KETONE BODIES METABOLIC PATHWAY (PW:0000069) Description
The ketone bodies metabolic pathway is used to convert acetyl-CoA formed in the liver into "ketone bodies": acetone, and more importantly acetoacetate and 3-hydroxybutyrate, which are transported in the blood to extrahepatic tissues where they are converted to acetyl-CoA and oxidized via the citrate cycle pathway for energy. The brain, which usually uses glucose for energy, can utilize ketone bodies under starvation conditions, when glucose is not available. When acetyl-CoA is not being metabolized in the citrate cycle pathway during starvation, its conversion to ketone bodies and export from the liver permits continued operation of the fatty acid beta degradation pathway. To form ketone bodies, two molecules of acetyl-CoA are condensed by acetyl-CoA C-acetyltransferase (Acat1) into acetoacetyl-CoA. Several pathway enzymes have mitochondrial and cytosolic isoforms; the former, predominantly operant enzymes are shown in the forefront in the diagram. Another molecule of acetyl-CoA is then condensed with acetoacetyl-CoA by 3-hydroxy-3-methylglutaryl-CoA synthase (Hmgcs2) to form 3-hydroxy-3-methylglutaryl-CoA. This is cleaved by 3-hydroxy-3-methylglutaryl-CoA lyase to generate acetyl-CoA and acetoacetate. The acetoacetate is reduced reversibly by 3-hydroxybutyrate dehydrogenase (Bdh1) to yield 3-hydroxybutyrate, or is decarboxylated spontaneously or via acetoacetate decarboxylase (Adc) to generate acetone. To date, the Adc gene has only been cloned from prokaryotes, although enzyme activity has been studied in mammals (see PMID:
12726989 ). Outside the liver, 3-hydroxybutyrate is oxidized back to acetoacetate (Bdh1), which is then converted to acetoacetyl-CoA by 3-oxoacid CoA transferase (Oxct1), with succinyl-CoA donating its coenzyme. This reaction can also be performed by acetoacetate CoA synthetase (Aacs) using coenzyme A. Acat1 cleaves the acetoacetyl-CoA into two molecules of acetyl-CoA, which can generate energy by entering the citric acid cycle pathway. In diabetes, reduced insulin enhances ketone body production by activating lipase and Hmgcs2 and inhibiting acetyl CoA carboxylase-mediated conversion of acetyl-CoA to malonyl-CoA, the first step of the fatty acid biosynthetic pathway. This lifts the malonyl-CoA-mediated inhibition of fatty acid transport across the mitochondrial membrane by carnitine palmitoyltransferase 1 where they are oxidized via the fatty acid beta degradation pathway into ketone bodies.
To see the ontology report for annotations, GViewer and download click here [Click here to see related GO term - GO:0042180 , associated KEGG map -
map00072 and entry at Reactome -
REACT_1861.3 ]
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Pathway Diagram:
GO TO:
Genes in Pathway:
Symbol Object Name Evidence Notes Source PubMed Reference(s) RGD Reference(s) Position
G
Aacs acetoacetyl-CoA synthetase
ISO RGD
PMID:15877199 RGD:2326093
NCBI chr12:36,774,471...36,817,835
G
Acat1 acetyl-CoA acetyltransferase 1
IEA ISO KEGG SMPDB PMID:15877199 SMP:00071 rno:00072, RGD:2326093
NCBI chr 8:62,876,003...62,905,080
G
Acat2 acetyl-CoA acetyltransferase 2
ISO IEA KEGG PMID:15877199 rno:00072, RGD:2326093
NCBI chr 1:50,100,840...50,118,886
G
Bdh1 3-hydroxybutyrate dehydrogenase 1
ISO IEA SMPDB KEGG PMID:15877199 SMP:00071 rno:00072, RGD:2326093
NCBI chr11:82,806,125...82,848,133
G
Bdh2 3-hydroxybutyrate dehydrogenase 2
IEA KEGG rno:00072
NCBI chr 2:226,376,346...226,397,010
G
Hmgcl 3-hydroxy-3-methylglutaryl-CoA lyase
IEA ISO KEGG SMPDB PMID:15877199 SMP:00071 rno:00072, RGD:2326093
NCBI chr 5:153,461,738...153,475,552
G
