Phosphoglycerate mutase 2 (PGAM2), also known as muscle-specific phosphoglycerate mutase (PGAM-M), is a

phosphoglycerate mutase :''This enzyme is not to be confused with Bisphosphoglycerate mutase which catalyzes the conversion of 1,3-bisphosphoglycerate to 2,3-bisphosphoglycerate.'' Phosphoglycerate mutase (PGM) is any enzyme that catalyzes step 8 of glycolysis ...

that, in humans, is encoded by the ''PGAM2''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

on chromosome 7.

Phosphoglycerate mutase :''This enzyme is not to be confused with Bisphosphoglycerate mutase which catalyzes the conversion of 1,3-bisphosphoglycerate to 2,3-bisphosphoglycerate.'' Phosphoglycerate mutase (PGM) is any enzyme that catalyzes step 8 of glycolysis ...

(PGAM)

catalyze Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

s the reversible reaction of

3-phosphoglycerate 3-Phosphoglyceric acid (3PG, 3-PGA, or PGA) is the conjugate acid of 3-phosphoglycerate or glycerate 3-phosphate (GP or G3P). This glycerate is a biochemically significant metabolic intermediate in both glycolysis and the Calvin-Benson cycle. The ...

(3-PGA) to 2-phosphoglycerate (2-PGA) in the

glycolytic 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) ...

pathway. The PGAM is a dimeric

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...

containing, in different tissues, different proportions of a slow-migrating muscle (MM)

isozyme In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. dif ...

, a fast-migrating brain (BB) isozyme, and a hybrid form (MB). This gene encodes muscle-specific PGAM subunit. Mutations in this gene cause muscle phosphoglycerate mutase deficiency, also known as

glycogen storage disease A glycogen storage disease (GSD, also glycogenosis and dextrinosis) is a metabolic disorder caused by an enzyme deficiency affecting glycogen synthesis, glycogen breakdown, or glucose breakdown, typically in muscles and/or liver cells. GSD ha ...

X. rovided by RefSeq, Sep 2009ref name="entrez"/>

Structure

''PGAM2'' is one of two genes in humans encoding a PGAM subunit, the other being '' PGAM1''.

Gene

The ''PGAM2'' gene is composed of three

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequenc ...

s of lengths spanning 454, 180, and 202 bp, separated by two

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene ...

s of 103 bp and 5.6 kb. Located 29 bp upstream of the

transcription start site Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules calle ...

is a

TATA box In molecular biology, the TATA box (also called the Goldberg–Hogness box) is a sequence of DNA found in the core promoter region of genes in archaea and eukaryotes. The bacterial homolog of the TATA box is called the Pribnow box which ...

-like element, and 40 bp upstream of this element is an inverted CCAAT box element (ATTGG). Despite its muscle-specific expression, no muscle-specific

consensus sequence In molecular biology and bioinformatics, the consensus sequence (or canonical sequence) is the calculated order of most frequent residues, either nucleotide or amino acid, found at each position in a sequence alignment. It serves as a simplified r ...

s were identified in the 5'-

untranslated region In molecular genetics, an untranslated region (or UTR) refers to either of two sections, one on each side of a coding sequence on a strand of mRNA. If it is found on the 5' side, it is called the 5' UTR (or leader sequence), or if it is f ...

of human ''PGAM2'', though one consensus sequence has been proposed in rat and chicken. Unlike ''PGAM1'', which is present as several copies in the human genome, only one copy of ''PGAM2'' is found in the genome, indicating that this gene arose from gene duplication of and subsequent modifications in the ''PGAM1'' gene.

Protein

The isozyme encoded by ''PGAM2'' spans 253

residues Residue may refer to: Chemistry and biology * An amino acid, within a peptide chain * Crop residue, materials left after agricultural processes * Pesticide residue, refers to the pesticides that may remain on or in food after they are appli ...

, which demonstrates highly sequence similarity (81% identity) to the protein PGAM1. Both form either homo- or

heterodimer In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...

s. The MM homodimer is found primarily in adult muscle, while the MB heterodimer, composed of a subunit from each isozyme, is found in the heart. One key residue in the active site of PGAM2, lysine 100 (K100), is highly conserved across bacteria, to yeast, plant, and mammals, indicating its evolutionary importance. K100 directly contacts the substrate (3-PGA) and intermediate (2,3-PGA); however, the

acetylation : In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply ''acetates''. Deacetylation is the opp ...

of this residue under normal cellular conditions neutralizes its positive charge and interferes with this binding.

