Krebs cycle disorders (WP4236)

Homo sapiens

This pathway shows an simplified version of the Krebs cycle (for more details see [https://www.wikipathways.org/index.php/Pathway:WP78] ), 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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Authors

Richard Delava , Egon Willighagen , Denise Slenter , Irene Hemel , Josien Landman , Eric Weitz , Finterly Hu , and Friederike Ehrhart

Cited In

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Organism

Homo sapiens

Communities

Diseases Inherited Metabolic Disorders (IMD) Pathways Rare Diseases

Annotations

Disease Ontology: mitochondrial encephalomyopathy methylmalonic acidemia

Pathway Ontology: citric acid cycle pathway fumaric aciduria pathway

Participants

Label Type Compact Identifier Comment
Alanine Metabolite chebi:16977
alpha-ketoglutarate Metabolite chebi:16810
Fumarate Metabolite chebi:18012
Oxaloacetate Metabolite wikidata:Q408658 Not in original drawing, adapted from https://www.wikipathways.org/index.php/Pathway:WP78
Methylmalonyl-CoA Metabolite hmdb:HMDB0001269
(S)-malate Metabolite wikidata:Q27104150 Not in original drawing, adapted from https://www.wikipathways.org/index.php/Pathway:WP78
pyruvate Metabolite chebi:15361
lactate Metabolite chebi:24996
Succinyl coenzyme A Metabolite chebi:15380
Acetyl-CoA Metabolite wikidata:Q715317
ADP Metabolite chebi:16761
propionyl Metabolite chebi:26294
ATP Metabolite chebi:15422
METHYLMALONIC ACID Metabolite chebi:30860
GTP Metabolite chebi:15996
citrate Metabolite chebi:133748
succinate Metabolite chebi:30031
methylcitrate Metabolite wikidata:Q27104155 a.k.a. 2-methylcitric acid
METHYLMALONYL CARNITINE ESTER (C4DC) Metabolite hmdb:HMDB0062785
SUCCINYL CARNITINEESTER (C4DC) Metabolite wikidata:Q27140249
3-HYDROXYPROPIONATE Metabolite wikidata:Q27101949
PROPIONYLCARNITINE (C3) Metabolite wikidata:Q27103933 a.k.a. 2-methylcitric acid
GDP Metabolite chebi:17552
pyruvate Metabolite chebi:15361
Alanine Metabolite chebi:16977
FH GeneProduct ncbigene:2271 Fumarate hydratase
NDPK Protein eccode:2.7.4.6 Nucleoside diphosphate kinase
LDH Protein eccode:1.1.1.27 AKA LDH lactate dehydrogenase
SUCLA2 Protein uniprot:Q9P2R7
PDH Protein eccode:1.2.4.1 AKA pyruvate dehydrogenase
MPC Protein uniprot:Q9Y5U8 AKA Mitochondrial pyruvate transport
ALT Protein uniprot:P24298 AKA alanine aminotransferase
ADP-forming (A-SCS) Protein eccode:6.2.1.5 SCS (succinyl-CoA syntethase)
For more info see: https://en.wikipedia.org/wiki/Succinyl_coenzyme_A_synthetase
LDHB Protein uniprot:P07195
PEPCK Protein ncbigene:5106 AKA phosphoenolpyruvate carboxykinase
LDHC Protein uniprot:P07864 AKA lactate dehydrogenase C; expressed in testes.
E1-subunit Protein uniprot:Q96HY7
GDP-forming(G-SCS) Protein eccode:6.2.1.4 SCS (succinyl-CoA syntethase)
For more info see: https://en.wikipedia.org/wiki/Succinyl_coenzyme_A_synthetase
2-KGD complex Protein uniprot:Q1B4V6 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]
E2-subunit Protein uniprot:P36957
E3-subunit Protein uniprot:O00330
SUCLG1 Protein uniprot:P53597 Succinate-CoA ligase alpha-subunit
SUCLG2 Protein uniprot:Q96I99
SUCLG1 Protein uniprot:P53597
GDP-forming(G-SCS) Protein eccode:6.2.1.4 SCS (succinyl-CoA syntethase)
For more info see: https://en.wikipedia.org/wiki/Succinyl_coenzyme_A_synthetase
SUCLG1 Protein uniprot:P53597 Succinate-CoA ligase alpha-subunit
SUCLG2 Protein uniprot:Q96I99
SUCLA2 Protein uniprot:Q9P2R7
ADP-forming (A-SCS) Protein eccode:6.2.1.5 SCS (succinyl-CoA syntethase)
For more info see: https://en.wikipedia.org/wiki/Succinyl_coenzyme_A_synthetase
SUCLG1 Protein uniprot:P53597
GDP-forming(G-SCS) Protein eccode:6.2.1.4 SCS (succinyl-CoA syntethase)
For more info see: https://en.wikipedia.org/wiki/Succinyl_coenzyme_A_synthetase
SUCLG1 Protein uniprot:P53597 Succinate-CoA ligase alpha-subunit
SUCLG2 Protein uniprot:Q96I99
NDPK Protein eccode:2.7.4.6 Nucleoside diphosphate kinase
SUCLA2 Protein uniprot:Q9P2R7
ADP-forming (A-SCS) Protein eccode:6.2.1.5 SCS (succinyl-CoA syntethase)
For more info see: https://en.wikipedia.org/wiki/Succinyl_coenzyme_A_synthetase
SUCLG1 Protein uniprot:P53597
NDPK Protein eccode:2.7.4.6 Nucleoside diphosphate kinase
LDH1 Protein eccode:1.1.1.27 AKA LDH-1 lactate dehydrogenase 1, 4H; expressed in heart, red blood cells (RBC), brain)
LDH2 Protein eccode:1.1.1.27 AKA LDH-2 lactate dehydrogenase 2 (3H1M); expressed in reticuloendohelial system
LDH3 Protein eccode:1.1.1.27 AKA LDH-3 lactate dehydrogenase 3 (2H2M); expressed in lungs
LDH4 Protein eccode:1.1.1.27 AKA LDH-4 lactate dehydrogenase 4 (1H3M); expressed in kidneys, placenta, pancreas.
LDH5 Protein eccode:1.1.1.27 AKA LDH-5 lactate dehydrogenase 5 (4M); expressed in liver, striated muscle, brain.
LDHB Protein uniprot:P07195
LDHB Protein uniprot:P07195
LDHB Protein uniprot:P07195
LDHB Protein uniprot:P07195
LDHB Protein uniprot:P07195
LDHB Protein uniprot:P07195
LDHA Protein uniprot:P00338
LDHB Protein uniprot:P07195
LDHB Protein uniprot:P07195
LDHA Protein uniprot:P00338
LDHA Protein uniprot:P00338
LDHB Protein uniprot:P07195
LDHA Protein uniprot:P00338
LDHA Protein uniprot:P00338
LDHA Protein uniprot:P00338
LDHA Protein uniprot:P00338
LDHA Protein uniprot:P00338
LDHA Protein uniprot:P00338
LDHA Protein uniprot:P00338
ALT Protein uniprot:P24298 AKA alanine aminotransferase
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References

