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Phosphoglycerate kinase () (PGK 1) is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
that catalyzes the reversible transfer of a phosphate group from
1,3-bisphosphoglycerate 1,3-Bisphosphoglyceric acid (1,3-Bisphosphoglycerate or 1,3BPG) is a 3-carbon organic molecule present in most, if not all, living organisms. It primarily exists as a metabolic intermediate in both glycolysis during respiration and the Calvin cy ...
(1,3-BPG) to
ADP Adp or ADP may refer to: Aviation * Aéroports de Paris, airport authority for the Parisian region in France * Aeropuertos del Perú, airport operator for airports in northern Peru * SLAF Anuradhapura, an airport in Sri Lanka * Ampara Airp ...
producing 3-phosphoglycerate (3-PG) and ATP : :1,3-bisphosphoglycerate + ADP glycerate 3-phosphate + ATP Like all
kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
s it is a
transferase A transferase is any one of a class of enzymes that catalyse the transfer of specific functional groups (e.g. a methyl or glycosyl group) from one molecule (called the donor) to another (called the acceptor). They are involved in hundreds o ...
. PGK is a major enzyme used in
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
, in the first ATP-generating step of the glycolytic pathway. In
gluconeogenesis Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non- carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verteb ...
, the reaction catalyzed by PGK proceeds in the opposite direction, generating ADP and 1,3-BPG. In humans, two isozymes of PGK have been so far identified,
PGK1 Phosphoglycerate kinase 1 is an enzyme that in humans is encoded by the ''PGK1'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ...
and PGK2. The isozymes have 87-88% identical
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
sequence identity and though they are structurally and functionally similar, they have different localizations: PGK2, encoded by an
autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosom ...
gene, is unique to meiotic and postmeiotic
spermatogenic Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubule ...
cells, while PGK1, encoded on the
X-chromosome The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex- ...
, is ubiquitously expressed in all cells.


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 standard conditions, the glycolytic direction is favored. In the
Calvin cycle The Calvin cycle, light-independent reactions, bio synthetic phase, dark reactions, or photosynthetic carbon reduction (PCR) cycle of photosynthesis is a series of chemical reactions that convert carbon dioxide and hydrogen-carrier compounds into ...
in
photosynthetic Photosynthesis is a process used by plants and other organisms to convert light energy into chemical energy that, through cellular respiration, can later be released to fuel the organism's activities. Some of this chemical energy is stored in ...
organisms, PGK catalyzes the phosphorylation of 3-PG, producing 1,3-BPG and ADP, as part of the reactions that regenerate ribulose-1,5-bisphosphate. PGK has been reported to exhibit thiol
reductase A reductase is an enzyme that catalyzes a reduction reaction. Examples * 5α-Reductase * 5β-Reductase * Dihydrofolate reductase * HMG-CoA reductase * Methemoglobin reductase * Ribonucleotide reductase * Thioredoxin reductase * ''E. coli' ...
activity on
plasmin Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) is encode ...
, leading to angiostatin formation, which inhibits
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splittin ...
and
tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
growth. The enzyme was also shown to participate in
DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritan ...
and repair in mammal cell nuclei. The human isozyme PGK2, which is only expressed during spermatogenesis, was shown to be essential for sperm function in mice.


Interactive pathway map


Structure


Overview

PGK is found in all living organisms and its sequence has been
highly conserved In evolutionary biology, conserved sequences are identical or similar sequences in nucleic acids ( DNA and RNA) or proteins across species ( orthologous sequences), or within a genome ( paralogous sequences), or between donor and receptor taxa ( ...
throughout evolution. The enzyme exists as a 415- residue
monomer In chemistry, a monomer ( ; '' mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization. Classification ...
containing two nearly equal-sized domains that correspond to the N- and C-termini of the protein. 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 A hexokinase is an enzyme that phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate for hexokinases, and glucose-6-phosphate is the most important product. Hexo ...
. The two domains of the protein are separated by a cleft and linked by two alpha-helices. 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. Though the binding of either substrate triggers a
conformational change In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or oth ...
, only through the binding of both substrates does domain closure occur, leading to the transfer of the phosphate group. The enzyme has a tendency to exist in the open conformation with short periods of closure and catalysis, which allow for rapid
diffusion Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemical ...
of substrate and products through the binding sites; the open conformation of PGK is more conformationally stable due to the exposure of a
hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, ...
region of the protein upon domain closure.


