Ketone body metabolism (Homo sapiens)

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510, 138, 151743, 9, 12, 141271611cytosolmitochondrial matrixNADHHMGCS2Ac-CoAPPiBDH1 HMG CoAH+CoA-SHACANAD+bHBAACA-CoAACAATPAMPBDH2 tetramerACAT1 tetramerSUCC-CoABDH1 tetramerHMGCL NADHPPiMg2+ bHMG-CoAAACSACSS3HMGCL dimerATPACAT1(35-427) CoA-SHCH3COO-BDH2 3HBACoA-SHH+OXCT1 OXCT2 SUCCAHMGCLL1:Mg2+Ac-CoAHMGCLL1 OXCT dimersCoA-SHadenosine5'-monophosphateNAD+ACA-CoA66


Acetoacetate, beta-hydroxybutyrate, and acetone collectively are called ketone bodies. The first two are synthesized from acetyl-CoA, in the mitochondria of liver cells; acetone is formed by spontaneous decarboxylation of acetoacetate. Ketone body synthesis in liver is effectively irreversible because the enzyme that catalyzes the conversion of acetoacetate to acetoacetyl-CoA is not present in liver cells.

Ketone bodies, unlike fatty acids and triglycerides, are water-soluble. They are exported from the liver, and are taken up by other tissues, notably brain and skeletal and cardiac muscle. There, they are broken down to acetyl-CoA which is oxidized via the TCA cycle to yield energy. In a normal person, this pathway of ketone body synthesis and utilization is most active during extended periods of fasting. Under these conditions, mobilization and breakdown of stored fatty acids generates abundant acetyl-CoA acetyl-CoA in liver cells for synthesis of ketone bodies, and their utilization in other tissues minimizes the demand of these tissues for glucose (Sass 2011). View original pathway at Reactome.</div>


Pathway is converted from Reactome ID: 74182
Reactome version: 73
Reactome Author 
Reactome Author: Gopinathrao, G

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  1. Haapalainen AM, Meriläinen G, Pirilä PL, Kondo N, Fukao T, Wierenga RK.; ''Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase: the importance of potassium and chloride ions for its structure and function.''; PubMed Europe PMC Scholia
  2. Marks AR, McIntyre JO, Duncan TM, Erdjument-Bromage H, Tempst P, Fleischer S.; ''Molecular cloning and characterization of (R)-3-hydroxybutyrate dehydrogenase from human heart.''; PubMed Europe PMC Scholia
  3. Watkins PA, Maiguel D, Jia Z, Pevsner J.; ''Evidence for 26 distinct acyl-coenzyme A synthetase genes in the human genome.''; PubMed Europe PMC Scholia
  4. Kassovska-Bratinova S, Fukao T, Song XQ, Duncan AM, Chen HS, Robert MF, Pérez-Cerdá C, Ugarte M, Chartrand C, Vobecky S, Kondo N, Mitchell GA.; ''Succinyl CoA: 3-oxoacid CoA transferase (SCOT): human cDNA cloning, human chromosomal mapping to 5p13, and mutation detection in a SCOT-deficient patient.''; PubMed Europe PMC Scholia
  5. Aguiló F, Camarero N, Relat J, Marrero PF, Haro D.; ''Transcriptional regulation of the human acetoacetyl-CoA synthetase gene by PPARgamma.''; PubMed Europe PMC Scholia
  6. Sass JO.; ''Inborn errors of ketogenesis and ketone body utilization.''; PubMed Europe PMC Scholia
  7. Guo K, Lukacik P, Papagrigoriou E, Meier M, Lee WH, Adamski J, Oppermann U.; ''Characterization of human DHRS6, an orphan short chain dehydrogenase/reductase enzyme: a novel, cytosolic type 2 R-beta-hydroxybutyrate dehydrogenase.''; PubMed Europe PMC Scholia
  8. Mitchell GA, Robert MF, Hruz PW, Wang S, Fontaine G, Behnke CE, Mende-Mueller LM, Schappert K, Lee C, Gibson KM, Miziorko HM.; ''3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL). Cloning of human and chicken liver HL cDNAs and characterization of a mutation causing human HL deficiency.''; PubMed Europe PMC Scholia
  9. Middleton B, Bartlett K, Romanos A, Gomez Vazquez J, Conde C, Cannon RA, Lipson M, Sweetman L, Nyhan WL.; ''3-Ketothiolase deficiency.''; PubMed Europe PMC Scholia
  10. Aledo R, Zschocke J, Pié J, Mir C, Fiesel S, Mayatepek E, Hoffmann GF, Casals N, Hegardt FG.; ''Genetic basis of mitochondrial HMG-CoA synthase deficiency.''; PubMed Europe PMC Scholia
  11. Tanaka H, Kohroki J, Iguchi N, Onishi M, Nishimune Y.; ''Cloning and characterization of a human orthologue of testis-specific succinyl CoA: 3-oxo acid CoA transferase (Scot-t) cDNA.''; PubMed Europe PMC Scholia
  12. Cotter DG, Schugar RC, Crawford PA.; ''Ketone body metabolism and cardiovascular disease.''; PubMed Europe PMC Scholia
  13. Endemann G, Goetz PG, Edmond J, Brunengraber H.; ''Lipogenesis from ketone bodies in the isolated perfused rat liver. Evidence for the cytosolic activation of acetoacetate.''; PubMed Europe PMC Scholia
  14. Ohgami M, Takahashi N, Yamasaki M, Fukui T.; ''Expression of acetoacetyl-CoA synthetase, a novel cytosolic ketone body-utilizing enzyme, in human brain.''; PubMed Europe PMC Scholia
  15. Montgomery C, Pei Z, Watkins PA, Miziorko HM.; ''Identification and characterization of an extramitochondrial human 3-hydroxy-3-methylglutaryl-CoA lyase.''; PubMed Europe PMC Scholia
  16. Arnedo M, Menao S, Puisac B, Teresa-Rodrigo ME, Gil-Rodríguez MC, López-Viñas E, Gómez-Puertas P, Casals N, Casale CH, Hegardt FG, Pié J.; ''Characterization of a novel HMG-CoA lyase enzyme with a dual location in endoplasmic reticulum and cytosol.''; PubMed Europe PMC Scholia


