Leucine, isoleucine and valine metabolism (Homo sapiens)

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1BCAA aminotransferase deficencyHydrataseBCKDHMethacrylic acid conjugates:alloisoleucinePCCBBCAT1MethylmalonateBiotinKetolysis E1 (alpha)Ketone body synthesis TPPE2 (aka DBT)3-Methylcrotonyl-CoA3-HydroxybutyrateHydratase32-OxoisovalerateMCC alphaIsobutyrylcarnitine2IVDMethylmalonate3-Hydroxy-3-methylglutaryl-CoAIsoleucine3-HydroxyisobutyrateMethylcrotonylglycinuriaMalonic acidIsovaleric acidemiaMalonyl-CoA decarboxylaseMethylglutaconic aciduria type IVL-ValineACSF3Isobutyrylglycine2-Hydroxyisovalerate3-Hydroxy-3-methylglutaric aciduriaS-2-carboxypropylcysteineBCAA aminotransferase deficencyMalonate2-Methyl-3-hydroxy-butyryl-CoA dehydrogenase deficiencyMethylmalonyl-CoA2-Methylbutyryl-glycinuria3-HydroxyisobutyrylcarnitineAcetoacetateAlpha-methyl-acetoacetic aciduria2-Methylaceto-acetyl-CoAAminotransferase2-Methyl-3-hydroxy-butyryl-CoAValineTiglyl-CoAL-Isoleucine2-Methylbutyryl-CoA2-Hydroxyisovalerate2-Oxo-3-methylvalerateL-LeucineAcetyl-CoA2-OxoisocaproateMHBDS-2-carboxypropylcysteamineHMG-CoA lyaseACADSBMalonyl-CoABeta-ketothiolase2-OxoisocaproateE3 (aka DLD)Isovaleryl-CoABCAA aminotransferase deficencyMaple syrup urine diseaseHIBCHSCEHIBDMethacrylyl-CoAIsobutyryl-CoA2-Oxo-isovalerateSuccinyl-CoAPropionyl-CoAMethylmalonate semialdehyde3-Hydroxyisobutyrate3-Hydroxyiso-butyryl-CoAPCCAMMSDHHIBADHMutase3-Hydroxyisobutyryl-CoAdecylase deficencyIsobutyryl-CoAdehydrogensae deficency3-Hydroxyisobutyratedehydrogenase deficiencyMethylmalonate semialdehyde dehydrogenase deficiencyPropionic acidemiaMethylmalonic acidemiaCombined MMA and MAMalonic aciduria2-Hydroxyisocaproate3-HydroxyisovalerateLeucineIsovalerylglycineIsovaleryglucuronideIsovaleric acid4-Hydroxyisovaleric acidIsovalerylcarnitine3-Hydroxyisovalerate3-MethylcrotonylglycineC5-Hydroxyacylcarnitine3-Methylglutaconate3-Methylglutarylcarnitine3-HydroxyisovalerateC5-Hydroxyacylcarnitine3-Methylglutarate3-Methylglutaconate3-Hydroxyisovalerate3-MethylglutarateC5-Hydroxyacylcarnitine3-Hydroxy-3-methylglutarate3-Methylcrotonylglycine3-Hydroxyhexanoyl-carnitineKetone BodiesMalonic acidEthylmalonic acidMethylmalonic acidMalonylcarnitine2-Oxo-3-methylvalerate2-Methylbutyrylcarnitine2-Hydroxy-3-methylvalerate2-Methylbutyrylglycine2-Ethylhydracrylic acidTiglylglycineTiglylgycineTiglylglycine2-Methylacetoacetic acid2-Methyl-3-hydroxybutyrate2-Methyl-3-hydroxybutyrateTiglylcarnitineTiglycarnitine2-Methyl-3-hydroxybutyryl-carnitine2-Methyl-3-hydroxy-butyrylcarnitine2-Hydroxyisovalerate3-Hydroxyisobutyrylcarnitine3-Aminoisobutyric acid3-Hydroxyisobutyrate3-Hydroxypropionic acidEthylmalonic acidBeta-alanine3-HydroxypropionatePropionylglycineTiglylglycinePropionylcarnitineR,S-MethylcitrateR,S-Methylcitrate3-HydroxypropionatePropionylcarnitineMethylmalonylcarnitineMethylmalonic acidMalonylcarnitineE1 (beta)TPPBCKDHE2 (aka DBT)E3 (aka DLD)E1 (alpha)TPPE1 (beta)TPPBCKDHE2 (aka DBT)E3 (aka DLD)E1 (alpha)TPPE1 (beta)TPP3-Methyl-glutaconyl-CoAMCC alphaBCAT22BCAT1AminotransferaseBCAT2BCAT1AminotransferaseBCAT2Maple syrup urine disease 1aMaple syrup urine disease 1bMaple syrup urine disease II


Description

This pathway shows disorders related to leucine, isoleusine and valine metabolism. These three substrates are part of a group of chemicals called Branched-chain amino acids (BCAAs), which are essential nutrients and can be found in meat, dairy, and legumes. BCAAs stimulate the building of protein in muscle and possibly reduce muscle breakdown. Disorders resulting from an enzyme defect are highlighted in pink. This pathway was inspired by Chapter 7 of the book of Blau (ISBN 3642403360 (978-3642403361)).

