GLYCOGEN BIOSYNTHETIC PATHWAY (PW:0000532)
Description
Glycogen - the storage form of glucose - is a ramified
polysaccharide formed by alpha1-4
linked glucose units branching at alpha1-6
bonds. Upon uptake into the cell, glucose is rapidly phosphorylated to G6P, a
key molecule at the intersection of several pathways of glucose metabolism. In
the glycogen biosynthetic pathway, G6P is converted to G1P via the reversible
reaction carried out by phosphoglucomutases (Pgm). UDP-glucose
pyrophosphorylase (Ugp2) catalyzes the formation of UDP-glucose by combining
G1P and UTP; hydrolysis of Ppi by the inorganic pyrophosphatase renders the
overall reaction exergonic. The initial priming of glycogen is carried out by
the self-glucosylating protein glycogenin (Gyg). Glycogen is then extended and
branched by glycogen synthase (Gys) and the glycogen branching enzyme (Gbe1),
respectively. Glycogen synthase catalyzes the transfer of glucosyl groups from
UDP-glucose to glycogen via alpha1-4
linkage; when the elongated glycogen has at least 11 residues, the branching
enzyme transfers a chain of ~seven glucosyl groups to another chain via alpha1-6
linkage. G6P is an allosteric regulator of glycogen synthase as well as
glycogen phosphorylase, a key component of the glycogen degradation pathway. Note
that the two essential enzymes of glycogen metabolism are subject to covalent
and allosteric regulation, aspects of which cross paths in opposite directions.
Glycogen synthase is inactivated and activated by phosphorylation/dephosphorylation,
respectively. The allosteric activation by G6P involves unfolding of the
enzyme which overrides the effect of phosphorylation and conformational changes
that prime it for dephosphorylation. Several kinases, including glycogen
synthase kinase-3 (Gsk3) phosphorylate the synthase; dephosphorylation is
primarily mediated by protein phosphatase-1 (Pp-1). The phosphatase is a
complex between a catalytic subunit encoded by three genes in mammals and any
of a host of regulatory subunits that allow for the formation of a variety of
distinct multimeric holoenzymes that regulate many cellular processes. In the
case of glycogen metabolism, the glycogen or G-targeting subunits are part of
the Pp-1 complex anchored to the glycogen particles to which the key enzymes of
glycogen anabolism and catabolism are bound. Pp-1 also modifies and inactivates
glycogen phosphorylase and phosphorylase kinase; the first, as mentioned, is a
key enzyme of glycogen degradation and the second is its activator.
Thus, the two arms of glycogen metabolism are
closely regulated at the level of the key enzymes involved in them. To see the ontology report for annotations, GViewer and download click here [click to see
the ontology report for associated GO term - GO:0005978 and entry at Reactome -
REACT_1736.2 ]
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Pathway Diagram:
Genes in Pathway:
G
Gbe1
1,4-alpha-glucan branching enzyme 1
IDA
RGD
PMID:6449198
RGD:1642743
NCBI chr11:22,181,194...22,446,640
Ensembl chr11:22,181,103...22,446,638
G
Gck
glucokinase
IDA
RGD
PMID:15138155
RGD:1582633
NCBI chr14:84,999,019...85,041,098
Ensembl chr14:84,999,020...85,040,949
G
Gsk3a
glycogen synthase kinase 3 alpha
ISO
RGD
PMID:17530463
RGD:2306093
NCBI chr 1:89,943,669...89,953,514
Ensembl chr 1:89,943,669...89,953,593
G
Gsk3b
glycogen synthase kinase 3 beta
ISO
RGD
PMID:17530463
RGD:2306093
NCBI chr11:76,004,502...76,154,665
Ensembl chr11:76,009,507...76,153,249
G
Gyg1
glycogenin 1
IDA
RGD
PMID:8224611 PMID:10710493
RGD:2303736 , RGD:2304070
