PYGB

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Glycogen phosphorylase, brain (PYGB, GPBB), is an enzyme that in humans is encoded by the PYGB gene on chromosome 20. The protein encoded by this gene is a glycogen phosphorylase found predominantly in the brain. The encoded protein forms homodimers which can associate into homotetramers, the enzymatically active form of glycogen phosphorylase. The activity of this enzyme is positively regulated by AMP and negatively regulated by ATP, ADP, and glucose-6-phosphate. This enzyme catalyzes the rate-determining step in glycogen degradation. [provided by RefSeq, Jul 2008] [1]

Contents

Structure

The PYGB gene encodes one of three major glycogen phosphorylase isoforms, which are distinguished by their different structures and subcellular localizations: brain (PYGB), muscle (PYGM), and liver (PYGL). [2] [3] GPBB is the longest of the three isozymes, with a length of 862 residues, due to the extended 3'-UTR at the enzyme's C-terminal. Nonetheless, it shares high homology in amino acid sequence with the other two isozymes, with 83% similarity with PYGM and 80% similarity with PYGL. Moreover, both its nucleotide and amino acid sequences and its codon usage share higher similarity with those of PYGM, thus indicating that the two share a closer evolutionary descent by gene duplication and translocation of a common ancestral gene. A possible pseudogene can be found on chromosome 10. [2]

Function

As a glycogen phosphorylase, GPBB catalyzes the phosphorolysis of glycogen to yield glucose 1-phosphate. [4] [5] This reaction serves as the rate-determining first step in glycogenolysis and, thus, contributes to the regulation of carbohydrate metabolism. [4] [6] [7] In particular, GPBB is responsible for supplying emergency glucose during periods of stress, including anoxia, hypoglycemia, or ischemia. [3] [4] [5] In normal cell conditions, GPBB is bound to the sarcoplasmic reticulum (SR) membrane by complexing with glycogen. [7] [6] When stimulated by stress conditions, [6] Under stress conditions such as hypoxia, glycogen is degraded and GPBB is released into the cytoplasm. [6] Though GPBB is primarily expressed in adult and fetal brain, it has also been detected in cardiomyocytes and at low levels in other adult and fetal tissues. [2] [7] [4] These other tissues also express PYGL and PYGM, but the purpose of expressing multiple glycogen phosphorylases remains unclear. [4] Nuclear localization was also cited for GPBB in gastrointestinal cancer. [8]

Clinical significance

Cancer

GPBB overexpression has been associated with several cancers, including colorectal cancer, gastrointestinal cancer, and non-small cell lung cancer (NSCLC). [3] [5] [8] Since GPBB is upregulated during the potential transition of adenoma cells into carcinoma cells, GPBB may be a useful biomarker to detect malignancy potential in precancerous lesions. [3]

Ischemia

Since GPBB is released from the SR membrane under ischemic conditions, it may serve as a biomarker for early detection of ischemia. [7] Specifically, its release in acute myocardial ischemia has been attributed to increased glycogenolysis and plasma membrane permeability, and has been correlated with poor outcome. [6] [7] As a highly sensitive marker for myocardial ischemia, GPBB may aid in detection of perioperative myocardial damage and infarction in patients undergoing coronary artery bypass grafting. Meanwhile, GPBB levels are elevated in patients with hypertrophic cardiomyopathy. [6]

See also

Related Research Articles

A protein phosphatase is a phosphatase enzyme that removes a phosphate group from the phosphorylated amino acid residue of its substrate protein. Protein phosphorylation is one of the most common forms of reversible protein posttranslational modification (PTM), with up to 30% of all proteins being phosphorylated at any given time. Protein kinases (PKs) are the effectors of phosphorylation and catalyse the transfer of a γ-phosphate from ATP to specific amino acids on proteins. Several hundred PKs exist in mammals and are classified into distinct super-families. Proteins are phosphorylated predominantly on Ser, Thr and Tyr residues, which account for 79.3, 16.9 and 3.8% respectively of the phosphoproteome, at least in mammals. In contrast, protein phosphatases (PPs) are the primary effectors of dephosphorylation and can be grouped into three main classes based on sequence, structure and catalytic function. The largest class of PPs is the phosphoprotein phosphatase (PPP) family comprising PP1, PP2A, PP2B, PP4, PP5, PP6 and PP7, and the protein phosphatase Mg2+- or Mn2+-dependent (PPM) family, composed primarily of PP2C. The protein Tyr phosphatase (PTP) super-family forms the second group, and the aspartate-based protein phosphatases the third. The protein pseudophosphatases form part of the larger phosphatase family, and in most cases are thought to be catalytically inert, instead functioning as phosphate-binding proteins, integrators of signalling or subcellular traps. Examples of membrane-spanning protein phosphatases containing both active (phosphatase) and inactive (pseudophosphatase) domains linked in tandem are known, conceptually similar to the kinase and pseudokinase domain polypeptide structure of the JAK pseudokinases. A complete comparative analysis of human phosphatases and pseudophosphatases has been completed by Manning and colleagues, forming a companion piece to the ground-breaking analysis of the human kinome, which encodes the complete set of ~536 human protein kinases.