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Quality Tags

Ontology Terms

 

Bibliography

  1. Blau N, Duran M, Gibson KM, Dionisi-Vici, C; ''Physician's Guidee to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases''; Springer ISBN 3642403360, 2014
  2. Chu CH, Cheng D; ''Expression, purification, characterization of human 3-methylcrotonyl-CoA carboxylase (MCCC).''; Protein Expr Purif, 2007 PubMed Europe PMC Scholia
  3. Agnihotri G, Liu HW; ''Enoyl-CoA hydratase. reaction, mechanism, and inhibition.''; Bioorg Med Chem, 2003 PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
128283view01:25, 30 January 2024EweitzSoften disease color, use standard font weight
122622view08:44, 22 April 2022DeSlAnnotated most side metabolites/biomarkers
122618view08:00, 22 April 2022DeSlAnnotated righthand side fully
122617view07:42, 22 April 2022DeSlAnnotated most of righthand side main reactions
122615view15:30, 21 April 2022DeSlAnnotated all remaining proteins
122614view15:23, 21 April 2022DeSlFinished annotating middle section
122613view15:00, 21 April 2022DeSlAdded three additional subtypes for Maple syrup urine disease
122612view13:40, 21 April 2022DeSlMore layout updates
122611view13:33, 21 April 2022DeSlFixing layout, connectiond to disorders, replacing complexes with groups for Metabolites
122610view13:11, 21 April 2022DeSlStarting to annotate middle section
122605view09:28, 21 April 2022DeSlUpdate description
122059view13:37, 9 March 2022SamDrabbeketone body synthesis and ketolysis pathway added
119122view08:55, 18 June 2021FinterlyAdded ISBN for book citation
117776view13:59, 22 May 2021EweitzModified title
108034view14:58, 25 November 2019L DupuisConnected unconnected line
106457view10:09, 30 August 2019DeSlAdded last biomarker IDs on left.
106456view10:08, 30 August 2019DeSlAdded IDs for biomarkers on left hand side of PW.
106379view15:18, 23 August 2019DeSlAdded biotin (needed for MCC functioning).
106378view15:15, 23 August 2019DeSlFinished annotating main metabolites left hand side.
106377view14:31, 23 August 2019DeSlAdded more metabolite IDs for starting compounds
106376view14:27, 23 August 2019DeSlAdded subunits for BCKDH complex, started adding metabolite IDs + rhea interaction IDs.
105884view07:26, 16 August 2019AkutmonAdded Protein Identifiers
105883view07:11, 16 August 2019AkutmonAdded Protein identifiers
105739view11:13, 15 August 2019AkutmonUpdated Metabolic Groups
105738view10:07, 15 August 2019AkutmonAdded Metabolite Groups
105737view09:41, 15 August 2019AkutmonAdded Metabolite Groups
105736view09:04, 15 August 2019AkutmonAdded Metabolite Groups
105735view07:59, 15 August 2019AkutmonAdded Metabolite Groups
105734view07:49, 15 August 2019Akutmon
105733view07:29, 15 August 2019Akutmon
105732view07:28, 15 August 2019Akutmon
105726view15:33, 14 August 2019DeSlOntology Term : 'methylmalonic acidemia pathway' added !
