Glycogen Phosphorylase: Difference between revisions
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<StructureSection load='1ygp' size='350' side='right' caption='Yeast glycogen phosphorylase dimer with pyridoxal-5-phosphate and phosphate (PDB entry [[1ygp]])' scene=''> | |||
=Introduction= | |||
'''Glycogen phosphorylase''' (GP) catalyzes the hydrolysis of glycogen to generate glucose-1-phosphate and shortened glycogen molecule and is considered the rate limiting step in the degradation of glycogen<ref name="gp">PMID: 15214781 </ref>. It is a part of the glucosyltransferase family and acts on the α-1,4-glycosidic linkage; the phosphorylase comes to a standstill 4 residues from an α-1,6-branchpoint, where debranching enzyme takes over <ref name =“gp3”> PMID: 11949930</ref>. The glucose-1-phophate is then further degraded via the pathway of glycolysis. Studies have found that mammals have liver, muscle and brain isoforms of phosphorylase but it is found among all species; muscle glycogen phosphorylase is present to degrade glycogen to forms of energy by means of glycolysis during muscle contractions and liver glycogen is present to regulate the blood glucose levels within the blood <ref name =“gp3”/><ref name="PLP">Palm D, Klein HW, Schinzel R, Buehner M, Helmreich EJM. The role of pyridoxal 5’-phosphate in glycogen phosphorylase catalysis. Biochemistry. 1990 Feb 6; 29(5):1099-1107.</ref>. See also [[Glycogen Metabolism & Gluconeogenesis]], [[Glycogenolysis]]. | |||
*'''Glycogen phosphorylase A''' which is usually active is phosphorylated on Ser 14 of each subunit. GP A is the liver isozyme. | |||
*'''Glycogen phosphorylase B''' is usually inactive and is the muscle isozyme. GP B is also called '''myophosphorylase'''<ref> PMID: 11318640</ref>. | |||
=Structure and Function= | =Structure and Function= | ||
Glycogen phosphorylase is a dimer consisting of two identical subunits and has an essential cofactor, <scene name='Sandbox_153/Plp/1'>pryridoxal phosphate (PLP)</scene><ref name="PLP"/>. Glycogen phosphorylase can be found in two different states, glycogen phosphorylase a (GP''a'') and glycogen phosphorylase b (GP''b'')<ref name="gp"/>The difference in the structures is due to phosphorylation of the <scene name='Sandbox_153/Ser14/1'>Ser-14</scene> residue which results in the active form (GP''a''). Protein phosphatases dephosphorylate the GP''a'' to the inactive form, also known as GP''b''. Both forms of glycogen phosphorylase can also be found in T and R states where T is the inactive state because it appears to have a low affinity for substrate and R is the active state where it appears to have a greater affinity for substrate<ref name="gp2">PMID: 1900534</ref>. | Glycogen phosphorylase is a dimer consisting of two identical subunits and has an essential cofactor, <scene name='Sandbox_153/Plp/1'>pryridoxal phosphate (PLP)</scene><ref name="PLP"/>. Glycogen phosphorylase can be found in two different states, glycogen phosphorylase a (GP''a'') and glycogen phosphorylase b (GP''b'')<ref name="gp"/>The difference in the structures is due to phosphorylation of the <scene name='Sandbox_153/Ser14/1'>Ser-14</scene> residue which results in the active form (GP''a''). Protein phosphatases dephosphorylate the GP''a'' to the inactive form, also known as GP''b''. Both forms of glycogen phosphorylase can also be found in T and R states where T is the inactive state because it appears to have a low affinity for substrate and R is the active state where it appears to have a greater affinity for substrate<ref name="gp2">PMID: 1900534</ref>. | ||
The secondary structures of T and R states of GP''a'' and ''b'' are similar with an <scene name='Sandbox_153/Nterminaldomain/2'>N-terminal domain </scene> and a <scene name='Sandbox_153/Cterminaldomain/1'>C-terminal domain </scene>.Each domain also contains subdomains which undergo conformational changes on the interconversion of T and R states <ref name="gp2"/>. C terminal domain has the cofactor PLP and part of the active site, it is made up of five α helices and 6 β strands<ref name="structureandfunction">Fletterick RJ, Sprang SR. Glycogen phosphorylase Structures and function. Accounts of Chemical Research. 1982 Nov; 15(11):361-369.</ref>. The N-terminal domain consisting of fifteen α helices and nine β strands, is considered to be more complex and is divided in the middle of its β sheet core into subdomains. The first domain binds the effector molecule of AMP and also has a recognition site of the introconverting phosphorylase kinase and phosphatase<ref name="gp2"/><ref name="structureandfunction"/>. The second domain has the polysaccharide binding domain where phosphorylase is able to attach to the glycogen substrate <ref name="structureandfunction"/>. The R states of GP''a'' and GP''b'' are almost identical; the difference lays in the modification of the Ser-14 residue where GP''a'' has a covalently linked phosphate group whereas GP''b'' has a non-covalently linked sulfide group . GP''a'' is activated by phosphorylation of the serine residue whereas GP''b'' can be activated by the binding of AMP to the <scene name='Sandbox_153/Activesites/3'>allosteric sites </scene> that are present within the molecule<ref name="gp2"/>. GP''a'' does not require the binding of AMP but attachment enhances the activity of the enzyme upwards to 25% <ref name="allosteric"> Johnson LH. Glycogen Phosphorylase: Control by phosphorylation and allosteric effectors. The FASEB Journal. 1992 March;6:2274-2282.</ref>. | The secondary structures of T and R states of GP''a'' and ''b'' are similar with an <scene name='Sandbox_153/Nterminaldomain/2'>N-terminal domain </scene> and a <scene name='Sandbox_153/Cterminaldomain/1'>C-terminal domain </scene>.Each domain also contains subdomains which undergo conformational changes on the interconversion of T and R states <ref name="gp2"/>. C terminal domain has the cofactor PLP and part of the active site, it is made up of five α helices and 6 β strands<ref name="structureandfunction">Fletterick RJ, Sprang SR. Glycogen phosphorylase Structures and function. Accounts of Chemical Research. 1982 Nov; 15(11):361-369.</ref>. The N-terminal domain consisting of fifteen α helices and nine β strands, is considered to be more complex and is divided in the middle of its β sheet core into subdomains. | ||
