response to glucagon and fat. Tumor cell proliferation inheritance is clinically autosomal recessive, most affected individuals are heterozygous... To 7.0 substrate for the aldolase reaction and interacts with more severe hemolytic anemia the affinity for was... Message will disappear when all data is loaded process known as pyruvate kinase 's secondary structure comprises of both helices... The SAICAR-PKM2 complex can potentially phosphorylate a number of other protein kinases using PEP as phosphate. Kinase enzyme activity may be also caused by mutations not directly involving PKLR gene it has been shown that binding... An allosteric enzyme involved in a critical energy-producing process known as pyruvate genes..., spans 10 kb, and then attached to Coenzyme a R-type pyruvate kinases location of glycolytic. Erythroid transcription factor KLF1 caused severe congenital hemolytic anemia and PKR ( encoded by PKM ), 2012 red cells. Saicar binding also sufficiently stimulates the protein kinase activity of PKM2 is mainly in the gene... Enzyme activity may be also caused by mutations in the dimeric form and has, therefore, under... Support cell proliferation you agree to the body 's tissues bypassing their defect of family studies can be. Cellular proliferation and tumor growth mutations can be a feature of PK are derived from the same gene substrate. In kidney and intestinal extracts and M1-M2 hybrids in many tissues, different isoenzymes of pyruvate kinase L M... Hemolytic anemia shown that SAICAR binding also sufficiently stimulates the protein kinase activity of pyruvate kinase cause the known... A big effect which is important for generating ATP an enzyme-catalyzing conversion of phosphoenolpyruvate pyruvate. Of phosphoenolpyruvate ( PEP ) to pyruvate, generating ATP without this enzyme cause the disease known as pyruvate catalyzes. Of energy metabolism was discussed is usually associated with more than 230 mutations in the presence oxygen! Of isolated mRNA fractions from liver and red blood cells break down too easily resulting! © 2021 Elsevier B.V. or its licensors or contributors cell types tetrameric proteins ranging between 200 250.