<span class="mw-page-title-main">Glycogen storage disease type V</span> Human disease caused by deficiency of a muscle enzyme

Glycogen storage disease type V, also known as McArdle's disease, is a metabolic disorder, one of the metabolic myopathies, more specifically a muscle glycogen storage disease, caused by a deficiency of myophosphorylase. Its incidence is reported as one in 100,000, roughly the same as glycogen storage disease type I.

<span class="mw-page-title-main">Glucagon</span> Peptide hormone

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

<span class="mw-page-title-main">Glycogenolysis</span> Breakdown of glycogen

Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase.

<span class="mw-page-title-main">Pyruvate kinase</span> Class of enzymes

Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Pyruvate kinase was inappropriately named before it was recognized that it did not directly catalyze phosphorylation of pyruvate, which does not occur under physiological conditions. Pyruvate kinase is present in four distinct, tissue-specific isozymes in animals, each consisting of particular kinetic properties necessary to accommodate the variations in metabolic requirements of diverse tissues.

<span class="mw-page-title-main">Glucokinase</span> Enzyme participating to the regulation of carbohydrate metabolism

Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.

<span class="mw-page-title-main">Aldolase A</span> Mammalian protein found in Homo sapiens

Aldolase A, also known as fructose-bisphosphate aldolase, is an enzyme that in humans is encoded by the ALDOA gene on chromosome 16.

<span class="mw-page-title-main">Glycogen phosphorylase</span> Class of enzymes

Glycogen phosphorylase is one of the phosphorylase enzymes. Glycogen phosphorylase catalyzes the rate-limiting step in glycogenolysis in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond. Glycogen phosphorylase is also studied as a model protein regulated by both reversible phosphorylation and allosteric effects.

<span class="mw-page-title-main">Glycogen synthase</span> Enzyme class, includes all types of glycogen/starch synthases

Glycogen synthase is a key enzyme in glycogenesis, the conversion of glucose into glycogen. It is a glycosyltransferase that catalyses the reaction of UDP-glucose and n to yield UDP and n+1.

<span class="mw-page-title-main">Glycogen debranching enzyme</span> Mammalian protein found in Homo sapiens

The glycogen debranching enzyme, in humans, is the protein encoded by the gene AGL. This enzyme is essential for the breakdown of glycogen, which serves as a store of glucose in the body. It has separate glucosyltransferase and glucosidase activities.

<span class="mw-page-title-main">Glycogen branching enzyme</span> Mammalian protein involved in glycogen production

1,4-alpha-glucan-branching enzyme, also known as brancher enzyme or glycogen-branching enzyme is an enzyme that in humans is encoded by the GBE1 gene.

<span class="mw-page-title-main">Myophosphorylase</span> Muscle enzyme involved in glycogen breakdown

Myophosphorylase or glycogen phosphorylase, muscle associated (PYGM) is the muscle isoform of the enzyme glycogen phosphorylase and is encoded by the PYGM gene. This enzyme helps break down glycogen into glucose-1-phosphate, so it can be used within the muscle cell. Mutations in this gene are associated with McArdle disease, a glycogen storage disease of muscle.

Glycogen phosphorylase isoenzyme BB is an isoenzyme of glycogen phosphorylase. This isoform of the enzyme exists in cardiac (heart) and brain tissue.

<span class="mw-page-title-main">Glucose-6-phosphate exchanger SLC37A4</span>

Glucose-6-phosphate exchanger SLC37A4, also known as glucose-6-phosphate translocase, is an enzyme that in humans is encoded by the SLC37A4 gene.

<span class="mw-page-title-main">TYMP (gene)</span> Protein-coding gene in the species Homo sapiens

TYMP is a gene that encodes for the enzyme thymidine phosphorylase. The TYMP gene is also known as ECGF1 and MNGIE due to its role in MNGIE syndrome.

<span class="mw-page-title-main">G6PC</span> Protein-coding gene in the species Homo sapiens

Glucose-6-phosphatase, catalytic subunit is an enzyme that in humans is encoded by the G6PC gene.

<span class="mw-page-title-main">ACSL4</span> Protein-coding gene in humans

Long-chain-fatty-acid—CoA ligase 4 is an enzyme that in humans is encoded by the ACSL4 gene.

