Krebs cycle disorders (Homo sapiens)

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32, 41, 2, 42, 4Complex formation of SCS with NDPK is inprotant for deoxyribonucleotide salvation, which is needed for mtDNA synthesis and integrity.Relevant metabolic pathways,illustrating the metabolic effects of succinyl-CoA sythethase deficiencySUCLA2NDPKmtDNA synthesisADP-forming (A-SCS)2-oxoglutaric aciduriaIn most patient, E2 subunit seems responsible for "classic metabolic" presentation of diseaseEncephalopathic form is related to E2 subunit deficiencyalpha-ketoglutarateFumarateE1-subunitGDP-forming(G-SCS)FH2-KGD complexOxaloacetateMethylmalonyl-CoA(S)-malatepyruvatelactateSuccinyl coenzyme AAcetyl-CoAADPpropionylATPMETHYLMALONIC ACIDGTPcitratesuccinatemethylcitrateMETHYLMALONYL CARNITINE ESTER (C4DC)SUCCINYL CARNITINEESTER (C4DC)3-HYDROXYPROPIONATEPROPIONYLCARNITINE (C3)E2-subunitE3-subunit2-oxoglutaric aciduria:encephalopathic form2-oxoglutaric aciduria:'DOOR syndrome"Clinically recognisable form of:deafness, onycho-osteodystrophy,thumbs and sensorineural deafness,is related to defect of E1 subunit.Fumarase deficiencySCS deficiencySUCLA2SCS deficiencySUCLG1SUCLG1SUCLG2GDPSUCLG1GDP-forming(G-SCS)SUCLG1SUCLG2SUCLA2ADP-forming (A-SCS)SUCLG1GDP-forming(G-SCS)SUCLG1SUCLG2NDPKSUCLA2ADP-forming (A-SCS)SUCLG1NDPK1, 2, 41, 2, 42, 4


Description

This pathway shows an simplified version of the Krebs cycle (for more details see [1] ), with 4 genetic diseases related to it.

For succinyl-CoA synthetase deficiencies, relevant metabolic markers are depicted in light green. Patients with a mutation in the SUCLG1 might present a severe (fatal) form of mitochondrial encephalomyopathy.

This pathway was inspired by Chapter 20 of the book of Blau (ISBN 3642403360 (978-3642403361)).

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Quality Tags

Ontology Terms

 

Bibliography

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  1. Kyle S McCommis, Brian N Finck; ''Mitochondrial pyruvate transport: a historical perspective and future research directions ''; Biochem J., 2015 PubMed Europe PMC Scholia
  2. Kowluru A, Tannous M, Chen HQ; ''Localization and characterization of the mitochondrial isoform of the nucleoside diphosphate kinase in the pancreatic beta cell: evidence for its complexation with mitochondrial succinyl-CoA synthetase.''; Arch Biochem Biophys, 2002 PubMed Europe PMC Scholia
  3. Kavanaugh-Black A, Connolly DM, Chugani SA, Chakrabarty AM; ''Characterization of nucleoside-diphosphate kinase from Pseudomonas aeruginosa: complex formation with succinyl-CoA synthetase.''; Proc Natl Acad Sci U S A, 1994 PubMed Europe PMC Scholia
  4. Lawrence R Gray, Sean C Tompkins, Eric B Taylor; ''Disorders of the Pyruvate Metabolism and the Krebs Cycle''; Cell Mol Life Sci ., 2014 PubMed Europe PMC Scholia
  5. Kadrmas EF, Ray PD, Lambeth DO; ''Apparent ATP-linked succinate thiokinase activity and its relation to nucleoside diphosphate kinase in mitochondrial matrix preparations from rabbit.''; Biochim Biophys Acta, 1991 PubMed Europe PMC Scholia
  6. Nenad Blau, Marinus Duran, K Michael Gibson, Carlo Dionisi-Vici.; ''Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases''; Springer-Verlag Berlin Heidelberg, 2014