NCBI chr 2:104,540,927...104,583,038
Ensembl chr 2:104,540,533...104,582,818
G
Gys1
glycogen synthase 1
ISO IDA
RGD
PMID:12297270 PMID:6449198
RGD:2304106 , RGD:1642743
NCBI chr 1:105,051,916...105,071,763
Ensembl chr 1:105,051,961...105,072,419
G
Gys2
glycogen synthase 2
IDA ISO
RGD
PMID:15138155 PMID:12297270 PMID:6449198
RGD:1582633 , RGD:2304106 , RGD:1642743
NCBI chr 4:177,096,063...177,137,236
Ensembl chr 4:177,096,063...177,137,236
G
Pgm1
phosphoglucomutase 1
ISO
RGD
PMID:9549096
RGD:2304188
NCBI chr 5:119,710,734...119,770,159
Ensembl chr 5:119,710,737...119,770,159
G
Pgm2
phosphoglucomutase 2
ISO
RGD
PMID:9549096
RGD:2304188
NCBI chr14:44,519,906...44,553,420
Ensembl chr14:44,519,906...44,553,770
G
Pgm3
phosphoglucomutase 3
ISO
RGD
PMID:9549096
RGD:2304188
NCBI chr 8:96,398,331...96,416,045
Ensembl chr 8:96,398,269...96,416,021
G
Ppp1ca
protein phosphatase 1 catalytic subunit alpha
ISO IDA
RGD
PMID:14715909 PMID:7720853
RGD:2304325 , RGD:2304267
NCBI chr 1:210,914,576...210,918,193
Ensembl chr 1:210,914,567...210,918,193
G
Ppp1cb
protein phosphatase 1 catalytic subunit beta
ISO IDA
RGD
PMID:14715909 PMID:7720853
RGD:2304325 , RGD:2304267
NCBI chr 6:29,681,099...29,712,835
Ensembl chr 6:29,681,100...29,712,924
G
Ppp1cc
protein phosphatase 1 catalytic subunit gamma
ISO
RGD
PMID:14715909
RGD:2304325
NCBI chr12:40,043,822...40,061,301
Ensembl chr12:40,043,822...40,061,341
G
Ppp1r3a
protein phosphatase 1, regulatory subunit 3A
ISO
RGD
PMID:14715909
RGD:2304325
NCBI chr 4:43,905,648...43,946,236
Ensembl chr 4:43,905,648...43,946,236
G
Ppp1r3b
protein phosphatase 1, regulatory subunit 3B
ISO IDA
RGD
PMID:14715909 PMID:7720853 PMID:11716774
RGD:2304325 , RGD:2304267 , RGD:2306167
NCBI chr16:63,533,318...63,545,683
Ensembl chr16:63,532,842...63,549,997
G
Ppp1r3c
protein phosphatase 1, regulatory subunit 3C
IDA
RGD
PMID:11716774
RGD:2306167
NCBI chr 1:243,873,524...243,878,527
Ensembl chr 1:243,871,704...243,878,835
G
Ppp1r3d
protein phosphatase 1, regulatory subunit 3D
IDA
RGD
PMID:11716774
RGD:2306167
NCBI chr 3:185,880,087...185,883,158
Ensembl chr 3:185,876,709...185,883,703
G
Ppp1r3e
protein phosphatase 1, regulatory subunit 3E
IDA
RGD
PMID:15752363
RGD:2306166
NCBI chr15:32,318,435...32,319,595
Pathway Gene Annotations
Disease Annotations Associated with Genes in the glycogen biosynthetic pathway
Gbe1 autosomal recessive cutis laxa type IB , Familial Cirrhosis with Deposition of Abnormal Glycogen , fetal akinesia deformation sequence syndrome 1 , genetic disease , glycogen storage disease , glycogen storage disease IV , GSD IV, Classic Hepatic , GSD IV, combined hepatic and myopathic , GSD IV, Neuromuscular Form, Childhood , GSD IV, Neuromuscular Form, Congenital , GSD IV, Neuromuscular Form, Fatal Perinatal , osteogenesis imperfecta type 15 , Polyglucosan Body Disease, Adult Form , polyneuropathy , pulmonary tuberculosis Gck Bone Marrow Failure Syndrome 2 , Congenital Hyperinsulinism , coronary artery disease , diabetes mellitus , Experimental Diabetes Mellitus , Experimental Liver Cirrhosis , familial hyperinsulinemic hypoglycemia 3 , genetic disease , gestational diabetes , hyperglycemia , hyperinsulinemic hypoglycemia , hyperinsulinism , hypertension , hypoglycemia , Insulin Resistance , Liver Injury , maturity-onset diabetes of the young , maturity-onset diabetes of the young type 1 , maturity-onset diabetes of the young type 2 , maturity-onset diabetes of the young type 3 , Metabolic Syndrome , neonatal diabetes mellitus , Nijmegen breakage syndrome , obesity , permanent neonatal diabetes mellitus , Permanent Neonatal