UREA CYCLE PATHWAY (PW:0000076)
Description
The urea cycle, the first known metabolic cycle, was elucidated by Krebs and Henseleit in 1932. It is composed of seven gene products, and operates predominantly in mammals to eliminate excess nitrogen arising from the breakdown of amino acids through the synthesis in the liver of urea, which is then excreted, while the amino acid carbon skeletons are converted to glucose or glycogen. Mitochondrial carbamoyl-phosphate synthetase (Cps1) condenses ammonia from amino acid catabolism, the first of urea's two nitrogens, and HCO3- to form input molecule carbamoyl phosphate in a reaction requiring two ATP. A related enzyme, CpsII or Cad, uses glutamine as its nitrogen donor and participates in pyrimidine biosynthesis. N-acetylglutamate transferase (Nags) converts Acetyl CoA and glutamate into N-acetylglutamate (NAG), an allosteric activator of Cps1. Nags deficiency leads to hyperammonemia, as Cps1 is inactive in the absence of NAG. Ornithine transcarbamoylase (Otc) then transfers the carbamoyl moiety of carbamoyl phosphate to ornithine to form citrulline in the mitochondrion, which is then exported to the cytosol. Otc deficiency can result in orotic aciduria. Argininosuccinate synthetase (Ass1) carries out the first step in the generation of arginine from citrulline. This is the ATP-dependent linking of citrulline and aspartate, carrying the second urea nitrogen, to form argininosuccinate. The second step is the cleavage of this product by argininosuccinate lyase (Asl) to generate arginine and fumarate. Ass1 and Asl along with nitric oxide synthase (Nos) form an abbreviated version of the cycle called the arginine-citrulline cycle, responsible for generating the key signaling molecule nitric oxide during the conversion of arginine back to citrulline. The final reaction of the urea cycle is carried out by the enzyme arginase. There are two isoenzymes; cytosolic arginase I (Arg1) is found in the liver and is the enzyme involved in the urea cycle. Arginase II is found in mitochondria of peripheral tissues such as the kidney and small intestine. Arginase I hydrolyzes arginine to regenerate ornithine and release for excretion the relatively nontoxic urea, bearing its two nitrogens. The ornithine is then imported into the mitochondrion in exchange for citrulline via the mitochondrial ornithine transporter, Ornt1 or Slc25a15, for another cycle. Slc25a15 defects can result in ornithine translocase deficiency, or hyperornithinemia-hyperammonemia-homocitrullinemia syndrome (HHH syndrome). As stated above, the first cycle enzyme Cps1 is activated by N-acetyl glutamate, whose level is directly related to the rate of amino acid breakdown. Thus, the increased nitrogen from elevated amino acid degradation is effectively dealt with by increased generation of easily eliminated urea by the urea cycle.
To see the ontology report for annotations, GViewer and download, click
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to see the ontology report for associated GO term -
GO:0000076 and related entry at Reactome -
REACT_R-HSA-70635 ]
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Pathway Diagram:
Genes in Pathway:
G
Arg1 arginase 1
IDA ISO SMPDB PMID:4062872 SMP:00059, RGD:2300098
NCBI chr 1:22,295,093...22,307,720
G
Arg2 arginase 2
ISO RGD
PMID:19764983 RGD:4144088
NCBI chr 6:103,669,001...103,694,375