Role of magnesium

Magnesium Magnesium is a chemical element with the symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 of the periodic ...
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. The
bivalent Bivalent may refer to: * Bivalent (chemistry), a molecule formed from two or more atoms bound together *Bivalent (engine), an engine that can operate on two different types of fuel *Bivalent (genetics), a pair of homologous chromosomes *Bivalent log ...
metal assists the enzyme
ligands In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
in shielding the bound phosphate group's negative charges, allowing the nucleophilic attack to occur; this charge-stabilization is a typical characteristic of phosphotransfer reaction. It is theorized that the ion may also encourage domain closure when PGK has bound both substrates.


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. Then, in the case of the forward glycolytic reaction, the beta-phosphate of ADP initiates a nucleophilic 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-stabilized
transition state In chemistry, the transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest potential energy along this reaction coordinate. It is often marked ...
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 by
ligands In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
, as opposed to only two stabilized oxygens in the initial bound state. In the glycolytic pathway,
1,3-BPG 1,3-Bisphosphoglyceric acid (1,3-Bisphosphoglycerate or 1,3BPG) is a 3-carbon organic molecule present in most, if not all, living organisms. It primarily exists as a metabolic intermediate in both glycolysis during respiration and the Calvin cycl ...
is the
phosphate In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid . The phosphate or orthophosphate ion is derived from phosph ...
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 can the carbon-oxidation reaction of the previous glycolytic step (converting glyceraldehyde 3-phosphate to 3-phosphoglycerate).


Regulation

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. PGK exhibits a wide specificity toward nucleotide substrates. Its activity is inhibited by salicylates, which appear to mimic the enzyme's nucleotide substrate. Macromolecular crowding has been shown to increase PGK activity in both computer simulations and
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...
environments simulating a cell interior; as a result of crowding, the enzyme becomes more enzymatically active and more compact.


Disease relevance

Phosphoglycerate kinase (PGK) deficiency is an X-linked recessive trait associated with hemolytic anemia,
mental disorders A mental disorder, also referred to as a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing and remitt ...
and
myopathy In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. This results in muscular weakness. ''Myopathy'' means muscle disease ( Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This me ...
in humans, depending on form – there exists a hemolytic form and a myopathic form. Since the trait is X-linked, it is usually fully expressed in males, who have one X chromosome; affected females are typically asymptomatic. The condition results from
mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
in Pgk1, the gene encoding PGK1, and twenty mutations have been identified. On a molecular level, the mutation in Pgk1 impairs the thermal stability and inhibits the catalytic activity of the enzyme. 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 the
erythrocytes Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
. Currently, no definitive treatment exists for PGK deficiency. PGK1 overexpression has been associated with
gastric cancer Stomach cancer, also known as gastric cancer, is a cancer that develops from the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes, including gastric adenocarcinomas. Lym ...
and has been found to increase the invasiveness of gastric cancer cells
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...
. The enzyme is secreted by
tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
cells and participates in the angiogenic process, leading to the release of angiostatin and the inhibition of tumor blood vessel growth. Due to its wide specificity towards
nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecu ...
substrates, PGK is known to participate in the phosphorylation and activation of HIV antiretroviral drugs, which are nucleotide-based.


Human isozymes


References


External links

*
Illustration at arizona.edu
{{Use dmy dates, date=April 2017 EC 2.7.2 Glycolysis enzymes Glycolysis