Diabetes Mellitus 1 , steatotic liver disease , transient neonatal diabetes mellitus , type 2 diabetes mellitus Gsk3a Alzheimer's disease , amyotrophic lateral sclerosis , bipolar disorder , craniosynostosis , depressive disorder , dilated cardiomyopathy , Experimental Diabetes Mellitus , Left Ventricular Hypertrophy , Parkinsonism , schizophrenia Gsk3b Aberrant Crypt Foci , acute kidney failure , acute myocardial infarction , Alzheimer's disease , amyotrophic lateral sclerosis , bipolar disorder , Brain Injuries , Breast Neoplasms , Burns , Cardiomegaly , cognitive disorder , colon cancer , Colonic Neoplasms , colorectal adenocarcinoma , congestive heart failure , degenerative disc disease , depressive disorder , diabetic encephalopathy , Diabetic Nephropathies , dilated cardiomyopathy , Drug-Induced Dyskinesia , endometrial carcinoma , Endometrial Neoplasms , Experimental Arthritis , Experimental Mammary Neoplasms , Hearing Loss, Cisplatin-Induced , heart disease , hypertension , intellectual disability , Intestinal Neoplasms , Liver Reperfusion Injury , mantle cell lymphoma , middle cerebral artery infarction , Multiple Abnormalities , muscular atrophy , myocardial infarction , Myocardial Reperfusion Injury , Neoplastic Cell Transformation , neuronal ceroid lipofuscinosis 6A , oral squamous cell carcinoma , Ovarian Neoplasms , Parkinson's disease , peritonitis , Poisoning , Prostatic Neoplasms , schizophrenia , sciatic neuropathy , Sepsis , status epilepticus , Subarachnoid Hemorrhage , substance-related disorder , Tachycardia , tauopathy , type 2 diabetes mellitus , urinary bladder cancer , vascular dementia Gyg1 Cardiac Arrhythmias , genetic disease , glycogen storage disease , glycogen storage disease XV , Muscle Weakness , Myocardial Ischemia , Polyglucosan Body Myopathy 2 Gys1 cardiovascular system disease , genetic disease , Glycogen Storage Disease 0, Muscle , Insulin Resistance Gys2 genetic disease , glycogen storage disease , Glycogen Storage Disease 0, Liver , hepatocellular carcinoma , schizophrenia Pgm1 Chemical and Drug Induced Liver Injury , Colorectal Neoplasms , congenital disorder of glycosylation , congenital disorder of glycosylation It , endometrial cancer , genetic disease , Myocardial Ischemia , teratoma Pgm2 COVID-19 Pgm3 cervical cancer , genetic disease , hyper IgE syndrome , immunodeficiency 23 , severe combined immunodeficiency , teratoma Ppp1ca congestive heart failure , dilated cardiomyopathy Ppp1cb Dandy-Walker syndrome , Desbuquois dysplasia , genetic disease , Noonan syndrome , Noonan syndrome-like disorder with loose anagen hair 2 , osteogenesis imperfecta type 4 , RASopathy , vitamin D-dependent rickets type 1A Ppp1cc congestive heart failure , Ovarian Neoplasms , Spinal Cord Injuries Ppp1r3a diabetes mellitus , hypoglycemia , Insulin Resistance , maturity-onset diabetes of the young type 1 , type 2 diabetes mellitus Ppp1r3b Experimental Liver Cirrhosis Ppp1r3c Experimental Liver Cirrhosis , prostate cancer , type 2 diabetes mellitus
Aberrant Crypt Foci Gsk3b acute kidney failure Gsk3b acute myocardial infarction Gsk3b Alzheimer's disease Gsk3a , Gsk3b amyotrophic lateral sclerosis Gsk3a , Gsk3b autosomal recessive cutis laxa type IB Gbe1 bipolar disorder Gsk3a , Gsk3b Bone Marrow Failure Syndrome 2 Gck Brain Injuries Gsk3b Breast Neoplasms Gsk3b Burns Gsk3b Cardiac Arrhythmias Gyg1 Cardiomegaly Gsk3b cardiovascular system disease Gys1 cervical cancer Pgm3 Chemical and Drug Induced Liver Injury Pgm1 cognitive disorder Gsk3b colon cancer Gsk3b Colonic Neoplasms Gsk3b colorectal adenocarcinoma