Hmgcs1 3-hydroxy-3-methylglutaryl-CoA synthase 1
IEA KEGG rno:00072
NCBI chr 2:53,379,457...53,399,807
G
Hmgcs2 3-hydroxy-3-methylglutaryl-CoA synthase 2
IEA ISO KEGG SMPDB SMP:00071 rno:00072
NCBI chr 2:188,564,348...188,590,872
G
Oxct1 3-oxoacid CoA transferase 1
ISO IEA SMPDB KEGG PMID:15877199 SMP:00071 rno:00072, RGD:2326093
NCBI chr 2:54,963,964...55,112,303
G
Oxct2a 3-oxoacid CoA transferase 2A
IEA KEGG rno:00072
NCBI chr 5:135,600,812...135,602,570
G
Oxct2b 3-oxoacid CoA transferase 2B
ISO RGD
PMID:11090426 RGD:2326216
NCBI chr 5:135,396,632...135,398,386
Symbol Object Name Evidence Notes Source PubMed Reference(s) RGD Reference(s) Position
G
Hmgcs1 3-hydroxy-3-methylglutaryl-CoA synthase 1
TAS RGD
PMID:9893938 RGD:2326134
NCBI chr 2:53,379,457...53,399,807
G
Hmgcs2 3-hydroxy-3-methylglutaryl-CoA synthase 2
TAS RGD
PMID:9893938 RGD:2326134
NCBI chr 2:188,564,348...188,590,872
Pathway Gene Annotations
Disease Annotations Associated with Genes in the ketone bodies metabolic pathway
Aacs Experimental Diabetes Mellitus , obesity Acat1 arteriosclerosis , ataxia telangiectasia , beta-ketothiolase deficiency , carbohydrate metabolic disorder , chromosome 11 partial duplication syndrome , end stage renal disease , Experimental Liver Cirrhosis , genetic disease , intellectual disability , nephrotic syndrome , steatotic liver disease Acat2 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome , arteriosclerosis , beta-ketothiolase deficiency , coronary artery disease , Cytosolic Acetoacetyl-CoA Thiolase Deficiency , Hypercholesterolemia , Metabolic Syndrome Bdh1 autistic disorder , Chemical and Drug Induced Liver Injury , COVID-19 , Experimental Diabetes Mellitus , Experimental Liver Cirrhosis , hyperthyroidism , schizophrenia Bdh2 beta-mannosidosis Hmgcl 3-hydroxy-3-methylglutaryl-CoA lyase deficiency , amino acid metabolic disorder , Diamond-Blackfan anemia , Experimental Diabetes Mellitus , galactose epimerase deficiency , genetic disease , Long-Chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency Hmgcs1 developmental and epileptic encephalopathy , early infantile epileptic encephalopathy , Experimental Diabetes Mellitus , Neurodevelopmental Disorders , obesity , rigid spine muscular dystrophy 1 , Spinal Cord Compression Hmgcs2 Colonic Neoplasms , congestive heart failure , Experimental Diabetes Mellitus , extrahepatic cholestasis , genetic disease , Hajdu-Cheney syndrome , hepatocellular carcinoma , Hepatomegaly , HMG-CoA synthase 2 deficiency , Mouth Neoplasms , Myocardial Ischemia , Neoplasm Invasiveness , PHGDH deficiency , Recurrence Oxct1 amyotrophic lateral sclerosis type 2 , Burns , carbohydrate metabolic disorder , Experimental Diabetes Mellitus , genetic disease , Neurodevelopmental Disorders , obesity , osteoporosis , Succinyl-CoA:3-oxoacid CoA transferase deficiency , type 2 diabetes mellitus Oxct2b Charcot-Marie-Tooth disease dominant intermediate C
3-hydroxy-3-methylglutaryl-CoA lyase deficiency Hmgcl 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome Acat2 amino acid metabolic disorder Hmgcl amyotrophic lateral sclerosis type 2 Oxct1 arteriosclerosis Acat1 , Acat2 ataxia telangiectasia Acat1 autistic disorder Bdh1 beta-ketothiolase deficiency Acat1 , Acat2 beta-mannosidosis Bdh2 Burns Oxct1 carbohydrate metabolic disorder Acat1 , Oxct1 Charcot-Marie-Tooth disease dominant intermediate C Oxct2b Chemical and Drug Induced Liver Injury Bdh1 chromosome 11 partial duplication syndrome Acat1 Colonic Neoplasms Hmgcs2 congestive heart failure Hmgcs2 coronary artery disease Acat2 COVID-19 Bdh1 Cytosolic Acetoacetyl-CoA Thiolase Deficiency Acat2 developmental and epileptic