105725view15:33, 14 August 2019DeSlOntology Term : 'methylmalonic acidemia' added !
105724view15:33, 14 August 2019DeSlOntology Term : 'propionic acidemia pathway' added !
105723view15:32, 14 August 2019DeSlOntology Term : 'propionic acidemia' added !
105722view15:32, 14 August 2019DeSlOntology Term : 'methylmalonate semialdehyde dehydrogenase deficiency pathway' added !
105721view15:30, 14 August 2019DeSlOntology Term : 'isobutyryl-CoA dehydrogenase deficiency pathway' added !
105720view15:29, 14 August 2019DeSlOntology Term : 'malonic aciduria pathway' added !
105719view15:27, 14 August 2019DeSlOntology Term : '3-hydroxy-3-methylglutaryl-CoA lyase deficiency pathway' added !
105718view15:26, 14 August 2019DeSlOntology Term : '3-methylglutaconic aciduria type 4' added !
105717view15:24, 14 August 2019DeSlOntology Term : '3-Methylcrotonyl-CoA carboxylase deficiency' added !
105716view15:24, 14 August 2019DeSlOntology Term : 'isovaleric acidemia pathway' added !
105715view15:24, 14 August 2019DeSlOntology Term : 'isovaleric acidemia' added !
105714view15:23, 14 August 2019DeSlOntology Term : 'maple syrup urine disease pathway' added !
105713view15:23, 14 August 2019DeSlOntology Term : 'maple syrup urine disease' added !
105712view14:47, 14 August 2019AkutmonOntology Term : 'valine metabolic pathway' added !
105711view14:46, 14 August 2019AkutmonOntology Term : 'isoleucine metabolic pathway' added !
105710view14:46, 14 August 2019AkutmonOntology Term : 'leucine metabolic pathway' added !
105709view14:46, 14 August 2019AkutmonOntology Term : 'inherited metabolic disorder' added !
105708view14:45, 14 August 2019AkutmonNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2-Ethylhydracrylic acidMetaboliteCHEBI:82956 (ChEBI)
2-Hydroxy-3-methylvalerateMetabolite10796774 (PubChem-compound) aka 2-hydroxy-3-methylpentanoic acid
2-HydroxyisocaproateMetaboliteCHEBI:133577 (ChEBI)
2-HydroxyisovalerateMetaboliteCHEBI:64669 (ChEBI)
2-Methyl-3-hydroxy-butyryl-CoAMetaboliteCHEBI:165613 (ChEBI)
2-Methyl-3-hydroxy-butyrylcarnitineMetabolite129663780 (PubChem-compound) aka 2-Methyl-3-hydroxybutyrylcarnitine, 2-Methyl-3-hydroxy-butyrylcarnitine, 2-Methyl-3-hydroxy-butyryl-carnitine, 2-Methyl-3-hydroxybutyryl-carnitine, 2-Methyl-3-hydroxybutyryl carnitine
2-Methyl-3-hydroxybutyrateMetaboliteCHEBI:78554 (ChEBI)
2-Methyl-3-hydroxybutyryl-carnitineMetabolite129663780 (PubChem-compound) aka 2-Methyl-3-hydroxybutyrylcarnitine, 2-Methyl-3-hydroxy-butyrylcarnitine, 2-Methyl-3-hydroxy-butyryl-carnitine, 2-Methyl-3-hydroxybutyryl-carnitine, 2-Methyl-3-hydroxybutyryl carnitine
2-Methylaceto-acetyl-CoAMetaboliteCHEBI:57335 (ChEBI) AKA 2-methyl-3-oxobutanoyl-CoA