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113293view11:36, 2 November 2020ReactomeTeamReactome version 74
112505view15:46, 9 October 2020ReactomeTeamReactome version 73
101417view11:30, 1 November 2018ReactomeTeamreactome version 66
100955view21:06, 31 October 2018ReactomeTeamreactome version 65
100492view19:40, 31 October 2018ReactomeTeamreactome version 64
100037view16:24, 31 October 2018ReactomeTeamreactome version 63
99590view14:58, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93597view11:28, 9 August 2017ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
3HBAMetaboliteCHEBI:10983 (ChEBI)
AACSProteinQ86V21 (Uniprot-TrEMBL)
ACA-CoAMetaboliteCHEBI:15345 (ChEBI)
ACAMetaboliteCHEBI:13705 (ChEBI)
ACAMetaboliteCHEBI:15344 (ChEBI)
ACAT1 tetramerComplexR-HSA-70839 (Reactome)
ACAT1(35-427) ProteinP24752 (Uniprot-TrEMBL)
ACSS3ProteinQ9H6R3 (Uniprot-TrEMBL)
AMPMetaboliteCHEBI:16027 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
BDH1 ProteinQ02338 (Uniprot-TrEMBL)
BDH1 tetramerComplexR-HSA-74280 (Reactome)
BDH2 ProteinQ9BUT1 (Uniprot-TrEMBL)
BDH2 tetramerComplexR-HSA-5696462 (Reactome)
CH3COO-MetaboliteCHEBI:30089 (ChEBI)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
HMG CoAMetaboliteCHEBI:15467 (ChEBI)
HMGCL ProteinP35914 (Uniprot-TrEMBL)
HMGCL dimerComplexR-HSA-74264 (Reactome)
HMGCLL1 ProteinQ8TB92 (Uniprot-TrEMBL)
HMGCLL1:Mg2+ComplexR-HSA-6788595 (Reactome)
HMGCS2ProteinP54868 (Uniprot-TrEMBL)
Mg2+ MetaboliteCHEBI:18420 (ChEBI)
NAD+MetaboliteCHEBI:57540 (ChEBI)
NADHMetaboliteCHEBI:57945 (ChEBI)
OXCT dimersComplexR-HSA-8955621 (Reactome)
OXCT1 ProteinP55809 (Uniprot-TrEMBL)
OXCT2 ProteinQ9BYC2 (Uniprot-TrEMBL)
PPiMetaboliteCHEBI:29888 (ChEBI)
SUCC-CoAMetaboliteCHEBI:57292 (ChEBI)
SUCCAMetaboliteCHEBI:30031 (ChEBI)
adenosine 5'-monophosphateMetaboliteCHEBI:16027 (ChEBI)
bHBAMetaboliteCHEBI:17066 (ChEBI)
bHMG-CoAMetaboliteCHEBI:15467 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
3HBAR-HSA-5696457 (Reactome)
AACSmim-catalysisR-HSA-5694494 (Reactome)
ACA-CoAArrowR-HSA-5694494 (Reactome)
ACA-CoAArrowR-HSA-73916 (Reactome)
ACA-CoAArrowR-HSA-74177 (Reactome)
ACA-CoAR-HSA-73918 (Reactome)
ACA-CoAR-HSA-74181 (Reactome)
ACAArrowR-HSA-5696457 (Reactome)
ACAArrowR-HSA-6788597 (Reactome)
ACAArrowR-HSA-73920 (Reactome)
ACAArrowR-HSA-74180 (Reactome)
ACAR-HSA-5694494 (Reactome)
ACAR-HSA-73912 (Reactome)
ACAR-HSA-74177 (Reactome)
ACAT1 tetramermim-catalysisR-HSA-73916 (Reactome)
ACAT1 tetramermim-catalysisR-HSA-74181 (Reactome)
ACSS3mim-catalysisR-HSA-8875071 (Reactome)
AMPArrowR-HSA-5694494 (Reactome)
ATPR-HSA-5694494 (Reactome)
ATPR-HSA-8875071 (Reactome)
Ac-CoAArrowR-HSA-6788597 (Reactome)
Ac-CoAArrowR-HSA-74180 (Reactome)
Ac-CoAArrowR-HSA-74181 (Reactome)
Ac-CoAArrowR-HSA-8875071 (Reactome)
Ac-CoAR-HSA-73916 (Reactome)
Ac-CoAR-HSA-73918 (Reactome)
BDH1 tetramermim-catalysisR-HSA-73912 (Reactome)
BDH1 tetramermim-catalysisR-HSA-73920 (Reactome)
BDH2 tetramermim-catalysisR-HSA-5696457 (Reactome)
