PYGL

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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. [1] [2] 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]. [1]

Contents

Structure

The PYGL 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). [3] [4] PYGL spans 846 amino acids and shares fairly high homology in amino acid sequence with the other two isozymes, with 73% similarity with PYGM and 74% similarity with PYGB. Nonetheless, PYGB and PYGM demonstrate greater homology to each other, indicating that PYGL evolved by a more distant descent from the common ancestral gene. [3] [5] This protein forms a homodimer, with each monomer composed of N-terminal and C-terminal domains of nearly equal size. The catalytic site forms at the interface between these two domains and interacts with the required cofactor, pyridoxal phosphate, to bind the substrate glycogen. [5] [6] This cofactor is attached by a covalent Schiff base linkage to Lys-680 in the C-terminal domain. [5] At the opposite side of the enzyme, the regulatory face opens up to the cytosol and contains the phosphorylation peptide, which is phosphorylated by phosphorylase kinase and dephosphorylated by the phosphatase PP1, and the AMP site, which is connected to the active site by an adenine loop. [5] Phosphorylation or binding of the allosteric sites induce conformational change that activates the enzyme. [5]

Function

As a glycogen phosphorylase, PYGL catalyzes the phosphorolysis of an α-1, 4-glycosidic bond in glycogen to yield glucose 1-phosphate. [4] [5] [7] Degradation of glycogen [7] [8] The glucose 1-phosphate product then contributes to glycolysis and other biosynthetic functions for energy metabolism. [4] [5] As the major isozyme in liver, PYGL is responsible for maintaining blood glucose homeostasis by regulating the release of glucose 1-phosphate from liver glycogen stores. [6] [7] [3] [9] One model suggests that Ca2+ oscillations play a role in activating glycogen phosphorylase in glycogen degradation in liver cells. Through its function in the liver, PYGL is also central to meeting the glycemic demands of the entire body. [5] Though other tissues may express all three forms in different proportions, the purpose of expressing multiple glycogen phosphorylases remains unclear. [7] [10]

Clinical Significance

PYGL has been implicated in glycogen storage disease type VI, also known as Hers disease, and both type 1 and type 2 diabetes. [7] [5] [11] Glycogen storage disease type VI has been attributed to PYGL deficiency as a result of causal mutations in PYGL gene, including two splice-site mutations and two missense mutations. [7] [11] [4] The function of PYGL in regulating liver glucose production also plays a role in diabetes. Since hyperglycemia in type 2 diabetes is the result of excessive glucose production by the liver, developing a drug that targets PYGL may prove effective in controlling blood glucose levels. [5] [6] Glycogen-induced hepatomegaly in type 1 diabetes and glycogen storage disease type VI present similar clinical manifestations such as liver dysfunction, fasting hypoglycemia, and ketosis. [11] [4]

Interactions

Inhibitors

PYGL has been known to interact with allosteric inhibitors, including Bayer W1807 and sugar derivatives that bind the glucose inhibitor site. In addition, glucose and purines stabilize the inactive conformation of PYGL, thus inhibiting binding to its active site. [6]

See also

Related Research Articles

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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">Phosphofructokinase 1</span> Class of enzymes

Phosphofructokinase-1 (PFK-1) is one of the most important regulatory enzymes of glycolysis. It is an allosteric enzyme made of 4 subunits and controlled by many activators and inhibitors. PFK-1 catalyzes the important "committed" step of glycolysis, the conversion of fructose 6-phosphate and ATP to fructose 1,6-bisphosphate and ADP. Glycolysis is the foundation for respiration, both anaerobic and aerobic. Because phosphofructokinase (PFK) catalyzes the ATP-dependent phosphorylation to convert fructose-6-phosphate into fructose 1,6-bisphosphate and ADP, it is one of the key regulatory steps of glycolysis. PFK is able to regulate glycolysis through allosteric inhibition, and in this way, the cell can increase or decrease the rate of glycolysis in response to the cell's energy requirements. For example, a high ratio of ATP to ADP will inhibit PFK and glycolysis. The key difference between the regulation of PFK in eukaryotes and prokaryotes is that in eukaryotes PFK is activated by fructose 2,6-bisphosphate. The purpose of fructose 2,6-bisphosphate is to supersede ATP inhibition, thus allowing eukaryotes to have greater sensitivity to regulation by hormones like glucagon and insulin.

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

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">Phosphorylase</span> Class of enzymes

In biochemistry, phosphorylases are enzymes that catalyze the addition of a phosphate group from an inorganic phosphate (phosphate+hydrogen) to an acceptor.

Glycogenesis is the process of glycogen synthesis, in which glucose molecules are added to chains of glycogen for storage. This process is activated during rest periods following the Cori cycle, in the liver, and also activated by insulin in response to high glucose levels.

<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.

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Glycogen storage disease type I is an inherited disease that prevents the liver from properly breaking down stored glycogen, which is necessary to maintain adequate blood sugar levels. GSD I is divided into two main types, GSD Ia and GSD Ib, which differ in cause, presentation, and treatment. There are also possibly rarer subtypes, the translocases for inorganic phosphate or glucose ; however, a recent study suggests that the biochemical assays used to differentiate GSD Ic and GSD Id from GSD Ib are not reliable, and are therefore GSD Ib.

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<span class="mw-page-title-main">Glucose 6-phosphatase</span> Enzyme

The enzyme glucose 6-phosphatase (EC 3.1.3.9, G6Pase; systematic name D-glucose-6-phosphate phosphohydrolase) catalyzes the hydrolysis of glucose 6-phosphate, resulting in the creation of a phosphate group and free glucose:

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<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.

<span class="mw-page-title-main">Enzyme activator</span> Molecules which increase enzyme activity

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

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Glycogen phosphorylase, brain, 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]

References

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