2-Methylacetoacetic acidMetaboliteCHEBI:37079 (ChEBI)
2-Methylbutyryl-CoAMetaboliteCHEBI:57336 (ChEBI) AKA 2-methylbutanoyl-CoA
2-MethylbutyrylcarnitineMetaboliteCHEBI:73026 (ChEBI)
2-MethylbutyrylglycineMetaboliteCHEBI:86366 (ChEBI) AKA N-(2-methylbutanoyl)glycine
2-Oxo-3-methylvalerateMetaboliteCHEBI:28654 (ChEBI) AKA 3-methyl-2-oxovalerate, a Branched-chain-keto acid (BCKA)
2-Oxo-isovalerateMetaboliteCHEBI:11851 (ChEBI)
2-OxoisocaproateMetaboliteCHEBI:17865 (ChEBI)
2-OxoisovalerateMetaboliteCHEBI:11851 (ChEBI)
3-Aminoisobutyric acidMetaboliteCHEBI:27389 (ChEBI)
3-Hydroxy-3-methylglutarateMetaboliteCHEBI:30920 (ChEBI)
3-Hydroxy-3-methylglutaryl-CoAMetaboliteCHEBI:43074 (ChEBI)
3-HydroxybutyrateMetaboliteCHEBI:37054 (ChEBI)
3-Hydroxyhexanoyl-carnitineMetabolite131770386 (PubChem-compound)
3-Hydroxyiso-butyryl-CoAMetaboliteCHEBI:62611 (ChEBI)
3-HydroxyisobutyrateMetaboliteCHEBI:62638 (ChEBI)
3-HydroxyisobutyrylcarnitineMetabolite129692225 (PubChem-compound) aka 3-Hydroxyisobutyryl-carnitine
3-HydroxyisovalerateMetaboliteCHEBI:82957 (ChEBI)
3-HydroxypropionateMetaboliteCHEBI:16510 (ChEBI)
3-Hydroxypropionic acidMetaboliteCHEBI:33404 (ChEBI)
3-Methyl-glutaconyl-CoAMetaboliteCHEBI:57346 (ChEBI)
3-Methylcrotonyl-CoAMetaboliteCHEBI:57344 (ChEBI)
3-MethylcrotonylglycineMetaboliteCHEBI:68499 (ChEBI)
3-MethylglutaconateMetaboliteCHEBI:133513 (ChEBI)
3-MethylglutarateMetabolite11781 (Chemspider)
3-MethylglutarylcarnitineMetaboliteCHEBI:70857 (ChEBI)
4-Hydroxyisovaleric acidMetabolite131760 (PubChem-compound)
ACADSBProteinP45954 (Uniprot-TrEMBL) MBD is abbreviation for disorder, not for the protein/gene
ACSF3ProteinQ4G176 (Uniprot-TrEMBL)
AcetoacetateMetaboliteCHEBI:13705 (ChEBI)
Acetyl-CoAMetaboliteCHEBI:57288 (ChEBI)
AminotransferaseProtein2.6.1.42 (Enzyme Nomenclature)
BCAT1ProteinP54687 (Uniprot-TrEMBL)
BCAT2ProteinO15382 (Uniprot-TrEMBL)
Beta-alanineMetaboliteCHEBI:16958 (ChEBI)
Beta-ketothiolaseProteinP24752 (Uniprot-TrEMBL) AKA ACAT1, confirmed with disorder Table from book and link to UniProt from Rhea
BiotinMetaboliteCHEBI:15956 (ChEBI) "alpha subunit is covalently bound to biotin, which is essential for the ATP-dependent carboxylation". Source: [https://en.wikipedia.org/wiki/Methylcrotonyl-CoA_carboxylase#Protein]
C5-HydroxyacylcarnitineMetaboliteAKA C5-OH Acylcarnitine ; no ID found in Pubchem, ChEBI, HMDB. Metabolite is considered a biomarker for several IMDs, see https://dshs.texas.gov/newborn/pdf/ACT-ElevatedC5-OH.pdf for details
E1 (alpha)ProteinP12694 (Uniprot-TrEMBL) E1 uses thiamine pyrophosphate (TPP) as a catalytic cofactor.
E1 (beta)ProteinP21953 (Uniprot-TrEMBL) E1 uses thiamine pyrophosphate (TPP) as a catalytic cofactor.