CH3COO-R-HSA-8875071 (Reactome)
CoA-SHArrowR-HSA-73916 (Reactome)
CoA-SHArrowR-HSA-73918 (Reactome)
CoA-SHR-HSA-5694494 (Reactome)
CoA-SHR-HSA-74181 (Reactome)
CoA-SHR-HSA-8875071 (Reactome)
H+ArrowR-HSA-5696457 (Reactome)
H+ArrowR-HSA-73920 (Reactome)
H+R-HSA-73912 (Reactome)
HMG CoAArrowR-HSA-73918 (Reactome)
HMG CoAR-HSA-74180 (Reactome)
HMGCL dimermim-catalysisR-HSA-74180 (Reactome)
HMGCLL1:Mg2+mim-catalysisR-HSA-6788597 (Reactome)
HMGCS2mim-catalysisR-HSA-73918 (Reactome)
NAD+ArrowR-HSA-73912 (Reactome)
NAD+R-HSA-5696457 (Reactome)
NAD+R-HSA-73920 (Reactome)
NADHArrowR-HSA-5696457 (Reactome)
NADHArrowR-HSA-73920 (Reactome)
NADHR-HSA-73912 (Reactome)
OXCT dimersmim-catalysisR-HSA-74177 (Reactome)
PPiArrowR-HSA-5694494 (Reactome)
PPiArrowR-HSA-8875071 (Reactome)
R-HSA-5694494 (Reactome) Ketone bodies (KBs) are an energy source utilised by mammals, the terminal oxidation of which (termed ketogenesis) is most active during fasting states or starvation. This process normally occurs in the mitochondria of cells. Cytoplasmic de novo lipogenesis and cholesterol synthesis are nonoxidative metabolic fates of ketone bodies. Acetoacetyl-CoA synthetase (AACS) mediates the activation of acetoacetate (ACA) to the KB acetoacetyl-CoA (ACA-CoA) in the cytosol of cells of lipogenic tissues (Aquilo et al. 2010). AACS is proposed to provide an alternative supply of acetyl units from that of mitochondrial ketogenesis for de novo lipogenesis and cholesterol synthesis in the brain, based on rat experiments (Endemann et al. 1982, review Cotter et al. 2013). Human AACS mRNA is abundant in the kidney, heart and brain, but low in liver (Ohgami et al. 2003).
R-HSA-5696457 (Reactome) Ketone bodies (KBs) are an energy source utilised by mammals, the terminal oxidation of which (termed ketogenesis) is most active during fasting states or starvation. This process normally occurs in the mitochondria of cells. Cytoplasmic de novo lipogenesis and cholesterol synthesis are nonoxidative metabolic fates of ketone bodies. 3-hydroxybutyrate dehydrogenase type 2 (BDH2 aka DHRS6) is a cytosolic, tetrameric enzyme that may have a (as yet undetermined) physiological role in ketone body metabolism, either for energy supply or to generate precursors for lipid and sterol synthesis. The KB substrate (R)-3-hydroxybutyrate (3HBA) is dehydrogenated into acetoacetate (ACA) which can be further metabolised to acetyl-CoA (Guo et al. 2006).
R-HSA-6788597 (Reactome) 3-hydroxy-3-methylglutaryl CoA lyase (HMGCL) catalyses the cleavage of beta-hydroxy-3-methylglutaryl CoA (bHMG-CoA) to acetoacetate (ACA) and acetyl-CoA (Ac-CoA). This reaction is the common final step in ketogenesis and leucine catabolism. HMGCL isoforms are usually located to the mitochondrial matrix or peroxisomes. The mitochondrial isoform contributes to ketone body production whereas the function of the peroxisomal form is unclear. Another isoform has recently been discovered, (HMGCLL1) which is expressed mainly in liver, lung, kidney and brain and has a dual location of ER and cytosolic cellular compartments. The metabolic function of HMGCLL1 is unknown but could provide support for energy production in the tissues mentioned above (Montgomery et al. 2012, Arnedo et al. 2012).