encephalopathy Hmgcs1 Diamond-Blackfan anemia Hmgcl early infantile epileptic encephalopathy Hmgcs1 end stage renal disease Acat1 Experimental Diabetes Mellitus Aacs , Bdh1 , Hmgcl , Hmgcs1 , Hmgcs2 , Oxct1 Experimental Liver Cirrhosis Acat1 , Bdh1 extrahepatic cholestasis Hmgcs2 galactose epimerase deficiency Hmgcl genetic disease Acat1 , Hmgcl , Hmgcs2 , Oxct1 Hajdu-Cheney syndrome Hmgcs2 hepatocellular carcinoma Hmgcs2 Hepatomegaly Hmgcs2 HMG-CoA synthase 2 deficiency Hmgcs2 Hypercholesterolemia Acat2 hyperthyroidism Bdh1 intellectual disability Acat1 Long-Chain 3-hydroxyacyl-CoA Dehydrogenase Deficiency Hmgcl Metabolic Syndrome Acat2 Mouth Neoplasms Hmgcs2 Myocardial Ischemia Hmgcs2 Neoplasm Invasiveness Hmgcs2 nephrotic syndrome Acat1 Neurodevelopmental Disorders Hmgcs1 , Oxct1 obesity Aacs , Hmgcs1 , Oxct1 osteoporosis Oxct1 PHGDH deficiency Hmgcs2 Recurrence Hmgcs2 rigid spine muscular dystrophy 1 Hmgcs1 schizophrenia Bdh1 Spinal Cord Compression Hmgcs1 steatotic liver disease Acat1 Succinyl-CoA:3-oxoacid CoA transferase deficiency Oxct1 type 2 diabetes mellitus Oxct1
Pathway Annotations Associated with Genes in the ketone bodies metabolic pathway
Aacs butanoate metabolic pathway , ketone bodies metabolic pathway Acat1 2-aminoadipic 2-oxoadipic aciduria pathway , 3-hydroxy-3-methylglutaryl-CoA lyase deficiency pathway , 3-hydroxyacyl-CoA dehydrogenase deficiency pathway , 3-hydroxyisobutyric aciduria pathway , 3-methylcrotonyl CoA carboxylase 1 deficiency pathway , 3-methylglutaconic aciduria type 1 pathway , 3-methylglutaconic aciduria type 3 pathway , butanoate metabolic pathway , carnitine palmitoyltransferase I deficiency pathway , ethylmalonic encephalopathy pathway , fatty acid beta degradation pathway , fatty acid metabolic pathway , glutaric aciduria type I pathway , glyoxylate and dicarboxylate metabolic pathway , hyperlysinemia pathway , isobutyryl-CoA dehydrogenase deficiency pathway , isovaleric acidemia pathway , ketone bodies metabolic pathway , Leigh disease pathway , lysine degradation pathway , malonic aciduria pathway , maple syrup urine disease pathway , medium chain acyl-CoA dehydrogenase deficiency pathway , methylmalonate semialdehyde dehydrogenase deficiency pathway , methylmalonic acidemia pathway , methylmalonic aciduria, cobalamin-related pathway , primary hyperoxaluria type 2 pathway , propanoate metabolic pathway , propionic acidemia pathway , pyruvate decarboxylase deficiency pathway , pyruvate dehydrogenase E1 deficiency pathway , pyruvate kinase deficiency of red cells pathway , pyruvate metabolic pathway , saccharopinuria pathway , short-chain acyl-CoA dehydrogenase deficiency pathway , succinyl-CoA:3-oxoacid transferase deficiency pathway , terpenoid biosynthetic pathway , trifunctional protein deficiency pathway , tryptophan metabolic pathway , valine, leucine and isoleucine degradation pathway , very long-chain acyl-CoA dehydrogenase deficiency pathway Acat2 alendronate pharmacodynamics pathway , butanoate metabolic pathway , cholesterol biosynthetic pathway , cholesterol ester storage disease pathway , congenital hemidysplasia with ichthyosiform erythroderma and limb defects pathway , desmosterolosis pathway , fatty acid metabolic pathway , glyoxylate and dicarboxylate metabolic pathway , hypercholesterolemia pathway , ibandronate pharmacodynamics pathway , ketone bodies metabolic pathway , lysine degradation pathway , mevalonic aciduria pathway , nitrogenous bisphosphonate pharmacodynamics pathway , pamidronate pharmacodynamics pathway , propanoate metabolic pathway , pyruvate metabolic pathway , risedronate pharmacodynamics pathway , Smith-Lemli-Opitz