History

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CompareRevisionActionTimeUserComment
128282view01:21, 30 January 2024EweitzFix legend layout
128281view01:18, 30 January 2024EweitzCopyedit nodes, standardize case
128280view01:08, 30 January 2024EweitzSoften disease color
123795view15:24, 12 August 2022DeSlAdded some more proteins, and cytosol vs mitochondrial matrix location
123794view15:18, 12 August 2022DeSlConvert arrow to translocation
123793view15:16, 12 August 2022DeSlAdded pyruvate transport
123792view15:11, 12 August 2022DeSlAdded reaction to Alanine
123791view15:05, 12 August 2022DeSlAdded LDH tetramers
123790view14:50, 12 August 2022DeSlAdded another lit. ref to full PW
123789view14:45, 12 August 2022DeSlAdding ID for Succinyl carnitine ester
120410view09:27, 30 November 2021Fehrhartboxed pathway node
119280view10:43, 23 June 2021FinterlyAdded ISBN for book citation
117701view12:21, 22 May 2021EweitzModified title
107304view14:36, 19 September 2019EgonwRemove an empty ChEBI identifier
107163view14:25, 17 September 2019MaintBotChEBI identifier normalization
106785view13:26, 17 September 2019MaintBotHMDB identifier normalization
104644view07:31, 7 June 2019JosienlandmanConverted the interaction lines to the diseases into graphical lines
104027view17:40, 25 April 2019IreneHemelModified description
102830view15:59, 24 January 2019DeSlModified description
102829view15:58, 24 January 2019DeSlAnnotated nodes.
102715view13:26, 21 January 2019DeSlModified description
98924view05:20, 16 October 2018EgonwModified description
98275view15:29, 15 August 2018DeSlModified description
98274view15:27, 15 August 2018DeSlModified description
98273view15:24, 15 August 2018DeSlOntology Term : 'mitochondrial encephalomyopathy' added !
98272view15:23, 15 August 2018DeSlChanged some MIM-conversion to arrows, since it's not sure if there is a one step conversion proccess involved.
98271view15:22, 15 August 2018DeSlAdded info on boxed metabolites.
98270view15:19, 15 August 2018DeSlAdded last unconnected line
98269view15:06, 15 August 2018DeSlAdded more info on SCS protein complex
98268view14:54, 15 August 2018DeSlAdded specific subunits of SCS complex
98267view14:17, 15 August 2018DeSlOntology Term : 'methylmalonic acidemia' added !
98266view14:15, 15 August 2018DeSlOntology Term : 'fumaric aciduria pathway' added !
98265view14:15, 15 August 2018DeSlOntology Term : 'citric acid cycle pathway' added !
98264view14:14, 15 August 2018DeSlModified description
98263view14:13, 15 August 2018DeSlAdded diseases as text boxes (with OMIM linkouts), changed layout, added some enzymes+metabolites to close the cycle.
96740view05:58, 2 April 2018EgonwReplaced secondary ChEBI identifiers with primary identifiers.
96739view05:57, 2 April 2018EgonwRemoved a wrong identifier
96576view13:54, 21 March 2018Richard97New pathway

External references

DataNodes

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NameTypeDatabase referenceComment
(S)-malateMetaboliteQ27104150 (Wikidata) Not in original drawing, adapted from https://www.wikipathways.org/index.php/Pathway:WP78
2-KGD complexProteinQ1B4V6 (Uniprot-TrEMBL)
  • Composed of 3 subunits
  • "Homodimer. The 2-oxoglutarate dehydrogenase (ODH) complex contains multiple copies of three enzymatic components: 2-oxoglutarate dehydrogenase (E1), dihydrolipoamide succinyltransferase (E2) and lipoamide dehydrogenase (E3) (By similarity)." [https://www.uniprot.org/uniprot/Q1B4V6]
3-HYDROXYPROPIONATEMetaboliteQ27101949 (Wikidata)
ADP-forming (A-SCS)Protein6.2.1.5 (Enzyme Nomenclature)
  • SCS (succinyl-CoA syntethase)
  • For more info see: https://en.wikipedia.org/wiki/Succinyl_coenzyme_A_synthetase
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Acetyl-CoAMetaboliteQ715317 (Wikidata)
E1-subunitProteinQ96HY7 (Uniprot-TrEMBL)
E2-subunitProteinP36957 (Uniprot-TrEMBL)
E3-subunitProteinO00330 (Uniprot-TrEMBL)
FHGeneProduct2271 (Entrez Gene) Fumarate hydratase
FumarateMetaboliteCHEBI:18012 (ChEBI)
GDP-forming(G-SCS)Protein6.2.1.4 (Enzyme Nomenclature)
  • SCS (succinyl-CoA syntethase)
  • For more info see: https://en.wikipedia.org/wiki/Succinyl_coenzyme_A_synthetase
GDPMetaboliteCHEBI:17552 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
METHYLMALONIC ACIDMetaboliteCHEBI:30860 (ChEBI)
METHYLMALONYL CARNITINE ESTER (C4DC)MetaboliteHMDB0062785 (HMDB)
Methylmalonyl-CoAMetaboliteHMDB01269 (HMDB)
NDPKProtein2.7.4.6 (Enzyme Nomenclature) Nucleoside diphosphate kinase
OxaloacetateMetaboliteQ408658 (Wikidata) Not in original drawing, adapted from https://www.wikipathways.org/index.php/Pathway:WP78
PROPIONYLCARNITINE (C3)MetaboliteQ27103933 (Wikidata) a.k.a. 2-methylcitric acid
SUCCINYL CARNITINE ESTER (C4DC)Metabolite
SUCLA2ProteinQ9P2R7 (Uniprot-TrEMBL)
SUCLG1ProteinP53597 (Uniprot-TrEMBL)
SUCLG2ProteinQ96I99 (Uniprot-TrEMBL)
Succinyl coenzyme AMetaboliteCHEBI:15380 (ChEBI)
alpha-ketoglutarateMetaboliteCHEBI:16810 (ChEBI)
citrateMetaboliteCHEBI:133748 (ChEBI)
lactateMetaboliteCHEBI:24996 (ChEBI)
methylcitrateMetaboliteQ27104155 (Wikidata) a.k.a. 2-methylcitric acid
mtDNA synthesisPathwayWP111 (WikiPathways)
propionylMetaboliteCHEBI:26294 (ChEBI)
pyruvateMetaboliteCHEBI:15361 (ChEBI)
succinateMetaboliteCHEBI:30031 (ChEBI)

Annotated Interactions

No annotated interactions

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