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Pyruvate Kinase

Official Full Name
Pyruvate Kinase
Background
Pyruvate kinase is an enzyme involved in glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to ADP, yielding one molecule of pyruvate and one molecule of ATP.
Synonyms
Pyruvate kinase; EC 2.7.1.40; 9001-59-6; phosphoenolpyruvate kinase; phosphoenol transphosphorylase; pyruvate kinase (phosphorylating); fluorokinase; fluorokinase (phosphorylating); pyruvic kinase; pyruvate phosphotransferase; ATP:pyruvate 2-O-phosphotransferase; PK

Catalog
ProductName
EC No.
CAS No.
Source
Price
CatalogNATE-1720
EC No.EC 2.7.1.40
CAS No.9001-59-6
SourceMicroorganism
CatalogEXWM-3070
ProductNamepyruvate kinase
EC No.EC 2.7.1.40
CAS No.9001-59-6
Source
CatalogNATE-1158
EC No.EC 2.7.1.40
CAS No.9001-59-6
SourceThermophillic b...
CatalogNATE-0939
EC No.
CAS No.9001-59-6
SourceE. coli
CatalogNATE-0938
EC No.
CAS No.9001-59-6
SourceE. coli
CatalogNATE-0649
EC No.EC 2.7.1.40
CAS No.9001-59-6
SourceBacillus stearo...
CatalogNATE-0567
EC No.EC 2.7.1.40
CAS No.9001-59-6
SourceRabbit muscle
Related Services
Related Protocols
PYRUVATE KINASE -Enzymatic Assay Protocol
Related Reading

Pyruvate kinase plays a role in regulating cellular metabolism, and it is the enzyme that catalyzes the last step of glycolysis. Pyruvate kinase catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), which produces pyruvate and ATP. There are four different pyruvate kinase isoenzymes in mammals with unique tissue expression patterns and regulatory properties respectively.

Isozymes

There are four pyruvate kinase isoenzymes in mammals, which are L, R, M1 and M2. L isoenzyme (PKL) is mainly found in the liver, R isoenzyme (PKR) is mainly found in red blood cells, M1 isoenzyme (PKM1) is mainly found in heart, muscle and brain, M2 isoenzyme (PKM2) It is present in most adult tissues, but is detectable only in early fetal tissues. The R and L isozymes of pyruvate kinase have two critical conformational states, one with low substrate affinity and the other with high substrate affinity. The low substrate affinity conformation is an inactive form of pyruvate kinase, in which case pyruvate kinase stably binds to ATP and alanine, inhibiting pyruvate kinase phosphorylation and glycolysis. The conformation of high substrate affinity is an activated form of pyruvate kinase that promotes the glycolytic pathway by binding to PEP and FBP. The R and L isozymes differ from M1 and M2 in that they are all allosteric and reversibly regulated. Gene expression varies between different isozymes, R and L isozymes are regulated by gene PKLR, and M1 and M2 isozymes are regulated by gene PKM.

Pyruvate Kinase

Structure

Mammalian pyruvate kinases are tetrameric proteins with the same subunits arranged in two dimers. Each pyruvate kinase monomer has an active site, and the main domain composition of this active site is A domain, B domain and C domain, respectively, and A domain is the largest. The structure of the A domain is a symmetric α8/β8 TIM barrel. The active site is located at one end of the barrel, in the crack between the A domain and the B domain. The B domain is mobile and closes at the active site upon binding to the Mg2+-ADP substrate complex. The C domain is located on the opposite side of the A domain, and the amino acids encoded by the alternative splicing exons of PKM1 and PKM2 are located in the C domain. The C domain contains a fructose-1,6-diphosphate (FBP) binding pocket. FBP is a major allosteric activator of PKM2, PKL and PKR, which plays an important role in regulating PK activity. The PKM1 monomer is inactive, the dimer remains catalytically active, and the tetramer PKM1 is most active. Unlike PKM1, PKM2 is not a constitutive tetramer, and PKM2 is reversibly dissociated and inactivated in the absence of FBP. The reversible activation of PKM2 by FBP allows for the dynamic regulation of its enzymatic activity.

Mechanism

Pyruvate kinase catalyzes the direct transfer of a phosphate group from phosphoenolpyruvate (PEP) to ADP to produce ATP and pyruvate. During the catalytic process, the active site of pyruvate kinase is occupied by substrates (PEP and ADP) and metal cations (K+ and Mg2+). Metal ions contribute to the binding and coordination of the substrate. The reaction is divided into two steps. The first step is a nucleophilic attack on the PEP phosphorus atom by β-phosphoryl oxygen of ADP, which replaces the enolpyruvate when forming ATP. The second step is the tautomerization of enolpyruvate to pyruvic acid. This reaction is favorable due to the high hydrolysis energy of the PEP.

Regulation

The activity of pyruvate kinase is regulated by allosteric effectors, covalent modifications and hormone control. Among them, the allosteric effector can bind to other sites than the active site of the protein, causing a conformational change, resulting in a change in the activity of the enzyme or protein. The most important allosteric effector of pyruvate kinase is fructose-1,6-diphosphate (FBP). FBP binds to the allosteric binding site on domain C of pyruvate kinase and alters the conformation of the enzyme, causing activation of pyruvate kinase activity. ATP and alanine can allosterically inactivate pyruvate kinase. A covalent modifier is an indirect regulator of enzymatic activity that activates or inhibits the activity of an enzyme by controlling phosphorylation and dephosphorylation of the enzyme. Glucagon, cyclic AMP and epinephrine inhibit pyruvate kinase, while insulin interferes with glucagon, cyclic AMP and adrenaline, causing pyruvate kinase to function normally. The carbohydrate response element binding protein (ChREBP) is an essential protein in the transcription of the pyruvate kinase L gene.

Pyruvate Kinase Deficiency

Pyruvate kinase deficiency is an autosomal recessive disorder that affects red blood cell survival and is the second most common cause of enzyme-deficient hemolytic anemia. Pyruvate kinase deficiency is caused by abnormalities in the PK gene, mainly PK gene point mutations, and a small number of patients present with gene deletion or insertion. When pyruvate kinase is deficient, ATP production is reduced. ATP deficiency is a major factor in hemolysis caused by pyruvate kinase deficiency. Because when ATP deficiency, K+ and H2O in red blood cells are lost, and red blood cells shrink into spine cells, which are less deformed and remain in the spleen and are destroyed, leading to hemolytic anemia. There is no cure for pyruvate kinase deficiency and it can only be relieved by treatment. The most common treatment is blood transfusion, especially for infants and young children. Bone marrow transplantation is also a treatment option.


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