Krebs cycle disorders (WP4236)

Homo sapiens

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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)).

Authors

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

Activity

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Organisms

Homo sapiens

Communities

Diseases Inherited Metabolic Disorders (IMD) Pathways Rare Diseases

Annotations

Disease Ontology

methylmalonic acidemia mitochondrial encephalomyopathy

Pathway Ontology

citric acid cycle pathway fumaric aciduria pathway

Participants
Query Drugst.One

Label Type Compact URI 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
Methylmalonicacid 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 carnitineester (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
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
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.
LDHA Protein uniprot:P00338

References

  1. Physician’s Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases [Internet]. Blau N, Duran M, Gibson KM, Dionisi-Vici C. Springer; 2014. 0 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