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Phosphoglycerate kinase (

In humans, two isozymes of PGK have been so far identified, PGK1 and PGK2. The isoenzymes have 87-88% identical amino acid sequence identity and though they are structurally and functionally similar, they have different localizations: PGK2, encoded by an autosomal gene, is unique to meiotic and postmeiotic spermatogenic cells, while PGK1, encoded on the X-chromosome, is ubiquitously expressed in all cells.[2]

Biological function

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 biochemical

The human isozyme PGK2, which is only expressed during spermatogenesis, was shown to be essential for sperm function in mice.[4]

Structure

Overview

PGK is found in all living organisms and its sequence has been highly conserved throughout evolution. The enzyme exists as a 415-residue monomer containing two nearly equal-sized domains that correspond to the N- and C-termini of the protein.^[5] 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 in hexokinase.^[6] The two proteins of the domain are separated by a cleft and linked by two alpha-helices.^[2] At the core of each domain is a 6-stranded parallel beta-sheet surrounded by alpha helices. The two lobes are capable of folding independently, consistent with the presence of intermediates on the folding pathway with a single domain folded.^[7][8] Though the binding of either substrate triggers a conformational change, only the concerted binding of both substrates allows domain closure then transfer of the phosphoryl group.^[2]

The enzyme has a tendency to exist in the open conformation with short periods of closure and catalysis, which allow for rapid diffusion of substrate and products through the binding sites; the open conformation of PGK is more conformationally stable due to the exposure of a hydrophobic region of the protein upon domain closure.^[7]

Role of magnesium

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. ^[9] The The bivalent metal assists the enzyme ligands in shielding the bound phosphate group's negative charges, allowing the nucleophilic attack to occur; this charge-stabilization is a typical characteristic of phospho-transfer reaction.^[10] It is theorized that the ion may also encourage domain closure when PGK has bound both substrates.^[9]

Mechanism

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.

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. [13] PGK activity is inhibited by salicylates, which appear to mimic the enzyme's nucleotide substrate.^[14]

Macromolecular crowding has been shown to increase PGK activity in both computer simluations and in vitro environments simulating a cell interior; as a result of crowding, the enzyme becomes more enyzmatically active and more compact.^[5]

Disease relevance

Phosphoglycerate kinase (PGK) deficiency is an X-linked recessive trait associated with

External links

• . GPnotebook https://www.gpnotebook.co.uk/simplepage.cfm?ID=-858783685. {{cite web}}: Missing or empty |title= (help)
• Phosphoglycerate+kinase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Illustration at arizona.edu

Category:EC 2.7.2

This article incorporates text from the public domain Pfam and InterPro: IPR001576

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