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 Glucose 1-phosphate (also called cori ester) is a glucose molecule with a phosphate group on the 1'-carbon. It can exist in either the α- or β-anomeric form. Reactions of α-glucose 1-phosphate Catabolic In glycogenolysis, it is the direct pro ...

from liver

glycogen Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body. Glycogen functions as one o ...

stores. This protein switches from inactive phosphorylase B to active phosphorylase A by

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

of serine residue 14. Activity of this enzyme is further regulated by multiple

allosteric In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site. The site to which the effector binds is termed the ''allosteric site ...

effectors and hormonal controls. Humans have three glycogen phosphorylase genes that encode distinct isozymes that are primarily expressed in liver, brain and

muscle Skeletal muscles (commonly referred to as muscles) are 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 types of muscl ...

, respectively. The liver isozyme serves the

glycemic The glycemic response to a food or meal is the effect that food or meal has on blood sugar (glucose) levels after consumption.Sadler M. Food, Glycaemic Response and Health. ILSI Europe Concise Monograph Series 2011:1-30Available from ILSI Europe ...

demands of the body in general while the brain and muscle isozymes supply just those tissues. In

glycogen storage disease type VI Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body. Glycogen functions as one of ...

, also known as Hers disease, mutations in liver glycogen phosphorylase inhibit the conversion of glycogen to glucose and results in moderate hypoglycemia, mild

ketosis Ketosis is a metabolic state characterized by elevated levels of ketone bodies in the blood or urine. Physiological ketosis is a normal response to low glucose availability, such as low-carbohydrate diets or fasting, that provides an additional ...

, growth retardation and hepatomegaly.

Alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...

results in multiple transcript variants encoding different isoforms rovided by RefSeq, Feb 2011

Structure

The ''PYGL'' gene encodes one of three major glycogen phosphorylase isoforms, which are distinguished by their different structures and

subcellular localization The cells of eukaryotic organisms are elaborately subdivided into functionally-distinct membrane-bound compartments. Some major constituents of eukaryotic cells are: extracellular space, plasma membrane, cytoplasm, nucleus, mitochondria, Golgi ap ...

s: brain ( PYGB), muscle (PYGM), and liver (PYGL). 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. This protein forms a homodimer, with each monomer composed of

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

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 Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (locomotion), the surface over which an organism lo ...

glycogen. This cofactor is attached by a covalent Schiff base linkage to Lys-680 in the C-terminal domain. 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 Phosphorylase kinase (PhK) is a serine/threonine-specific protein kinase which activates glycogen phosphorylase to release glucose-1-phosphate from glycogen. PhK phosphorylates glycogen phosphorylase at two serine residues, triggering a conformatio ...

and dephosphorylated by the phosphatase

PP1 Protein phosphatase 1 (PP1) belongs to a certain class of phosphatases known as protein serine/threonine phosphatases. This type of phosphatase includes metal-dependent protein phosphatases (PPMs) and aspartate-based phosphatases. PP1 has been f ...

, and the AMP site, which is connected to the active site by an adenine loop. Phosphorylation or binding of the

sites induce conformational change that activates the enzyme.

Function

As a glycogen phosphorylase, PYGL catalyzes the

phosphorolysis Phosphorolysis is the cleavage of a compound in which inorganic phosphate is the attacking group. It is analogous to hydrolysis.Stryer, L. (1988) Biochemistry, 3rd ed., Freeman (p. 451) An example of this is glycogen breakdown by glycogen phospho ...

of an α-1, 4-glycosidic bond in glycogen to yield glucose 1-phosphate. Degradation of glycogen The glucose 1-phosphate product then contributes to

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 ...

and other biosynthetic functions for energy metabolism. 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. 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. Though other tissues may express all three forms in different proportions, the purpose of expressing multiple glycogen phosphorylases remains unclear.

Clinical Significance

PYGL has been implicated in

, also known as Hers disease, and both type 1 and type 2 diabetes. 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. 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. Glycogen-induced hepatomegaly in type 1 diabetes and glycogen storage disease type VI present similar clinical manifestations such as liver dysfunction, fasting hypoglycemia, and

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.

References