7-oxo-C and 7-beta-HC pathways (WP5064)

The Oxysterol group of compounds are oxygenated derivatives of cholesterol or its sterol precursors, e.g. 7-dehydrocholesterol (7-DHC) or desmosterol. There are three mechanisms leading to the formation of oxysterols: 1. Enzymatically (first steps of sterol metabolism, being intermediates for the formation of steroid hormones, bile acids and 1,25-dihydroxyvitamin D3); see [https://www.wikipathways.org/index.php/Pathway:WP4545 WP4545]. 2. Non-enzymatically by encountering reactive oxygen species (ROS), providing a second pool of metabolites (this pool also includes oxidized cholesterol molecules taken in from diet); described in this pathway. 3. Generation by the gut microflora and uptake through the enterohepatic circulation. Previously oxysterols where though to be inactive metabolic intermediates, however recent findings have established that these metabolites are involved in cholesterol homoeostasis, can be ligands to nuclear and G protein-coupled receptors and biomarkers of diseases (for example Niemann-Pick disease). This pathway describes Figure 4 and 5 from Griffiths et al (2020) [https://dx.doi.org/10.1016%2Fj.prostaglandins.2019.106381] and will be extended with disease information.
last edited

Authors

Denise Slenter , Eric Weitz , and Egon Willighagen

Cited In

Are you planning to include this pathway in your next publication? See How to Cite and add a link here to your paper once it's online.

Organism

Homo sapiens

Communities

Inborn Errors of Metabolism (IEM) Pathways Lipids and LIPID MAPS

Annotations

Pathway Ontology: cholesterol metabolic pathway classic metabolic pathway Smith-Lemli-Opitz Syndrome pathway

Disease Ontology: Niemann-Pick disease type A Niemann-Pick disease type B Niemann-Pick disease type C1 Smith-Lemli-Opitz syndrome Niemann-Pick disease type C2