Syndrome pathway , statin pharmacodynamics pathway , terpenoid biosynthetic pathway , tryptophan metabolic pathway , valine, leucine and isoleucine degradation pathway , Wolman disease pathway , X-linked dominant chondrodysplasia punctata 2 pathway , zoledronate pharmacodynamics pathway Bdh1 butanoate metabolic pathway , forkhead class A signaling pathway , ketone bodies metabolic pathway , succinyl-CoA:3-oxoacid transferase deficiency pathway Bdh2 butanoate metabolic pathway , ketone bodies metabolic pathway Hmgcl 3-hydroxy-3-methylglutaryl-CoA lyase deficiency pathway , 3-hydroxyisobutyric aciduria pathway , 3-methylcrotonyl CoA carboxylase 1 deficiency pathway , 3-methylglutaconic aciduria type 1 pathway , 3-methylglutaconic aciduria type 3 pathway , butanoate metabolic pathway , isobutyryl-CoA dehydrogenase deficiency pathway , isovaleric acidemia pathway , ketone bodies metabolic pathway , maple syrup urine disease pathway , methylmalonate semialdehyde dehydrogenase deficiency pathway , methylmalonic acidemia pathway , propionic acidemia pathway , succinyl-CoA:3-oxoacid transferase deficiency pathway , valine, leucine and isoleucine degradation pathway Hmgcs1 alendronate pharmacodynamics pathway , butanoate metabolic pathway , cholesterol biosynthetic pathway , cholesterol ester storage disease pathway , congenital hemidysplasia with ichthyosiform erythroderma and limb defects pathway , desmosterolosis pathway , forkhead class A signaling pathway , hypercholesterolemia pathway , ibandronate pharmacodynamics pathway , ketone bodies biosynthetic pathway , ketone bodies metabolic pathway , mevalonic aciduria pathway , nitrogenous bisphosphonate pharmacodynamics pathway , pamidronate pharmacodynamics pathway , risedronate pharmacodynamics pathway , Smith-Lemli-Opitz Syndrome pathway , statin pharmacodynamics pathway , terpenoid biosynthetic pathway , valine, leucine and isoleucine degradation pathway , Wolman disease pathway , X-linked dominant chondrodysplasia punctata 2 pathway , zoledronate pharmacodynamics pathway Hmgcs2 3-hydroxy-3-methylglutaryl-CoA lyase deficiency pathway , 3-hydroxyisobutyric aciduria pathway , 3-methylcrotonyl CoA carboxylase 1 deficiency pathway , 3-methylglutaconic aciduria type 1 pathway , 3-methylglutaconic aciduria type 3 pathway , butanoate metabolic pathway , eicosanoid signaling pathway via peroxisome proliferator-activated receptor gamma , isobutyryl-CoA dehydrogenase deficiency pathway , isovaleric acidemia pathway , ketone bodies biosynthetic pathway , ketone bodies metabolic pathway , maple syrup urine disease pathway , methylmalonate semialdehyde dehydrogenase deficiency pathway , methylmalonic acidemia pathway , propionic acidemia pathway , succinyl-CoA:3-oxoacid transferase deficiency pathway , terpenoid biosynthetic pathway , valine, leucine and isoleucine degradation pathway Oxct1 3-hydroxy-3-methylglutaryl-CoA lyase deficiency pathway , 3-hydroxyisobutyric aciduria pathway , 3-methylcrotonyl CoA carboxylase 1 deficiency pathway , 3-methylglutaconic aciduria type 1 pathway , 3-methylglutaconic aciduria type 3 pathway , butanoate metabolic pathway , isobutyryl-CoA dehydrogenase deficiency pathway , isovaleric acidemia pathway , ketone bodies metabolic pathway , maple syrup urine disease pathway , methylmalonate semialdehyde dehydrogenase deficiency pathway , methylmalonic acidemia pathway , propionic acidemia pathway , succinyl-CoA:3-oxoacid transferase deficiency pathway , valine, leucine and isoleucine degradation pathway Oxct2a butanoate metabolic pathway , ketone bodies metabolic pathway , valine, leucine and isoleucine degradation pathway Oxct2b ketone bodies metabolic pathway