G
Asl argininosuccinate lyase
IDA ISO SMPDB PMID:4062872 SMP:00059, RGD:2300098
NCBI chr12:32,295,779...32,313,257
G
Ass1 argininosuccinate synthase 1
IDA ISO SMPDB PMID:4062872 SMP:00059, RGD:2300098
NCBI chr 3:35,144,765...35,194,632
G
Cps1 carbamoyl-phosphate synthase 1
IDA ISO SMPDB PMID:3680220 PMID:4062872 SMP:00059, RGD:1582379 , RGD:2300098
NCBI chr 9:76,063,863...76,186,739
G
Gls2 glutaminase 2
ISO SMPDB SMP:00059
NCBI chr 7:1,201,757...1,218,014
G
Glud1 glutamate dehydrogenase 1
ISO SMPDB SMP:00059
NCBI chr16:9,646,569...9,680,215
G
Got2 glutamic-oxaloacetic transaminase 2
ISO SMPDB SMP:00059
NCBI chr19:9,180,428...9,206,113
G
Gpt glutamic--pyruvic transaminase
ISO SMPDB SMP:00059
NCBI chr 7:110,295,599...110,300,134
G
Otc ornithine transcarbamylase
IDA ISO SMPDB PMID:3680220 PMID:4062872 SMP:00059, RGD:1582379 , RGD:2300098
NCBI chr X:15,126,358...15,202,473
G
Slc1a4 solute carrier family 1 member 4
ISO SMPDB SMP:00059
NCBI chr14:98,718,646...98,761,672
G
Slc1a5 solute carrier family 1 member 5
ISO SMPDB SMP:00059
NCBI chr 1:86,584,949...86,599,052
G
Slc25a12 solute carrier family 25 member 12
ISO SMPDB SMP:00059
NCBI chr 3:76,504,868...76,599,536
G
Slc25a15 solute carrier family 25 member 15
ISO SMPDB SMP:00059
NCBI chr16:76,334,037...76,357,325
Pathway Gene Annotations
Disease Annotations Associated with Genes in the urea cycle pathway
Arg1 acute kidney failure , acute necrotizing pancreatitis , amino acid metabolic disorder , Animal Disease Models , asbestosis , asthma , autosomal recessive intellectual developmental disorder 18 , Chemical and Drug Induced Liver Injury , cholestasis , Citrullinemia Type 2 , colitis , Experimental Diabetes Mellitus , Experimental Liver Cirrhosis , Fetal Growth Retardation , genetic disease , hair disease , hepatocellular carcinoma , hyperargininemia , Hypercapnia , Hyperoxia , hypertension , Immediate Hypersensitivity , immune system disease , Insulin Resistance , Intestinal Fistula , leishmaniasis , liver disease , Liver Failure , lung adenocarcinoma , Middle East respiratory syndrome , muscular disease , Plaque, Atherosclerotic , pre-malignant neoplasm , Reperfusion Injury , silicosis , ureteral obstruction , uveitis , Wounds and Injuries Arg2 acute kidney failure , asthma , congestive heart failure , Diabetic Nephropathies , Disease Progression , end stage renal disease , Experimental Diabetes Mellitus , Experimental Liver Cirrhosis , Hemorrhagic Shock , Hyperoxia , hypertension , Immediate Hypersensitivity , Leber congenital amaurosis 13 , Necrosis , Nerve Degeneration , Optic Nerve Injuries , pancreatic ductal carcinoma , Prostatic Neoplasms , pulmonary hypertension , retinal degeneration , Sepsis , ureteral obstruction Asl amino acid metabolic disorder , argininosuccinic aciduria , autistic disorder , congenital myasthenic syndrome 4C , Endotoxemia , genetic disease , hepatocellular carcinoma , Hyperoxia , Hypoxia , Liver Failure , mucopolysaccharidosis type VII , Neurodevelopmental Disorders , pleomorphic xanthoastrocytoma , Reperfusion Injury , type 2 diabetes mellitus Ass1 Acute Liver Failure , Acute-Phase Reaction , adult-onset type II citrullinemia , Alzheimer's disease , Cardiac Arrhythmias , citrullinemia , classic citrullinemia , developmental and epileptic encephalopathy , diabetic angiopathy , Drug-Related Side Effects and Adverse Reactions , dystonia , early infantile