E2 (aka DBT)ProteinP11182 (Uniprot-TrEMBL)
E3 (aka DLD)ProteinP09622 (Uniprot-TrEMBL)
Ethylmalonic acidMetaboliteCHEBI:741548 (ChEBI)
HIBADHProteinP31937 (Uniprot-TrEMBL)
HIBCHProteinQ6NVY1 (Uniprot-TrEMBL)
HMG-CoA lyaseProteinQ8TB92 (Uniprot-TrEMBL)
HydrataseProteinQ13825 (Uniprot-TrEMBL) AKA Methylglutaconyl-CoA hydratase
IBDProteinQ9UKU7 (Uniprot-TrEMBL)
IVDProteinP26440 (Uniprot-TrEMBL)
Isobutyryl-CoAMetaboliteCHEBI:15479 (ChEBI)
IsobutyrylcarnitineMetaboliteCHEBI:73017 (ChEBI)
IsobutyrylglycineMetaboliteCHEBI:70979 (ChEBI)
IsoleucineMetaboliteCHEBI:24898 (ChEBI)
Isovaleric acidMetaboliteCHEBI:28484 (ChEBI)
IsovaleryglucuronideMetabolite137383 (PubChem-compound)
Isovaleryl-CoAMetaboliteCHEBI:57345 (ChEBI)
IsovalerylcarnitineMetaboliteCHEBI:73025 (ChEBI)
IsovalerylglycineMetaboliteCHEBI:70984 (ChEBI)
Ketolysis PathwayWP5195 (WikiPathways)
Ketone BodiesMetaboliteCHEBI:73693 (ChEBI)
Ketone body synthesis PathwayWP5175 (WikiPathways)
L-IsoleucineMetaboliteCHEBI:17191 (ChEBI)
L-LeucineMetaboliteCHEBI:15603 (ChEBI)
L-ValineMetaboliteCHEBI:57762 (ChEBI)
LeucineMetaboliteCHEBI:25017 (ChEBI)
MCC alphaProteinQ96RQ3 (Uniprot-TrEMBL) "alpha subunit is covalently bound to biotin, which is essential for the ATP-dependent carboxylation". Source: [https://en.wikipedia.org/wiki/Methylcrotonyl-CoA_carboxylase#Protein]
MCC alphaProteinQ9HCC0 (Uniprot-TrEMBL)
MHBDProteinQ99714 (Uniprot-TrEMBL)
MMSDHProteinQ02252 (Uniprot-TrEMBL) AKA ALDH6A1
MalonateMetaboliteCHEBI:15792 (ChEBI)
Malonic acidMetaboliteCHEBI:30794 (ChEBI)
Malonyl-CoA decarboxylaseProteinO95822 (Uniprot-TrEMBL) AKA MLYCD
Malonyl-CoAMetaboliteCHEBI:15531 (ChEBI) Potentially interesting Rhea ID: https://www.rhea-db.org/rhea/18817 , for reaction with malonate and Acetyl-CoA, however no directionality known.
MalonylcarnitineMetaboliteCHEBI:73028 (ChEBI)
Methacrylyl-CoAMetaboliteCHEBI:62500 (ChEBI) AKA (2E)-2-methylpropenoyl-CoA (Rhea match)
Methylmalonate semialdehydeMetaboliteCHEBI:62413 (ChEBI)
MethylmalonateMetaboliteCHEBI:17453 (ChEBI)
Methylmalonic acidMetaboliteCHEBI:30860 (ChEBI)
Methylmalonyl-CoAMetaboliteCHEBI:57327 (ChEBI)
MethylmalonylcarnitineMetaboliteCHEBI:73031 (ChEBI)
MutaseProteinP22033 (Uniprot-TrEMBL) AKA MMUT, confired by Rhea linking to UniProt and Table in book on disorders.