Mechanism

PGAM2 catalyzes the 3-PG-to-2-PG

isomerization In chemistry, isomerization or isomerisation is the process in which a molecule, polyatomic ion or molecular fragment is transformed into an isomer with a different chemical structure. Enolization is an example of isomerization, as is tautome ...

via a 2-step process: # a

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 ...

group from the phospho

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the ...

in the active site is transferred to the C-2 carbon of 3-PGA to form 2,3-bisphosglycerate (2,3-PGA), and then # the phosphate group linked to the C-3 carbon of 2,3-PG is transferred to the catalytic histidine to form 2-PGA and regenerate the phosphohistidine.

Function

PGAM2 is one of two PGAM subunits found in humans and is predominantly expressed in adult

muscle Skeletal muscles (commonly referred to as muscles) are Organ (biology), organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other ...

. Both isozymes of PGAM are glycolytic enzymes that catalyze the reversible conversion of 3-PGA to 2-PGA using

2,3-bisphosphoglycerate 2,3-Bisphosphoglyceric acid (conjugate base 2,3-bisphosphoglycerate) (2,3-BPG), also known as 2,3-diphosphoglyceric acid (conjugate base 2,3-diphosphoglycerate) (2,3-DPG), is a three-carbon isomer of the glycolytic intermediate 1,3-bisphosphoglyce ...

as a cofactor. Since both 3-PGA and 2-PGA are allosteric regulators of the

pentose phosphate pathway The pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt and the HMP Shunt) is a metabolic pathway parallel to glycolysis. It generates NADPH and pentoses (5-carbon sugars) as well as ribose 5-p ...

(PPP) and glycine and serine synthesis pathways, respectively, PGAM2 may contribute to the biosynthesis of amino acids, 5-carbon sugar, and nucleotides precursors.

Clinical significance

PGAM activity is upregulated in

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...

s, including

lung cancer Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissues of the lung. Lung carcinomas derive from transformed, malign ...

colon cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel ...

liver cancer Liver cancer (also known as hepatic cancer, primary hepatic cancer, or primary hepatic malignancy) is cancer that starts in the liver. Liver cancer can be primary (starts in liver) or secondary (meaning cancer which has spread from elsewhere to th ...

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...

, and

leukemia Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...

. One possible mechanism involves the deacetylation of residue K100 in the PGAM active site by sirtuin 2 ( SIRT2) under conditions of

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal re ...

. This deacetylation activates PGAM activity, resulting in increased NADPH production and cell proliferation, and thus

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. In a patient with intolerance for strenuous exercise and persistent pigmenturia, PGAM2 activity was found to be decreased relative to other glycolytic enzymes. This PGAM2 deficiency results in a

metabolic myopathy Metabolic myopathies are myopathies that result from defects in biochemical metabolism that primarily affect muscle. They are generally genetic defects that interfere with muscle's ability to create energy. At the cellular level, metabolic myopathi ...

(

glycogenosis A glycogen storage disease (GSD, also glycogenosis and dextrinosis) is a metabolic disorder caused by an enzyme deficiency affecting glycogen synthesis, glycogen breakdown, or glucose breakdown, typically in muscles and/or liver cells. GSD ha ...

type X) and has been traced to mutations in the ''PGAM2'' gene. Currently, four mutations have been identified from African-American, Caucasian, and Japanese families. One G-to-A transition mutation in codon 78 produced a truncated protein product, while mutations at codons 89 and 90 may have disrupted the active site and resulted in an inactive protein product. Meanwhile, two patients

heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

for the G97D mutation presented with

exercise intolerance Exercise intolerance is a condition of inability or decreased ability to perform physical exercise at the normally expected level or duration for people of that age, size, sex, and muscle mass. It also includes experiences of unusually severe post ...

and muscle cramps.

Interactions

PGAM2 is known to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizat ...

with: * SIRT2.

Interactive pathway map

References

{{Use dmy dates, date=April 2017 Genes on human chromosome 7