epileptic encephalopathy , Endotoxemia , Experimental Diabetes Mellitus , Experimental Liver Cirrhosis , genetic disease , glycogen storage disease I , glycogen storage disease Ia , hepatocellular carcinoma , Hyperammonemia , Hyperoxia , Hypoxia , liver disease , Liver Failure , melanoma , primary coenzyme Q10 deficiency 7 , Reperfusion Injury , uveitis Cps1 Acidoses , Alcoholic Liver Diseases , Animal Hepatitis , brain disease , carbamoyl phosphate synthetase I deficiency disease , CARBONIC ANHYDRASE VA DEFICIENCY, HYPERAMMONEMIA DUE TO , Chemical and Drug Induced Liver Injury , Coma , Endotoxemia , Experimental Diabetes Mellitus , Experimental Liver Cirrhosis , Experimental Liver Neoplasms , Fetal Growth Retardation , genetic disease , hepatocellular carcinoma , hereditary breast ovarian cancer syndrome , Hyperammonemia , hypertension , intellectual disability , Liver Failure , Neonatal Pulmonary Hypertension , Neurodevelopmental Disorders , obesity , persistent fetal circulation syndrome , pre-malignant neoplasm , primary pulmonary hypertension , steatotic liver disease , trichorhinophalangeal syndrome type I , vascular disease Gls2 cataract 15 multiple types , Charcot-Marie-Tooth disease axonal type 2U , Experimental Liver Cirrhosis , INTERSTITIAL LUNG AND LIVER DISEASE , paraplegia Glud1 Alzheimer's disease , brain ischemia , Canavan disease , Chemical and Drug Induced Liver Injury , childhood absence epilepsy , Congenital Hyperinsulinism , diabetes mellitus , Experimental Autoimmune Encephalomyelitis , Experimental Seizures , familial hyperinsulinemic hypoglycemia 6 , fascioliasis , Fetal Growth Retardation , genetic disease , hepatic encephalopathy , Hyperammonemia , hyperinsulinism , hypoglycemia , intellectual disability , juvenile polyposis syndrome , PTEN hamartoma tumor syndrome , Reperfusion Injury , temporal lobe epilepsy Got2 acute kidney failure , Bardet-Biedl syndrome , Chromosome 16q12 Duplication Syndrome , developmental and epileptic encephalopathy , developmental and epileptic encephalopathy 82 , early infantile epileptic encephalopathy , Febrile Seizures , neurodegenerative disease , obesity , Pulmonary Hypertension, Hypoxia-Induced , schizophrenia , Spinal Cord Injuries , Transplant Rejection Gpt acute kidney failure , Acute Liver Failure , Baller-Gerold syndrome , Bone Fractures , Chemical and Drug Induced Liver Injury , Chronic Hepatitis B , Chronic Hepatitis C , Endotoxemia , epidermolysis bullosa simplex with muscular dystrophy , Experimental Liver Cirrhosis , Halothane Hepatitis , Heat Stroke , Hemorrhagic Shock , holoprosencephaly , Intestinal Reperfusion Injury , limb reperfusion injury , liver cancer , liver cirrhosis , liver disease , Liver Reperfusion Injury , metabolic dysfunction-associated steatotic liver disease , myocardial infarction , Myocardial Ischemia , obstructive jaundice , primary hyperoxaluria type 1 , Recombinant Chromosome 8 Syndrome , Reperfusion Injury , Sepsis , steatotic liver disease , type 2 diabetes mellitus Otc Acidoses , Alcoholic Liver Diseases , Animal Hepatitis , autistic disorder , brain disease , cholestasis , cognitive disorder , Developmental Disabilities , Endotoxemia , Experimental Diabetes Mellitus , Experimental Liver Cirrhosis , Fetal Growth Retardation , genetic disease , Hemorrhagic Shock , hepatocellular carcinoma , Hyperammonemia , Liver Failure , Nerve