PCCAProteinP05165 (Uniprot-TrEMBL)
PCCBProteinP05166 (Uniprot-TrEMBL)
Propionyl-CoAMetaboliteCHEBI:57392 (ChEBI) AKA propanoyl-CoA in Rhea
PropionylcarnitineMetaboliteCHEBI:28867 (ChEBI)
PropionylglycineMetaboliteCHEBI:89836 (ChEBI)
R,S-MethylcitrateMetaboliteCHEBI:10860 (ChEBI) aka (2R,3S)-2-methylcitrate(3−)
S-2-carboxypropylcysteamineMetaboliteCHEBI:184285 (ChEBI)
S-2-carboxypropylcysteineMetabolite129651610 (PubChem-compound) AKA S-2-carboxypropyl-cysteine; annotated based on closest match in PubChem compound (carboxypropyl-cysteine, which doesn't specifiy the location and orientation of the carboxypropyl group).
SCEHProteinP30084 (Uniprot-TrEMBL) aka ECHS1, protein confirmed by Rhea and UniProt
Succinyl-CoAMetaboliteCHEBI:57292 (ChEBI)
TiglycarnitineMetaboliteCHEBI:71179 (ChEBI)
Tiglyl-CoAMetaboliteCHEBI:15478 (ChEBI) AKA 2-methylcrotonoyl-CoA
TiglylcarnitineMetaboliteCHEBI:71179 (ChEBI)
TiglylglycineMetaboliteCHEBI:73018 (ChEBI)
TiglylgycineMetaboliteCHEBI:73018 (ChEBI)
ValineMetaboliteCHEBI:27266 (ChEBI)
alloisoleucineMetaboliteCHEBI:43433 (ChEBI)
  • Connection of this metabolite to pathway is unclear, figure in book links this to the protein?)
  • Assumed to be the L-form, according to [https://en.wikipedia.org/wiki/Isoleucine] Table with isomers, where the synonym of L-alloisoleucine is alloisoleucine.

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2-Methyl-3-hydroxy-butyryl-CoA2-Methylaceto-acetyl-CoAmim-conversion13282 (Rhea)
2-Methylaceto-acetyl-CoAAcetyl-CoAmim-conversion30721 (Rhea)
2-Methylbutyryl-CoATiglyl-CoAmim-conversion31120 (Rhea)
2-Oxo-isovalerateIsobutyryl-CoAmim-conversion13458 (Rhea)
2-OxoisocaproateIsovaleryl-CoAmim-conversion25178 (Rhea)
3-Hydroxy-3-methylglutaryl-CoAAcetoacetatemim-conversion24405 (Rhea)
3-Hydroxyiso-butyryl-CoA3-Hydroxyisobutyratemim-conversion31252 (Rhea)
3-HydroxyisobutyrateMethylmalonate semialdehydemim-conversion31276 (Rhea)
3-Methyl-glutaconyl-CoA3-Hydroxy-3-methylglutaryl-CoAmim-conversion21538 (Rhea)
3-Methylcrotonyl-CoA3-Methyl-glutaconyl-CoAmim-conversion13590 (Rhea)
Acetyl-CoAmim-conversion24405 (Rhea)
Isobutyryl-CoAMethacrylyl-CoAmim-conversion31096 (Rhea)
Isovaleryl-CoA3-Methylcrotonyl-CoAmim-conversion31064 (Rhea) Annotated with RHEA:31064 (uses FAD) iso RHEA:12277 (which uses flavoproteins, unlikely being used in this reaction). Rhea links out to correct Uniprot ID, however Uniprot only provides later Rhea-ID.
L-Isoleucine2-Oxo-3-methylvaleratemim-conversion24802 (Rhea)
L-Valine2-Oxo-isovaleratemim-conversion22913 (Rhea)
MalonateMalonyl-CoAmim-conversion32140 (Rhea)
Methacrylyl-CoA3-Hydroxyiso-butyryl-CoAmim-conversion31176 (Rhea)
Methylmalonate semialdehydePropionyl-CoAmim-conversion31048 (Rhea)
MethylmalonateMethylmalonyl-CoAmim-conversion17347 (Rhea)
Methylmalonyl-CoASuccinyl-CoAmim-conversion22889 (Rhea)
Propionyl-CoAMethylmalonyl-CoAmim-conversion23721 (Rhea) Reaction confirmed by UniProt linked to Rhea
Propionyl-CoAmim-conversion30721 (Rhea)
Tiglyl-CoA2-Methyl-3-hydroxy-butyryl-CoAmim-conversion31121 (Rhea)
Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP4686"
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