  1. Blau N, Duran M, Gibson KM, Dionisi-Vici C. Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases [Internet]. Springer; 2014. 867 p. Available from: https://books.google.com/books/about/Physician_s_Guide_to_the_Diagnosis_Treat.html?hl=&id=wJRBnwEACAAJ OpenLibrary Worldcat
  2. Apparent ATP-linked succinate thiokinase activity and its relation to nucleoside diphosphate kinase in mitochondrial matrix preparations from rabbit. Kadrmas EF, Ray PD, Lambeth DO. Biochim Biophys Acta. 1991 Aug 6;1074(3):339–46. PubMed Europe PMC Scholia
  3. Characterization of nucleoside-diphosphate kinase from Pseudomonas aeruginosa: complex formation with succinyl-CoA synthetase. Kavanaugh-Black A, Connolly DM, Chugani SA, Chakrabarty AM. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):5883–7. PubMed Europe PMC Scholia
  4. 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. Kowluru A, Tannous M, Chen HQ. Arch Biochem Biophys. 2002 Feb 15;398(2):160–9. PubMed Europe PMC Scholia
  5. Regulation of pyruvate metabolism and human disease. Gray LR, Tompkins SC, Taylor EB. Cell Mol Life Sci. 2014 Jul;71(14):2577–604. PubMed Europe PMC Scholia
  6. Mitochondrial pyruvate transport: a historical perspective and future research directions. McCommis KS, Finck BN. Biochem J. 2015 Mar 15;466(3):443–54. PubMed Europe PMC Scholia