Carnitine synthesis (Homo sapiens)

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6, 104, 978, 112, 53, 61mitochondrial matrixcytosolPXLP-SHMT1 AscH- NAD+TMLHE:AscH-:Fe2+dimercarnitine exporter2OGTMLHE H2OFe2+ SUCCAO2SUCCATMLYSTEABLCO2SHMT1 tetramerBBOX1 TEABTAscH- NADHFe2+ GlyALDH9A1 O2CARCARCO2HTMLYSHTMLYSBBOX1:AscH-:Fe2+dimerH+2OGALDH9A1 tetramer14, 984, 98, 11


Description

Carnitine is synthesized in four steps from trimethyllysine (generated in turn by the S-adenosyl-methionine-mediated methylation of lysine residues in proteins, followed by protein hydrolysis). The enzymes that catalyze the first three steps of carnitine synthesis, converting trimethyllysine to gamma-butyrobetaine, are widely distributed in human tissues. The enzyme that catalyzes the last reaction, converting gamma-butyrobetaine to carnitine, is found only in liver and kidney cells, and at very low levels in brain tissues. Other tissues that require carnitine, such as muscle, are dependent on transport systems that mediate its export from the liver and uptake by other tissues (Bremer 1983, Kerner and Hoppel 1998). View original pathway at Reactome.

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Pathway is converted from Reactome ID: 71262
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Reactome version: 73

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Bibliography

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  1. Kurys G, Ambroziak W, Pietruszko R.; ''Human aldehyde dehydrogenase. Purification and characterization of a third isozyme with low Km for gamma-aminobutyraldehyde.''; PubMed Europe PMC Scholia
  2. Sandor A, Kispal G, Melegh B, Alkonyi I.; ''Release of carnitine from the perfused rat liver.''; PubMed Europe PMC Scholia
  3. Lindstedt S, Nordin I.; ''Multiple forms of gamma-butyrobetaine hydroxylase (EC 1.14.11.1).''; PubMed Europe PMC Scholia
  4. Bremer J.; ''Carnitine--metabolism and functions.''; PubMed Europe PMC Scholia
  5. Vaz FM, van Gool S, Ofman R, Ijlst L, Wanders RJ.; ''Carnitine biosynthesis: identification of the cDNA encoding human gamma-butyrobetaine hydroxylase.''; PubMed Europe PMC Scholia
  6. Longo N, Frigeni M, Pasquali M.; ''Carnitine transport and fatty acid oxidation.''; PubMed Europe PMC Scholia
  7. Kerner J, Hoppel C.; ''Genetic disorders of carnitine metabolism and their nutritional management.''; PubMed Europe PMC Scholia
  8. Kispal G, Melegh B, Alkonyi I, Sandor A.; ''Enhanced uptake of carnitine by perfused rat liver following starvation.''; PubMed Europe PMC Scholia
  9. Vaz FM, Ofman R, Westinga K, Back JW, Wanders RJ.; ''Molecular and Biochemical Characterization of Rat epsilon -N-Trimethyllysine Hydroxylase, the First Enzyme of Carnitine Biosynthesis.''; PubMed Europe PMC Scholia
  10. Vaz FM, Fouchier SW, Ofman R, Sommer M, Wanders RJ.; ''Molecular and biochemical characterization of rat gamma-trimethylaminobutyraldehyde dehydrogenase and evidence for the involvement of human aldehyde dehydrogenase 9 in carnitine biosynthesis.''; PubMed Europe PMC Scholia
  11. Hulse JD, Ellis SR, Henderson LM.; ''Carnitine biosynthesis. beta-Hydroxylation of trimethyllysine by an alpha-ketoglutarate-dependent mitochondrial dioxygenase.''; PubMed Europe PMC Scholia