<span class="mw-page-title-main">PHKG2</span> Protein-coding gene in the species Homo sapiens

Phosphorylase b kinase gamma catalytic chain, testis/liver isoform is an enzyme that in humans is encoded by the PHKG2 gene.

<span class="mw-page-title-main">Inborn errors of carbohydrate metabolism</span> Medical condition

Inborn errors of carbohydrate metabolism are inborn error of metabolism that affect the catabolism and anabolism of carbohydrates.

Glycogen phosphorylase, liver form (PYGL), also known as human liver glycogen phosphorylase (HLGP), is an enzyme that in humans is encoded by the PYGL gene on chromosome 14. This gene encodes a homodimeric protein that catalyses the cleavage of alpha-1,4-glucosidic bonds to release glucose-1-phosphate from liver glycogen stores. This protein switches from inactive phosphorylase B to active phosphorylase A by phosphorylation of serine residue 14. Activity of this enzyme is further regulated by multiple allosteric effectors and hormonal controls. Humans have three glycogen phosphorylase genes that encode distinct isozymes that are primarily expressed in liver, brain and muscle, respectively. The liver isozyme serves the glycemic demands of the body in general while the brain and muscle isozymes supply just those tissues. In glycogen storage disease type VI, also known as Hers disease, mutations in liver glycogen phosphorylase inhibit the conversion of glycogen to glucose and results in moderate hypoglycemia, mild ketosis, growth retardation and hepatomegaly. Alternative splicing results in multiple transcript variants encoding different isoforms [provided by RefSeq, Feb 2011].

References

  1. ↑ "PYGB phosphorylase, glycogen; brain". NCBI Entrez Gene database.
  2. 1 2 3 Newgard, CB; Littman, DR; van Genderen, C; Smith, M; Fletterick, RJ (15 March 1988). "Human brain glycogen phosphorylase. Cloning, sequence analysis, chromosomal mapping, tissue expression, and comparison with the human liver and muscle isozymes". The Journal of Biological Chemistry. 263 (8): 3850–7. PMID   3346228.
  3. 1 2 3 4 Tashima, S; Shimada, S; Yamaguchi, K; Tsuruta, J; Ogawa, M (January 2000). "Expression of brain-type glycogen phosphorylase is a potentially novel early biomarker in the carcinogenesis of human colorectal carcinomas". The American Journal of Gastroenterology. 95 (1): 255–63. PMID   10638593.
  4. 1 2 3 4 5 Gelinas, RP; Froman, BE; McElroy, F; Tait, RC; Gorin, FA (November 1989). "Human brain glycogen phosphorylase: characterization of fetal cDNA and genomic sequences". Brain Research. Molecular Brain Research. 6 (2–3): 177–85. doi:10.1016/0169-328x(89)90052-1. PMID   2615594.
  5. 1 2 3 Lee, MK; Kim, JH; Lee, CH; Kim, JM; Kang, CD; Kim, YD; Choi, KU; Kim, HW; Kim, JY; Park do, Y; Sol, MY (December 2006). "Clinicopathological significance of BGP expression in non-small-cell lung carcinoma: relationship with histological type, microvessel density and patients' survival". Pathology. 38 (6): 555–60. doi:10.1080/00313020601024029. PMID   17393985.
  6. 1 2 3 4 5 6 Pudil, R; Vasatová, M; Lenco, J; Tichý, M; Rehácek, V; Fucíková, A; Horácek, JM; Vojácek, J; Pleskot, M; Stulík, J; Palicka, V (August 2010). "Plasma glycogen phosphorylase BB is associated with pulmonary artery wedge pressure and left ventricle mass index in patients with hypertrophic cardiomyopathy". Clinical Chemistry and Laboratory Medicine. 48 (8): 1193–5. doi:10.1515/cclm.2010.231. PMID   20482380.
  7. 1 2 3 4 5 Lillpopp, L; Tzikas, S; Ojeda, F; Zeller, T; Baldus, S; Bickel, C; Sinning, CR; Wild, PS; Genth-Zotz, S; Warnholtz, A; Lackner, KJ; Münzel, T; Blankenberg, S; Keller, T (1 November 2012). "Prognostic information of glycogen phosphorylase isoenzyme BB in patients with suspected acute coronary syndrome". The American Journal of Cardiology. 110 (9): 1225–30. doi:10.1016/j.amjcard.2012.06.020. PMID   22818785.
  8. 1 2 Uno, K; Shimada, S; Tsuruta, J; Matsuzaki, H; Tashima, S; Ogawa, M (August 1998). "Nuclear localization of brain-type glycogen phosphorylase in some gastrointestinal carcinoma". The Histochemical Journal. 30 (8): 553–9. doi:10.1023/A:1003239302471. PMID   9792273.

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