R-HSA-73912 (Reactome) D-beta-hydroxybutyrate dehydrogenase tetramer (BDH1) in the mitochondrial matris catalyzes the reversible reaction of acetoacetate with NADH + H+ to form D-beta hydroxybutyrate and NAD+ (Marks et al. 1992).
R-HSA-73916 (Reactome) Acetyl-CoA acetyltransferase tetramer (ACAT1) in the mitochondrial matrix catalyzes the reversible reaction of two molecules of acetyl-CoA to form acetoacetyl-CoA and CoA (Middleton et al. 1986).
R-HSA-73918 (Reactome) Hydroxymethylglutaryl-CoA synthase tetramer (HMGCS2) in the mitochondrial matrix catalyzes the reaction of acetoacetyl-CoA and acetyl-CoA to form beta-hydroxy-beta-methylglutaryl coenzyme A (HMG CoA) and CoA (Aledo et al. 2001).
R-HSA-73920 (Reactome) D-beta-hydroxybutyrate dehydrogenase tetramer (BDH1) in the mitochondrial matrix catalyzes the reversible reaction of D-beta hydroxybutyrate and NAD+ to form acetoacetate and NADH + H+ (Marks et al. 1992).
R-HSA-74177 (Reactome) Mitochondrial succinyl-CoA:3-ketoacid coenzyme A transferases 1 and 2 (OXCT1 and OXCT2) are key enzymes for the metabolism of ketone bodies, catalysing the first rate-limiting step of ketone body utilisation in peripheral tissues. In dimeric form, they mediate the transfer of a CoA moiety from succinyl-CoA (SUCC-CoA) to acetoacetate (ACA) to form acetoacetyl-CoA (ACA-CoA) and succinate (SUCCA) (Kassovska-Bratinova et al. 1996, Tanaka et al. 2002). ACA-CoA can be converted to acetyl-CoA which can be utilised by the tricarboxylic acid cycle for energy production.
R-HSA-74180 (Reactome) Hydroxymethylglutaryl-CoA lyase dimer (HMGCL) in the mitochondrial matrix catalyzes the reaction of beta-hydroxy-beta-methylglutaryl coenzyme A (HMG CoA) to form acetyl-CoA and acetoacetate (Mitchell et al. 1993).
R-HSA-74181 (Reactome) Acetyl-CoA acetyltransferase tetramer (ACAT1) in the mitochondrial matrix catalyzes the reversible reaction of acetoacetyl-CoA and CoA to form two molecules of acetyl-CoA (Middleton et al. 1986).
R-HSA-8875071 (Reactome) Mitochondrial acyl-CoA synthetase short-chain family member 3 (ACSS3) belongs to the acyl-coenzyme A synthetase family that catalyse the "activation" of fatty acids by forming a thioester with coenzyme A (CoA-SH). ACSSs typically activate acetate, propionate, or butyrate. Ligation of acetate (CH3COO-) with CoA-SH is described here (Watkins et al. 2007).
SUCC-CoAR-HSA-74177 (Reactome)
SUCCAArrowR-HSA-74177 (Reactome)
adenosine 5'-monophosphateArrowR-HSA-8875071 (Reactome)
bHBAArrowR-HSA-73912 (Reactome)
bHBAR-HSA-73920 (Reactome)
bHMG-CoAR-HSA-6788597 (Reactome)

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