The first domain binds the effector molecule of AMP and also has a recognition site of the introconverting phosphorylase kinase and phosphatase<ref name="gp2"/><ref name="structureandfunction"/>. The second domain has the polysaccharide binding domain where phosphorylase is able to attach to the glycogen substrate <ref name="structureandfunction"/>. The R states of GP''a'' and GP''b'' are almost identical; the difference lays in the modification of the <scene name='38/382926/Ser14_interactions/1'>Ser-14</scene> residue where GP''a'' has a covalently linked phosphate group whereas GP''b'' has a non-covalently linked sulfide group . GP''a'' is activated by phosphorylation of the serine residue whereas GP''b'' can be activated by the binding of AMP to the <scene name='Sandbox_153/Activesites/3'>allosteric sites </scene> that are present within the molecule<ref name="gp2"/>. GP''a'' does not require the binding of AMP but attachment enhances the activity of the enzyme upwards to 25% <ref name="allosteric"> Johnson LH. Glycogen Phosphorylase: Control by phosphorylation and allosteric effectors. The FASEB Journal. 1992 March;6:2274-2282.</ref>. | |||
Glycogen phosphorylase is different from other enzymes that require the cofactor PLP because instead of utilizing the pyrimidine ring, phosphorylase uses the phosphate group <ref name="allosteric"/>. The 4'aldehyde of PLP binds to the ε-amino group of lysine 680 and the 5'-phosphate of PLP has been found to be the group participating in the catalysis of glycogen phosphorylase <ref name="PLP"/>. The binding sites in glycogen phosphorylase include: a catalytic, inhibiting, AMP, glycogen and new allosteric site <ref name="gp"/>. The glycogen binding site is located more than 30Å from the catalytic and allosteric sites. The residues that make up the site are <scene name='Sandbox_153/Glycogen_binding_site/1'>Arg426, Glu433, Gly434, and Ala435</scene><ref name="allosteric"/>. The <scene name='Sandbox_153/Inhibitorbindingsite/1'>inhibitor site</scene>binds purine analogs or fused-ring molecules such as adenosine, caffeine, FMN, NADH and AMP when there are increased concentrations available<ref name="gp2"/>. The heterocyclic rings of the compounds bind to the inhibiting site, stablilizing it and blocking access to the catalytic center <ref name="allosteric"/>. The <scene name='Sandbox_153/Catalyticsite/1'>catalytic site</scene> can be accessed once the Ser-14 residue has been phosphorylated and conformational changes in glycogen phosphorylation have been observed<ref name="structureandfunction"/><ref name="allosteric"/>. The structure and function of glycogen phosphorylase is complex, though the function of the enzyme is due to the structure. | Glycogen phosphorylase is different from other enzymes that require the cofactor PLP because instead of utilizing the pyrimidine ring, phosphorylase uses the phosphate group <ref name="allosteric"/>. The 4'aldehyde of PLP binds to the ε-amino group of lysine 680 and the 5'-phosphate of PLP has been found to be the group participating in the catalysis of glycogen phosphorylase <ref name="PLP"/>. The binding sites in glycogen phosphorylase include: a catalytic, inhibiting, AMP, glycogen and new allosteric site <ref name="gp"/>. The glycogen binding site is located more than 30Å from the catalytic and allosteric sites. The residues that make up the site are <scene name='Sandbox_153/Glycogen_binding_site/1'>Arg426, Glu433, Gly434, and Ala435</scene><ref name="allosteric"/>. The <scene name='Sandbox_153/Inhibitorbindingsite/1'>inhibitor site</scene>binds purine analogs or fused-ring molecules such as adenosine, caffeine, FMN, NADH and AMP when there are increased concentrations available<ref name="gp2"/>. The heterocyclic rings of the compounds bind to the inhibiting site, stablilizing it and blocking access to the catalytic center <ref name="allosteric"/>. The <scene name='Sandbox_153/Catalyticsite/1'>catalytic site</scene> can be accessed once the Ser-14 residue has been phosphorylated and conformational changes in glycogen phosphorylation have been observed<ref name="structureandfunction"/><ref name="allosteric"/>. The structure and function of glycogen phosphorylase is complex, though the function of the enzyme is due to the structure. | ||
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1GPA is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus]. Additional information on 1GPA is available in a page on [http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb24_1.html Glycogen Phosphorylase] at the RCSB PDB [http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GPA OCA]. | 1GPA is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus]. Additional information on 1GPA is available in a page on [http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb24_1.html Glycogen Phosphorylase] at the RCSB PDB [http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GPA OCA]. | ||
=3D structures of glycogen phosphorylase= | |||
[[Glycogen phosphorylase 3D structures]] | |||
[[ | |||
</StructureSection> | |||
=Additional Resources= | |||
For additional information, see: [[Carbohydrate Metabolism]] | For additional information, see: [[Carbohydrate Metabolism]] | ||
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