Mevalonate arm of cholesterol biosynthesis pathway (WP4190)
Homo sapiens
This pathway describes the mevalonate arm of the cholesterol biosynthesis pathway within different cellular regions. This pathway is also known as the isoprenoid pathway or HMG-CoA reductase pathway, and is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. This pathway produces two five-carbon building blocks (isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP)), which are the precursors for various isoprenoids, a compound class containing cholesterol, vitamin K, coenzyme Q10, and all steroid hormones. View more details on which drugs are related to these reactions at WP4189. View the broader scope of cholesterol metabolism at WP430.
For a description of pathway objects, see the WikiPathways Legend.
Authors
Denise Slenter , Egon Willighagen , Friederike Ehrhart , Lauren J. Dupuis , and Martina Summer-KutmonActivity
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Organisms
Homo sapiensCommunities
ONTOXAnnotations
Cell Type Ontology
cell obsolete metabolising cellPathway Ontology
cholesterol biosynthetic pathway cholesterol biosynthetic pathway mitochondria transport pathway altered cholesterol biosynthetic pathway isoprenoid biosynthetic pathway| Label | Type | Compact URI | Comment |
|---|---|---|---|
| dimethylallyl-PP | Metabolite | chebi:57623 | AKA Dimethylallyl diphosphate |
| NAD(P)H | Metabolite | chebi:16474 | |
| acetoacetate | Metabolite | chebi:13705 | |
| HS-CoA | Metabolite | chebi:57287 | Added due to information present in Rhea |
| Acetyl-CoA | Metabolite | chebi:57288 | |
| NADH | Metabolite | chebi:57945 | |
| 3-hydroxy-3-methylglutaryl-CoA | Metabolite | chebi:43074 | Annotated with (3S) ID |
| acetoacetyl-CoA | Metabolite | wikidata:Q2639429 | TESTCASE: Annotated with ID missing charge; according to Rhea should be CHEBI:57286 |
| mevaldyl-CoA | Metabolite | inchikey:RGCJQGNQJYHPPZ-FMMSQWOCSA-I | Annotated through ChemSpider API [https://www.chemspider.com/InChI.asmx], starting from SMILES: C[C@](O)(CC([O-])=O)CC(O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP([O-])(=O)OP([O-])(=O)OC[C@H]1O[C@H]([C@H](O)[C@@H]1OP([O-])([O-])=O)n1cnc2c(N)ncnc12 ; converted to InCHI and then to InCHIKey 'hemithioacetal, most likely the prominent reaction intermediate' [PMID:23898905] |
| mevalonate | Metabolite | chebi:36464 | Annotated with (R)-mevalonate ID |
| mevalonate-P | Metabolite | chebi:58146 | AKA (R)-5-phosphomevalonate |
| mevalonate-PP | Metabolite | chebi:57557 | AKA (R)-5-diphosphomevalonate |
| isopenthyl-PP | Metabolite | chebi:128769 | |
| geranyl-PP | Metabolite | chebi:58057 | |
| famesyl-PP | Metabolite | chebi:175763 | |
| geranylgeranyl-PP | Metabolite | chebi:58756 | |
| presqualene-PP | Metabolite | chebi:57310 | |
| squalene | Metabolite | wikidata:Q407560 | TESTCASE: correct mapping from Wikidata to ChEBI-ID (based on Rhea) |
| 3-hydroxy-3-methylglutaryl-CoA | Metabolite | chebi:43074 | Annotated with (3S) IDaka HMG-CoA |
| acetoacetyl-CoA | Metabolite | chebi:57286 | |
| 3-hydroxy-3-methylglutaryl-CoA | Metabolite | chebi:43074 | |
| mevaldyl | Metabolite | wikidata:Q113961354 | Annotated through ChemSpider API [https://www.chemspider.com/InChI.asmx], starting from SMILES: C[C@@](O)(CC=O)CC([O-])=O ; converted to InCHI and then to InCHIKey'aldehyde intermediate, which has never been detected experimentally' [PMID:23898905] |
| NAD(P)+ | Metabolite | chebi:18009 | |
| HS-CoA | Metabolite | chebi:57287 | |
| H⁺ | Metabolite | chebi:15378 | |
| NAD(P)H | Metabolite | chebi:57783 | |
| NAD(P)+ | Metabolite | chebi:58349 | |
| NAD+ | Metabolite | chebi:57540 | |
| FDFT1 | Protein | uniprot:P37268 | |
| ACAT1 | Protein | uniprot:P24752 | |
| HMGCL | Protein | uniprot:P35914 | |
| HMGCS1 | Protein | uniprot:Q01581 | |
| IDI1 | Protein | uniprot:Q13907 | TESTCASE: Protein 1 of two individual proteins carrying out the same conversion; same Rhea, diff. kinetic values. |
| MVK | Protein | uniprot:Q03426 | |
| FDPS | Protein | uniprot:P14324 | |
| PMVK | Protein | uniprot:Q15126 | |
| MVD | Protein | uniprot:P53602 | EC 4.1.1.33 |
| GGPS1 | Protein | uniprot:O95749 | |
| IDI2 | Protein | uniprot:Q9BXS1 | TESTCASE: Protein 2 of two individual proteins carrying out the same conversion; same Rhea, diff. kinetic values. |
| ACAT2 | Protein | uniprot:Q9BWD1 | |
| HMGCR | Protein | uniprot:P04035 | Note: 1.1.1.88 is EC class relevant for bacteria, with corresponding Rhea:14833. This Protein has been annotated with the mammalian EC class 1.1.1.34, corresponding Rhea:15989. |
References
- A comprehensive machine-readable view of the mammalian cholesterol biosynthesis pathway. Mazein A, Watterson S, Hsieh WY, Griffiths WJ, Ghazal P. Biochem Pharmacol. 2013 Jul 1;86(1):56–66. PubMed Europe PMC Scholia
- The increasingly complex mechanism of HMG-CoA reductase. Haines BE, Wiest O, Stauffacher CV. Acc Chem Res. 2013 Nov 19;46(11):2416–26. PubMed Europe PMC Scholia
- Is systems pharmacology ready to impact upon therapy development? A study on the cholesterol biosynthesis pathway. Benson HE, Watterson S, Sharman JL, Mpamhanga CP, Parton A, Southan C, et al. Br J Pharmacol. 2017 Dec;174(23):4362–82. PubMed Europe PMC Scholia