Degeneration , Neurodevelopmental Disorders , obesity , ornithine carbamoyltransferase deficiency , primary ciliary dyskinesia , Reperfusion Injury , retinitis pigmentosa 3 , Sepsis , steatotic liver disease , Sudden Death , syndromic X-linked intellectual disability Lubs type , X-linked chronic granulomatous disease Slc1a4 autism spectrum disorder , genetic disease , microcephaly , spastic tetraplegia, thin corpus callosum, and progressive microcephaly Slc1a5 COVID-19 , esophagus squamous cell carcinoma , hereditary spastic paraplegia , lung adenocarcinoma , pancreatic cancer , pulmonary hypertension , Right Ventricular Hypertrophy , tongue squamous cell carcinoma Slc25a12 Asperger syndrome , autism spectrum disorder , autistic disorder , developmental and epileptic encephalopathy 1 , developmental and epileptic encephalopathy 39 , fetal alcohol spectrum disorder , genetic disease , rheumatoid arthritis , split hand-foot malformation 5 Slc25a15 amino acid metabolic disorder , Cardiac Arrhythmias , citrullinemia , genetic disease , hereditary breast ovarian cancer syndrome , Hyperammonemia , intellectual disability , ornithine translocase deficiency
Acidoses Cps1 , Otc acute kidney failure Arg1 , Arg2 , Got2 , Gpt Acute Liver Failure Ass1 , Gpt acute necrotizing pancreatitis Arg1 Acute-Phase Reaction Ass1 adult-onset type II citrullinemia Ass1 Alcoholic Liver Diseases Cps1 , Otc Alzheimer's disease Ass1 , Glud1 amino acid metabolic disorder Arg1 , Asl , Slc25a15 Animal Disease Models Arg1 Animal Hepatitis Cps1 , Otc argininosuccinic aciduria Asl asbestosis Arg1 Asperger syndrome Slc25a12 asthma Arg1 , Arg2 autism spectrum disorder Slc1a4 , Slc25a12 autistic disorder Asl , Otc , Slc25a12 autosomal recessive intellectual developmental disorder 18 Arg1 Baller-Gerold syndrome Gpt Bardet-Biedl syndrome Got2 Bone Fractures Gpt brain disease Cps1 , Otc brain ischemia Glud1 Canavan disease Glud1 carbamoyl phosphate synthetase I deficiency disease Cps1 CARBONIC ANHYDRASE VA DEFICIENCY, HYPERAMMONEMIA DUE TO Cps1 Cardiac Arrhythmias Ass1 , Slc25a15 cataract 15 multiple types Gls2 Charcot-Marie-Tooth disease axonal type 2U Gls2 Chemical and Drug Induced Liver Injury Arg1 , Cps1 , Glud1 , Gpt childhood absence epilepsy Glud1 cholestasis Arg1 , Otc Chromosome 16q12 Duplication Syndrome Got2 Chronic Hepatitis B Gpt Chronic Hepatitis C Gpt citrullinemia Ass1 , Slc25a15 Citrullinemia Type 2 Arg1 classic citrullinemia Ass1 cognitive disorder Otc colitis Arg1 Coma Cps1 Congenital Hyperinsulinism Glud1 congenital myasthenic syndrome 4C Asl congestive heart failure Arg2 COVID-19 Slc1a5 developmental and epileptic encephalopathy Ass1 , Got2 developmental and epileptic encephalopathy 1 Slc25a12 developmental and epileptic encephalopathy 39 Slc25a12 developmental and epileptic encephalopathy 82 Got2 Developmental Disabilities Otc diabetes mellitus Glud1 diabetic angiopathy Ass1 Diabetic Nephropathies Arg2 Disease Progression Arg2 Drug-Related Side Effects and Adverse Reactions Ass1 dystonia Ass1 early infantile epileptic encephalopathy Ass1 , Got2 end stage renal disease Arg2 Endotoxemia Asl , Ass1 , Cps1 , Gpt , Otc epidermolysis bullosa simplex with muscular dystrophy Gpt esophagus squamous cell carcinoma Slc1a5 Experimental Autoimmune Encephalomyelitis Glud1 Experimental Diabetes Mellitus Arg1 , Arg2 , Ass1 , Cps1 , Otc Experimental Liver Cirrhosis