Participants

Label Type Compact Identifier
7-Dehydrocholesterol Metabolite inchikey:UCTLRSWJYQTBFZ-DDPQNLDTSA-N
3b,5a,6b-Trihydroxycholan-24-oyl-glycine Metabolite inchikey:PVXZQUUYXFMXMF-ABSIFXOISA-N
3b,7b-Dihydroxychol-5-en-24-oic acid Metabolite inchikey:PXHCARRJGFGPAC-SZQOYVLDSA-N
Cholesterol Metabolite inchikey:HVYWMOMLDIMFJA-DPAQBDIFSA-N
7b-Hydroxycholesterol Metabolite inchikey:OYXZMSRRJOYLLO-KGZHIOMZSA-N
(25R)26-Hydroxy-7-oxocholesterol Metabolite inchikey:LFNAJBFFWWMSEW-HNFKANRHSA-N
Dendrogenin A Metabolite inchikey:AVFNYTPENXWWCA-BULFVYHESA-N
Cholestane-3b,5a,6b,(25R)26-tetrol Metabolite inchikey:PFYSRSDOSXYIFG-JKYVJSSTSA-N
3b,5a,6b-Trihydroxycholestan-(25R)26-oic acid Metabolite inchikey:LMWUOMGULHFSQR-HDEGCWFHSA-N
3b-Hydroxy-7-oxochol-5-en-24-oyl-CoA Metabolite inchikey:HEPNPBUPTRNGJT-ILFWFKRZSA-N
Cholestane-3b,5a,6b-triol Metabolite inchikey:YMMFNKXZULYSOQ-RUXQDQFYSA-N
7-Oxocholesterol Metabolite inchikey:YIKKMWSQVKJCOP-ABXCMAEBSA-N
3b,7b-Dihydroxychol-5-en-24-oyl-glycine Metabolite inchikey:BMRAURDLHOPSBE-FRMRTHFDSA-N
7b-Peroxycholesterol Metabolite inchikey:KJIGLXGIVLBXCF-UOQFGJKXSA-N
3b-Hydroxy-7-oxocholest-5-en-(25R)26-oic acid Metabolite inchikey:QOEPZHFZXUROGV-BXDHRDAUSA-N
3b-Hydroxy-7-oxochol-5-en-24-oic acid Metabolite inchikey:JHFXTNJNQOZGEJ-HICUSVRDSA-N
3b,5a,6b-Trihydroxycholan-24-oic acid Metabolite inchikey:NMKAZCXSXYNCFW-DWQVTILUSA-N
3b-Hydroxy-7-oxochol-5-en-24-oyl-glycine Metabolite inchikey:AXBXXYALPXTOOI-UBKHJBOVSA-N
3b,5a-DiH-cholestan-6-one Metabolite inchikey:SJZZRXMQSAXCFD-FRAMIZMOSA-N
3b,7b-Dihydroxycholest-5-en-(25R)26-oic acid Metabolite inchikey:GYJSAWZGYQXRBS-WMYDBBFWSA-N
3b,5a,6b-Trihydroxycholan-24-oyl-CoA Metabolite inchikey:WRWBXZATSFAUGF-UJKOPXFNSA-N
3b,7b-Dihydroxychol-5-en-24-oyl-CoA Metabolite inchikey:XRRIYAPQOCXHCP-NRNJIOKESA-N
3b,24R-Dihydroxy-7-oxocholest-5-en-(25R)26-oyl-CoA Metabolite inchikey:UOHZUNSDJHLARD-JLLVOJIKSA-N
3b,5a,6b,24R-Tetrahydroxycholestan-(25R)26-oyl-CoA Metabolite inchikey:PJJHUKDTGITXML-MFOUGJSISA-N
5,6-Epoxycholesterol Metabolite inchikey:PRYIJAGAEJZDBO-XXGHXXDPSA-N
7b,(25R)26-Dihydroxycholesterol Metabolite inchikey:RXMHNAKZMGJANZ-BMOLSTJGSA-N
3b,7b,24R-Trihydroxycholest-5-en-(25R)26-oyl-CoA Metabolite inchikey:BZALPCSTIFZGTP-YBYDULIXSA-N
Cholesterol Metabolite inchikey:HVYWMOMLDIMFJA-DPAQBDIFSA-N
Cholesterol Metabolite inchikey:HVYWMOMLDIMFJA-DPAQBDIFSA-N
CYP7A1 GeneProduct hgnc.symbol:CYP7A1
NPC1 GeneProduct hgnc.symbol:NPC1
HSD11B1 GeneProduct hgnc.symbol:HSD11B1
HSD11B2 GeneProduct hgnc.symbol:HSD11B2
CYP27A1 GeneProduct hgnc.symbol:CYP27A1
BACS (SLC27A5) GeneProduct hgnc.symbol:SLC27A5
VLCS (SLC27A2) GeneProduct hgnc.symbol:SLC27A2
AMACR GeneProduct hgnc.symbol:AMACR
ACOX2 GeneProduct hgnc.symbol:ACOX2
DBP GeneProduct hgnc.symbol:DBP
SCPx (SCP2) GeneProduct hgnc.symbol:SCP2
DBP GeneProduct hgnc.symbol:DBP
BAAT GeneProduct hgnc.symbol:BAAT
CYP27A1 GeneProduct hgnc.symbol:CYP27A1
BACS (SLC27A5) GeneProduct hgnc.symbol:SLC27A5
VLCS (SLC27A2) GeneProduct hgnc.symbol:SLC27A2
AMACR GeneProduct hgnc.symbol:AMACR
ACOX2 GeneProduct hgnc.symbol:ACOX2
DBP GeneProduct hgnc.symbol:DBP
SCPx (SCP2) GeneProduct hgnc.symbol:SCP2
DBP GeneProduct hgnc.symbol:DBP
BAAT GeneProduct hgnc.symbol:BAAT
HSD11B2 GeneProduct hgnc.symbol:HSD11B2
HSD11B1 GeneProduct hgnc.symbol:HSD11B1
HSD11B2 GeneProduct hgnc.symbol:HSD11B2
HSD11B1 GeneProduct hgnc.symbol:HSD11B1
HSD11B2 GeneProduct hgnc.symbol:HSD11B2
NPC2 GeneProduct hgnc.symbol:NPC2
ACOT1 Protein uniprot:Q86TX2
ACOT Protein eccode:3.1.2.2
ACOT2 Protein uniprot:P49753
ACOT4 Protein uniprot:Q8N9L9
ACOT6 Protein uniprot:Q3I5F7
ACOT7 Protein uniprot:O00154
ACOT8 Protein uniprot:O14734
ACOT9 Protein uniprot:Q9Y305
ACOT11 Protein uniprot:Q8WXI4
ACOT12 Protein uniprot:Q8WYK0
ACOT13 Protein uniprot:Q9NPJ3
ACOT7L Protein uniprot:Q6ZUV0
ACOT15 Protein uniprot:Q8N1Q8
ChEH Protein uniprot:P34913
ACOT1 Protein uniprot:Q86TX2
ACOT Protein eccode:3.1.2.2
ACOT2 Protein uniprot:P49753
ACOT4 Protein uniprot:Q8N9L9
ACOT6 Protein uniprot:Q3I5F7
ACOT7 Protein uniprot:O00154
ACOT8 Protein uniprot:O14734
ACOT9 Protein uniprot:Q9Y305
ACOT11 Protein uniprot:Q8WXI4
ACOT12 Protein uniprot:Q8WYK0
ACOT13 Protein uniprot:Q9NPJ3
ACOT7L Protein uniprot:Q6ZUV0
ACOT15 Protein uniprot:Q8N1Q8
DHCR7 Protein uniprot:Q9UBM7
D8D7I Protein uniprot:Q15125

References

  1. Jones JM, Gould SJ. Identification of PTE2, a human peroxisomal long-chain acyl-CoA thioesterase. Biochem Biophys Res Commun. 2000 Aug 18;275(1):233–40. PubMed Europe PMC Scholia
  2. Schweizer RAS, Zürcher M, Balazs Z, Dick B, Odermatt A. Rapid hepatic metabolism of 7-ketocholesterol by 11beta-hydroxysteroid dehydrogenase type 1: species-specific differences between the rat, human, and hamster enzyme. J Biol Chem. 2004 Apr 30;279(18):18415–24. PubMed Europe PMC Scholia
  3. Hult M, Elleby B, Shafqat N, Svensson S, Rane A, Jörnvall H, et al. Human and rodent type 1 11beta-hydroxysteroid dehydrogenases are 7beta-hydroxycholesterol dehydrogenases involved in oxysterol metabolism. Cell Mol Life Sci. 2004 Apr;61(7–8):992–9. PubMed Europe PMC Scholia
  4. Hunt MC, Rautanen A, Westin MAK, Svensson LT, Alexson SEH. Analysis of the mouse and human acyl-CoA thioesterase (ACOT) gene clusters shows that convergent, functional evolution results in a reduced number of human peroxisomal ACOTs. FASEB J. 2006 Sep;20(11):1855–64. PubMed Europe PMC Scholia
  5. de Medina P, Paillasse MR, Segala G, Poirot M, Silvente-Poirot S. Identification and pharmacological characterization of cholesterol-5,6-epoxide hydrolase as a target for tamoxifen and AEBS ligands. Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13520–5. PubMed Europe PMC Scholia
  6. Porter FD, Scherrer DE, Lanier MH, Langmade SJ, Molugu V, Gale SE, et al. Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Sci Transl Med. 2010 Nov 3;2(56):56ra81. PubMed Europe PMC Scholia
  7. Clayton PT. Disorders of bile acid synthesis. J Inherit Metab Dis. 2011 Jun;34(3):593–604. PubMed Europe PMC Scholia
  8. Shinkyo R, Xu L, Tallman KA, Cheng Q, Porter NA, Guengerich FP. Conversion of 7-dehydrocholesterol to 7-ketocholesterol is catalyzed by human cytochrome P450 7A1 and occurs by direct oxidation without an epoxide intermediate. J Biol Chem. 2011 Sep 23;286(38):33021–8. PubMed Europe PMC Scholia
  9. Shackleton CHL. Role of a disordered steroid metabolome in the elucidation of sterol and steroid biosynthesis. Lipids. 2012 Jan;47(1):1–12. PubMed Europe PMC Scholia
  10. Mitić T, Shave S, Semjonous N, McNae I, Cobice DF, Lavery GG, et al. 11β-Hydroxysteroid dehydrogenase type 1 contributes to the balance between 7-keto- and 7-hydroxy-oxysterols in vivo. Biochem Pharmacol. 2013 Jul 1;86(1):146–53. PubMed Europe PMC Scholia
  11. de Medina P, Paillasse MR, Segala G, Voisin M, Mhamdi L, Dalenc F, et al. Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties. Nat Commun. 2013;4:1840. PubMed Europe PMC Scholia
  12. Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. 2014 Feb;13(2):397–406. PubMed Europe PMC Scholia
  13. Vance JE, Karten B. Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin. J Lipid Res. 2014 Aug;55(8):1609–21. PubMed Europe PMC Scholia
  14. Klinke G, Rohrbach M, Giugliani R, Burda P, Baumgartner MR, Tran C, et al. LC-MS/MS based assay and reference intervals in children and adolescents for oxysterols elevated in Niemann-Pick diseases. Clin Biochem. 2015 Jun;48(9):596–602. PubMed Europe PMC Scholia
  15. Raleigh DR, Sever N, Choksi PK, Sigg MA, Hines KM, Thompson BM, et al. Cilia-Associated Oxysterols Activate Smoothened. Mol Cell. 2018 Oct 18;72(2):316-327.e5. PubMed Europe PMC Scholia
  16. Griffiths WJ, Wang Y. Oxysterols as lipid mediators: Their biosynthetic genes, enzymes and metabolites. Prostaglandins Other Lipid Mediat. 2020 Apr;147:106381. PubMed Europe PMC Scholia