2-aminoadipic 2-oxoadipic aciduria pathway Acat1 3-hydroxy-3-methylglutaryl-CoA lyase deficiency pathway Acat1 , Hmgcl , Hmgcs2 , Oxct1 3-hydroxyacyl-CoA dehydrogenase deficiency pathway Acat1 3-hydroxyisobutyric aciduria pathway Acat1 , Hmgcl , Hmgcs2 , Oxct1 3-methylcrotonyl CoA carboxylase 1 deficiency pathway Acat1 , Hmgcl , Hmgcs2 , Oxct1 3-methylglutaconic aciduria type 1 pathway Acat1 , Hmgcl , Hmgcs2 , Oxct1 3-methylglutaconic aciduria type 3 pathway Acat1 , Hmgcl , Hmgcs2 , Oxct1 alendronate pharmacodynamics pathway Acat2 , Hmgcs1 butanoate metabolic pathway Aacs , Acat1 , Acat2 , Bdh1 , Bdh2 , Hmgcl , Hmgcs1 , Hmgcs2 , Oxct1 , Oxct2a carnitine palmitoyltransferase I deficiency pathway Acat1 cholesterol biosynthetic pathway Acat2 , Hmgcs1 cholesterol ester storage disease pathway Acat2 , Hmgcs1 congenital hemidysplasia with ichthyosiform erythroderma and limb defects pathway Acat2 , Hmgcs1 desmosterolosis pathway Acat2 , Hmgcs1 eicosanoid signaling pathway via peroxisome proliferator-activated receptor gamma Hmgcs2 ethylmalonic encephalopathy pathway Acat1 fatty acid beta degradation pathway Acat1 fatty acid metabolic pathway Acat1 , Acat2 forkhead class A signaling pathway Bdh1 , Hmgcs1 glutaric aciduria type I pathway Acat1 glyoxylate and dicarboxylate metabolic pathway Acat1 , Acat2 hypercholesterolemia pathway Acat2 , Hmgcs1 hyperlysinemia pathway Acat1 ibandronate pharmacodynamics pathway Acat2 , Hmgcs1 isobutyryl-CoA dehydrogenase deficiency pathway Acat1 , Hmgcl , Hmgcs2 , Oxct1 isovaleric acidemia pathway Acat1 , Hmgcl , Hmgcs2 , Oxct1 ketone bodies biosynthetic pathway Hmgcs1 , Hmgcs2 ketone bodies metabolic pathway Aacs , Acat1 , Acat2 , Bdh1 , Bdh2 , Hmgcl , Hmgcs1 , Hmgcs2 , Oxct1 , Oxct2a , Oxct2b Leigh disease pathway Acat1 lysine degradation pathway Acat1 , Acat2 malonic aciduria pathway Acat1 maple syrup urine disease pathway Acat1 , Hmgcl , Hmgcs2 , Oxct1 medium chain acyl-CoA dehydrogenase deficiency pathway Acat1 methylmalonate semialdehyde dehydrogenase deficiency pathway Acat1 , Hmgcl , Hmgcs2 , Oxct1 methylmalonic acidemia pathway Acat1 , Hmgcl , Hmgcs2 , Oxct1 methylmalonic aciduria, cobalamin-related pathway Acat1 mevalonic aciduria pathway Acat2 , Hmgcs1 nitrogenous bisphosphonate pharmacodynamics pathway Acat2 , Hmgcs1 pamidronate pharmacodynamics pathway Acat2 , Hmgcs1 primary hyperoxaluria type 2 pathway Acat1 propanoate metabolic pathway Acat1 , Acat2 propionic acidemia pathway Acat1 , Hmgcl , Hmgcs2 , Oxct1 pyruvate decarboxylase deficiency pathway Acat1 pyruvate dehydrogenase E1 deficiency pathway Acat1 pyruvate kinase deficiency of red cells pathway Acat1 pyruvate metabolic pathway Acat1 , Acat2 risedronate pharmacodynamics pathway Acat2 , Hmgcs1 saccharopinuria pathway Acat1 short-chain acyl-CoA dehydrogenase deficiency pathway Acat1 Smith-Lemli-Opitz Syndrome pathway Acat2 , Hmgcs1 statin pharmacodynamics pathway Acat2 , Hmgcs1 succinyl-CoA:3-oxoacid transferase deficiency pathway Acat1 , Bdh1 , Hmgcl , Hmgcs2 , Oxct1 terpenoid biosynthetic pathway Acat1 , Acat2 , Hmgcs1 , Hmgcs2 trifunctional protein deficiency pathway Acat1 tryptophan metabolic pathway Acat1 , Acat2 valine, leucine and isoleucine degradation pathway Acat1 , Acat2 , Hmgcl , Hmgcs1 , Hmgcs2 , Oxct1 , Oxct2a very long-chain acyl-CoA dehydrogenase deficiency pathway Acat1 Wolman disease pathway Acat2 , Hmgcs1 X-linked dominant chondrodysplasia punctata 2 pathway Acat2 , Hmgcs1 zoledronate pharmacodynamics pathway Acat2 , Hmgcs1
References Associated with the ketone bodies metabolic pathway:
Ontology Path Diagram:
Import into Pathway Studio:
