| Phosphoglycerate kinase | |||||||||
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| Identifiers | |||||||||
| EC no. | 2.7.2.3 | ||||||||
| CAS no. | 9001-83-6 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDBPDBePDBsum | ||||||||
| Gene Ontology | AmiGO /QuickGO | ||||||||
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| Phosphoglycerate kinase | |||||||
|---|---|---|---|---|---|---|---|
 Structure of yeast phosphoglycerate kinase.[1] | |||||||
| Identifiers | |||||||
| Symbol | PGK | ||||||
| Pfam | PF00162 | ||||||
| InterPro | IPR001576 | ||||||
| PROSITE | PDOC00102 | ||||||
| SCOP2 | 3pgk /SCOPe /SUPFAM | ||||||
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Phosphoglycerate kinase (EC2.7.2.3) (PGK 1) is anenzyme that catalyzes thereversible transfer of a phosphate group from 1,3-bisphosphoglyceric acid (1,3-BPG) to adenosine diphosphate (ADP) producing 3-phosphoglyceric acid (3-PG) and adenosine triphosphate (ATP):[2]
Like allkinases it is atransferase. PGK is a major enzyme used inglycolysis, in the first ATP-generating step of the glycolytic pathway. Ingluconeogenesis, the reaction catalyzed by PGK proceeds in the opposite direction, generating ADP and 1,3-BPG.
In humans, twoisozymes of PGK have been so far identified,PGK1 and PGK2. The isozymes have 87-88% identicalamino acid sequence identity and though they are structurally and functionally similar, they have different localizations: PGK2, encoded by anautosomal gene, is unique to meiotic and postmeioticspermatogenic cells, while PGK1, encoded on theX-chromosome, is ubiquitously expressed in all cells.[3]
PGK is present in all living organisms as one of the two ATP-generating enzymes in glycolysis. In the gluconeogenic pathway, PGK catalyzes the reverse reaction. Under biochemicalstandard conditions, the glycolytic direction is favored.[1]
In theCalvin cycle inphotosynthetic organisms, PGK catalyzes the phosphorylation of 3-PG, producing 1,3-BPG and ADP, as part of the reactions that regenerateribulose-1,5-bisphosphate.
PGK has been reported to exhibit thiolreductase activity onplasmin, leading toangiostatin formation, which inhibitsangiogenesis andtumor growth. The enzyme was also shown to participate inDNA replication and repair in mammal cellnuclei.[4]
The human isozyme PGK2, which is only expressed during spermatogenesis, was shown to be essential for sperm function in mice.[5]
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
PGK is found in all living organisms and its sequence has beenhighly conserved throughout evolution. The enzyme exists as a 415-residuemonomer containing two nearly equal-sized domains that correspond to the N- and C-termini of the protein.[6] 3-phosphoglycerate (3-PG) binds to the N-terminal, while the nucleotide substrates, MgATP or MgADP, bind to the C-terminal domain of the enzyme. This extended two-domain structure is associated with large-scale 'hinge-bending' conformational changes, similar to those found inhexokinase.[7] The two domains of the protein are separated by a cleft and linked by twoalpha-helices.[3] At the core of each domain is a 6-stranded parallelbeta-sheet surrounded by alpha helices. The two lobes are capable of folding independently, consistent with the presence of intermediates on thefolding pathway with a single domain folded.[8][9] Though the binding of either substrate triggers aconformational change, only through the binding of both substrates does domain closure occur, leading to the transfer of the phosphate group.[3]
The enzyme has a tendency to exist in the open conformation with short periods of closure and catalysis, which allow for rapiddiffusion of substrate and products through the binding sites; the open conformation of PGK is more conformationally stable due to the exposure of ahydrophobic region of the protein upon domain closure.[8]
Magnesium ions are normally complexed to the phosphate groups the nucleotide substrates of PGK. It is known that in the absence of magnesium, no enzyme activity occurs.[10] Thebivalent metal assists the enzymeligands in shielding the bound phosphate group's negative charges, allowing thenucleophilic attack to occur; this charge-stabilization is a typical characteristic of phosphotransfer reaction.[11] It is theorized that the ion may also encourage domain closure when PGK has bound both substrates.[10]
Without either substrate bound, PGK exists in an "open"conformation. After both the triose and nucleotide substrates are bound to the N- and C-terminal domains, respectively, an extensive hinge-bending motion occurs, bringing the domains and their bound substrates into close proximity and leading to a "closed" conformation.[12] Then, in the case of the forward glycolytic reaction, the beta-phosphate of ADP initiates anucleophilic attack on the 1-phosphate of 1,3-BPG. The Lys219 on the enzyme guides the phosphate group to the substrate.
PGK proceeds through a charge-stabilizedtransition state that is favored over the arrangement of the bound substrate in the closed enzyme because in the transition state, all three phosphate oxygens are stabilized byligands, as opposed to only two stabilized oxygens in the initial bound state.[13]
In theglycolytic pathway,1,3-BPG is thephosphate donor and has a high phosphoryl-transfer potential. The PGK-catalyzed transfer of the phosphate group from 1,3-BPG to ADP to yield ATP canpower[clarification needed] the carbon-oxidation reaction of the previous glycolytic step (convertingglyceraldehyde 3-phosphate to3-phosphoglycerate).[citation needed]
The enzyme is activated by low concentrations of various multivalent anions, such as pyrophosphate, sulfate, phosphate, and citrate. High concentrations of MgATP and 3-PG activates PGK, while Mg2+ at high concentrations non-competitively inhibits the enzyme.[14]
PGK exhibits a wide specificity toward nucleotide substrates.[15] Its activity is inhibited by salicylates, which appear to mimic the enzyme's nucleotide substrate.[16]
Macromolecular crowding has been shown to increase PGK activity in both computer simulations andin vitro environments simulating a cell interior; as a result of crowding, the enzyme becomes more enzymatically active and more compact.[6]
Phosphoglycerate kinase (PGK) deficiency is an X-linked recessive trait associated withhemolytic anemia,mental disorders andmyopathy in humans,[17][18] depending on form – there exists a hemolytic form and a myopathic form.[19] Since the trait is X-linked, it is usually fully expressed in males, who have one X chromosome; affected females are typically asymptomatic.[3][18] The condition results frommutations in Pgk1, the gene encoding PGK1, and twenty mutations have been identified.[18][3] On a molecular level, the mutation in Pgk1 impairs the thermal stability and inhibits the catalytic activity of the enzyme.[3] PGK is the only enzyme in the immediate glycolytic pathway encoded by an X-linked gene. In the case of hemolytic anemia, PGK deficiency occurs in theerythrocytes. Currently, no definitive treatment exists for PGK deficiency.[20]
PGK1 overexpression has been associated withgastric cancer and has been found to increase the invasiveness of gastric cancer cellsin vitro.[21] The enzyme is secreted bytumor cells and participates in the angiogenic process, leading to the release ofangiostatin and the inhibition of tumor blood vessel growth.[4]
Due to its wide specificity towardsnucleotide substrates, PGK is known to participate in the phosphorylation and activation ofHIVantiretroviral drugs, which are nucleotide-based.[15][22]
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