Arg1 , Arg2 , Ass1 , Cps1 , Gls2 , Gpt , Otc Experimental Liver Neoplasms Cps1 Experimental Seizures Glud1 familial hyperinsulinemic hypoglycemia 6 Glud1 fascioliasis Glud1 Febrile Seizures Got2 fetal alcohol spectrum disorder Slc25a12 Fetal Growth Retardation Arg1 , Cps1 , Glud1 , Otc genetic disease Arg1 , Asl , Ass1 , Cps1 , Glud1 , Otc , Slc1a4 , Slc25a12 , Slc25a15 glycogen storage disease I Ass1 glycogen storage disease Ia Ass1 hair disease Arg1 Halothane Hepatitis Gpt Heat Stroke Gpt Hemorrhagic Shock Arg2 , Gpt , Otc hepatic encephalopathy Glud1 hepatocellular carcinoma Arg1 , Asl , Ass1 , Cps1 , Otc hereditary breast ovarian cancer syndrome Cps1 , Slc25a15 hereditary spastic paraplegia Slc1a5 holoprosencephaly Gpt Hyperammonemia Ass1 , Cps1 , Glud1 , Otc , Slc25a15 hyperargininemia Arg1 Hypercapnia Arg1 hyperinsulinism Glud1 Hyperoxia Arg1 , Arg2 , Asl , Ass1 hypertension Arg1 , Arg2 , Cps1 hypoglycemia Glud1 Hypoxia Asl , Ass1 Immediate Hypersensitivity Arg1 , Arg2 immune system disease Arg1 Insulin Resistance Arg1 intellectual disability Cps1 , Glud1 , Slc25a15 INTERSTITIAL LUNG AND LIVER DISEASE Gls2 Intestinal Fistula Arg1 Intestinal Reperfusion Injury Gpt juvenile polyposis syndrome Glud1 Leber congenital amaurosis 13 Arg2 leishmaniasis Arg1 limb reperfusion injury Gpt liver cancer Gpt liver cirrhosis Gpt liver disease Arg1 , Ass1 , Gpt Liver Failure Arg1 , Asl , Ass1 , Cps1 , Otc Liver Reperfusion Injury Gpt lung adenocarcinoma Arg1 , Slc1a5 melanoma Ass1 metabolic dysfunction-associated steatotic liver disease Gpt microcephaly Slc1a4 Middle East respiratory syndrome Arg1 mucopolysaccharidosis type VII Asl muscular disease Arg1 myocardial infarction Gpt Myocardial Ischemia Gpt Necrosis Arg2 Neonatal Pulmonary Hypertension Cps1 Nerve Degeneration Arg2 , Otc neurodegenerative disease Got2 Neurodevelopmental Disorders Asl , Cps1 , Otc obesity Cps1 , Got2 , Otc obstructive jaundice Gpt Optic Nerve Injuries Arg2 ornithine carbamoyltransferase deficiency Otc ornithine translocase deficiency Slc25a15 pancreatic cancer Slc1a5 pancreatic ductal carcinoma Arg2 paraplegia Gls2 persistent fetal circulation syndrome Cps1 Plaque, Atherosclerotic Arg1 pleomorphic xanthoastrocytoma Asl pre-malignant neoplasm Arg1 , Cps1 primary ciliary dyskinesia Otc primary coenzyme Q10 deficiency 7 Ass1 primary hyperoxaluria type 1 Gpt primary pulmonary hypertension Cps1 Prostatic Neoplasms Arg2 PTEN hamartoma tumor syndrome Glud1 pulmonary hypertension Arg2 , Slc1a5 Pulmonary Hypertension, Hypoxia-Induced Got2 Recombinant Chromosome 8 Syndrome Gpt Reperfusion Injury Arg1 , Asl , Ass1 , Glud1 , Gpt , Otc retinal degeneration Arg2 retinitis pigmentosa 3 Otc rheumatoid arthritis Slc25a12 Right Ventricular Hypertrophy Slc1a5 schizophrenia Got2 Sepsis Arg2 , Gpt , Otc silicosis Arg1 spastic tetraplegia, thin corpus callosum, and progressive microcephaly Slc1a4 Spinal Cord Injuries Got2 split hand-foot malformation 5 Slc25a12 steatotic liver disease Cps1 , Gpt , Otc Sudden Death Otc syndromic X-linked intellectual disability Lubs type Otc temporal lobe epilepsy Glud1 tongue squamous cell carcinoma Slc1a5 Transplant Rejection Got2 trichorhinophalangeal syndrome type I Cps1 type 2 diabetes mellitus Asl , Gpt ureteral obstruction Arg1 , Arg2 uveitis Arg1 , Ass1 vascular disease Cps1 Wounds and Injuries Arg1 X-linked chronic granulomatous disease Otc