History

CompareRevisionActionTimeUserComment
114893view16:40, 25 January 2021ReactomeTeamReactome version 75
113339view11:41, 2 November 2020ReactomeTeamReactome version 74
112814view18:20, 9 October 2020DeSlOntology Term : 'carnitine biosynthetic pathway' added !
112762view16:16, 9 October 2020ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2OGMetaboliteCHEBI:16810 (ChEBI)
ALDH9A1 ProteinP49189 (Uniprot-TrEMBL)
ALDH9A1 tetramerComplexR-HSA-71258 (Reactome)
AscH- MetaboliteCHEBI:38290 (ChEBI)
BBOX1 ProteinO75936 (Uniprot-TrEMBL)
BBOX1:AscH-:Fe2+ dimerComplexR-HSA-71107 (Reactome)
CARMetaboliteCHEBI:17126 (ChEBI)
CO2MetaboliteCHEBI:16526 (ChEBI)
Fe2+ MetaboliteCHEBI:29033 (ChEBI)
GlyMetaboliteCHEBI:57305 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HTMLYSMetaboliteCHEBI:15786 (ChEBI)
NAD+MetaboliteCHEBI:57540 (ChEBI)
NADHMetaboliteCHEBI:57945 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
PXLP-SHMT1 ProteinP34896 (Uniprot-TrEMBL)
SHMT1 tetramerComplexR-HSA-71243 (Reactome)
SUCCAMetaboliteCHEBI:30031 (ChEBI)
TEABLMetaboliteCHEBI:18020 (ChEBI)
TEABTMetaboliteCHEBI:16244 (ChEBI)
TMLHE ProteinQ9NVH6 (Uniprot-TrEMBL)
TMLHE:AscH-:Fe2+ dimerComplexR-HSA-71098 (Reactome)
TMLYSMetaboliteCHEBI:17311 (ChEBI)
carnitine exporterR-HSA-165022 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2OGR-HSA-71241 (Reactome)
2OGR-HSA-71261 (Reactome)
ALDH9A1 tetramermim-catalysisR-HSA-71260 (Reactome)
BBOX1:AscH-:Fe2+ dimermim-catalysisR-HSA-71261 (Reactome)
CARArrowR-HSA-164967 (Reactome)
CARArrowR-HSA-71261 (Reactome)
CARR-HSA-164967 (Reactome)
CO2ArrowR-HSA-71241 (Reactome)
CO2ArrowR-HSA-71261 (Reactome)
GlyArrowR-HSA-71249 (Reactome)
H+ArrowR-HSA-71260 (Reactome)
H2OR-HSA-71260 (Reactome)
HTMLYSArrowR-HSA-71241 (Reactome)
HTMLYSArrowR-HSA-8949413 (Reactome)
HTMLYSR-HSA-71249 (Reactome)
HTMLYSR-HSA-8949413 (Reactome)
NAD+R-HSA-71260 (Reactome)
NADHArrowR-HSA-71260 (Reactome)
O2R-HSA-71241 (Reactome)
O2R-HSA-71261 (Reactome)
R-HSA-164967 (Reactome) Studies of carnitine (CAR) export from intact rat liver indicate that this process is mediated by a specific, saturable transporter molecule (Sandor et al. 1985). The transporter itself has not been identified, but its properties are distinct from those of OCTN2, the major transport protein responsible for carnitine uptake (Kispal et al. 1987). The existence of a human transport reaction (again without an identified transporter) is inferred from the rat one.
R-HSA-71241 (Reactome) Trimethyllysine dioxygenase (TMLHE) dimer in the mitochondrial matrix catalyzes the reaction of oxygen, 2-oxoglutarate (2OG), and N6,N6,N6-trimethyl-L-lysine (TMLYS) to form CO2, 3-hydroxy-N6,N6,N6-trimethyl-L-lysine (HTMLYS), and succinate (SUCCA) (Vaz et al. 2001).
R-HSA-71249 (Reactome) Cytosolic serine hydroxymethyltransferase tetramer (SHMT1) catalyzes the reaction of 3-Hydroxy-N6,N6,N6-trimethyl-L-lysine (NTMLYS) to form glycine (Gly) and 4-trimethylammoniobutanal (TEABL) in vitro (Hulse et al. 1978). The possibility that an additional enzyme may catalyze this reaction in vivo has not been excluded (Bremer 1983).
R-HSA-71260 (Reactome) Cytosolic 4-trimethylaminobutyraldehyde dehydrogenase (ALDH9A1) tetramer catalyzes the reaction of NAD+ and 4-trimethylammoniobutanal (TEABL) to form 4-trimethylammoniobutanoate (TEABT) and NADH + H+ (Kurys et al. 1989; Vaz et al. 2000).
R-HSA-71261 (Reactome) Cytosolic gamma-butyrobetaine hydroxylase dimer (BBOX1), a dioxygenase, catalyzes the reaction of oxygen, 4-trimethylammoniobutanoate (TEABT), and 2-oxoglutarate (2OG)to form CO2, succinate (SUCCA), and carnitine (CAR) (Lindstedt and Nordin 1984; Vaz et al. 1998).
R-HSA-8949413 (Reactome) HTMLYS (3-Hydroxy-N6,N6,N6-trimethyl-L-lysine) moves from the mitochondrial matrix to the cytosol (Longo et al. 2016). The molecular mechanism for this translocation is unknown.
SHMT1 tetramermim-catalysisR-HSA-71249 (Reactome)
SUCCAArrowR-HSA-71241 (Reactome)
SUCCAArrowR-HSA-71261 (Reactome)
TEABLArrowR-HSA-71249 (Reactome)
TEABLR-HSA-71260 (Reactome)
TEABTArrowR-HSA-71260 (Reactome)
TEABTR-HSA-71261 (Reactome)
TMLHE:AscH-:Fe2+ dimermim-catalysisR-HSA-71241 (Reactome)
TMLYSR-HSA-71241 (Reactome)
carnitine exportermim-catalysisR-HSA-164967 (Reactome)
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