Gsk3b Colorectal Neoplasms Pgm1 congenital disorder of glycosylation Pgm1 congenital disorder of glycosylation It Pgm1 Congenital Hyperinsulinism Gck congestive heart failure Gsk3b , Ppp1ca , Ppp1cc coronary artery disease Gck COVID-19 Pgm2 craniosynostosis Gsk3a Dandy-Walker syndrome Ppp1cb degenerative disc disease Gsk3b depressive disorder Gsk3a , Gsk3b Desbuquois dysplasia Ppp1cb diabetes mellitus Gck , Ppp1r3a diabetic encephalopathy Gsk3b Diabetic Nephropathies Gsk3b dilated cardiomyopathy Gsk3a , Gsk3b , Ppp1ca Drug-Induced Dyskinesia Gsk3b endometrial cancer Pgm1 endometrial carcinoma Gsk3b Endometrial Neoplasms Gsk3b Experimental Arthritis Gsk3b Experimental Diabetes Mellitus Gck , Gsk3a Experimental Liver Cirrhosis Gck , Ppp1r3b , Ppp1r3c Experimental Mammary Neoplasms Gsk3b Familial Cirrhosis with Deposition of Abnormal Glycogen Gbe1 familial hyperinsulinemic hypoglycemia 3 Gck fetal akinesia deformation sequence syndrome 1 Gbe1 genetic disease Gbe1 , Gck , Gyg1 , Gys1 , Gys2 , Pgm1 , Pgm3 , Ppp1cb gestational diabetes Gck glycogen storage disease Gbe1 , Gyg1 , Gys2 Glycogen Storage Disease 0, Liver Gys2 Glycogen Storage Disease 0, Muscle Gys1 glycogen storage disease IV Gbe1 glycogen storage disease XV Gyg1 GSD IV, Classic Hepatic Gbe1 GSD IV, combined hepatic and myopathic Gbe1 GSD IV, Neuromuscular Form, Childhood Gbe1 GSD IV, Neuromuscular Form, Congenital Gbe1 GSD IV, Neuromuscular Form, Fatal Perinatal Gbe1 Hearing Loss, Cisplatin-Induced Gsk3b heart disease Gsk3b hepatocellular carcinoma Gys2 hyper IgE syndrome Pgm3 hyperglycemia Gck hyperinsulinemic hypoglycemia Gck hyperinsulinism Gck hypertension Gck , Gsk3b hypoglycemia Gck , Ppp1r3a immunodeficiency 23 Pgm3 Insulin Resistance Gck , Gys1 , Ppp1r3a intellectual disability Gsk3b Intestinal Neoplasms Gsk3b Left Ventricular Hypertrophy Gsk3a Liver Injury Gck Liver Reperfusion Injury Gsk3b mantle cell lymphoma Gsk3b maturity-onset diabetes of the young Gck maturity-onset diabetes of the young type 1 Gck , Ppp1r3a maturity-onset diabetes of the young type 2 Gck maturity-onset diabetes of the young type 3 Gck Metabolic Syndrome Gck middle cerebral artery infarction Gsk3b Multiple Abnormalities Gsk3b Muscle Weakness Gyg1 muscular atrophy Gsk3b myocardial infarction Gsk3b Myocardial Ischemia Gyg1 , Pgm1 Myocardial Reperfusion Injury Gsk3b neonatal diabetes mellitus Gck Neoplastic Cell Transformation Gsk3b neuronal ceroid lipofuscinosis 6A Gsk3b Nijmegen breakage syndrome Gck Noonan syndrome Ppp1cb Noonan syndrome-like disorder with loose anagen hair 2 Ppp1cb obesity Gck oral squamous cell carcinoma Gsk3b osteogenesis imperfecta type 15 Gbe1 osteogenesis imperfecta type 4 Ppp1cb Ovarian Neoplasms Gsk3b , Ppp1cc Parkinson's disease Gsk3b Parkinsonism Gsk3a peritonitis Gsk3b permanent neonatal diabetes mellitus Gck Permanent Neonatal Diabetes Mellitus 1 Gck Poisoning Gsk3b Polyglucosan Body Disease, Adult Form Gbe1 Polyglucosan Body Myopathy 2 Gyg1 polyneuropathy Gbe1 prostate cancer Ppp1r3c Prostatic Neoplasms Gsk3b pulmonary tuberculosis Gbe1 RASopathy Ppp1cb schizophrenia Gsk3a , Gsk3b , Gys2 sciatic neuropathy Gsk3b Sepsis Gsk3b severe combined immunodeficiency Pgm3 Spinal Cord Injuries Ppp1cc status epilepticus Gsk3b steatotic liver disease Gck Subarachnoid Hemorrhage Gsk3b substance-related disorder Gsk3b Tachycardia Gsk3b tauopathy Gsk3b teratoma Pgm1 , Pgm3 transient neonatal diabetes mellitus Gck type 2 diabetes mellitus Gck , Gsk3b , Ppp1r3a , Ppp1r3c urinary bladder cancer Gsk3b vascular dementia Gsk3b vitamin D-dependent rickets type 1A Ppp1cb