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)).
Authors
Richard Delava , Egon Willighagen , Denise Slenter , Irene Hemel , Josien Landman , Eric Weitz , Finterly Hu , and Friederike EhrhartActivity
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Organisms
Homo sapiensCommunities
Diseases Inherited Metabolic Disorders (IMD) Pathways Rare DiseasesAnnotations
Disease Ontology
methylmalonic acidemia mitochondrial encephalomyopathyPathway Ontology
citric acid cycle pathway fumaric aciduria pathway| 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 | |
| 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 |
References
- 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
- 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
- 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
- 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
- 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
- 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