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

Homo sapiens

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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/instance/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, and 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 and was extended with disease information.

Authors

Denise Slenter , Eric Weitz , Egon Willighagen , Conroy lipids , Ash Iyer , and Alex Pico

Activity

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Organisms

Homo sapiens

Communities

Inherited Metabolic Disorders (IMD) Pathways Lipids and LIPID MAPS

Annotations

Disease Ontology

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

Pathway Ontology

Smith-Lemli-Opitz Syndrome pathway classic metabolic pathway cholesterol metabolic pathway

Participants
Query Drugst.One

Label Type Compact URI Comment
7-Dehydrocholesterol Metabolite lipidmaps:LMST01010069 aka 7-DHC
abundant in SLOS.
3b,5a,6b-Trihydroxycholan-24-oyl-glycine Metabolite lipidmaps:LMST05030019
3b,7b-Dihydroxychol-5-en-24-oic acid Metabolite lipidmaps:LMST04010218
Cholesterol Metabolite lipidmaps:LMST01010001
7b-Hydroxycholesterol Metabolite lipidmaps:LMST01010047
(25R)26-Hydroxy-7-oxocholesterol Metabolite lipidmaps:LMST04030180
Dendrogenin A Metabolite lipidmaps:LMST05050025
Cholestane-3b,5a,6b,(25R)26-tetrol Metabolite lipidmaps:LMST01010458
3b,5a,6b-Trihydroxycholestan-(25R)26-oic acid Metabolite lipidmaps:LMST04030238
3b-Hydroxy-7-oxochol-5-en-24-oyl-CoA Metabolite lipidmaps:LMST01010461
Cholestane-3b,5a,6b-triol Metabolite lipidmaps:LMST01010052
7-Oxocholesterol Metabolite lipidmaps:LMST01010049 aka 7-OC
Elevated levels found in Wolman's disease
3b,7b-Dihydroxychol-5-en-24-oyl-glycine Metabolite lipidmaps:LMST05030017
7b-Peroxycholesterol Metabolite lipidmaps:LMST01010459
3b-Hydroxy-7-oxocholest-5-en-(25R)26-oic acid Metabolite lipidmaps:LMST04030239
3b-Hydroxy-7-oxochol-5-en-24-oic acid Metabolite lipidmaps:LMST04010394
3b,5a,6b-Trihydroxycholan-24-oic acid Metabolite lipidmaps:LMST04010339
3b-Hydroxy-7-oxochol-5-en-24-oyl-glycine Metabolite lipidmaps:LMST05030018
3b,5a-DiH-cholestan-6-one Metabolite lipidmaps:LMST01010126 aka 3b,5a-Dihydroxycholestan-6-one
3b,7b-Dihydroxycholest-5-en-(25R)26-oic acid Metabolite lipidmaps:LMST04030235
3b,5a,6b-Trihydroxycholan-24-oyl-CoA Metabolite lipidmaps:LMST04010459
3b,7b-Dihydroxychol-5-en-24-oyl-CoA Metabolite lipidmaps:LMST04010460
3b,24R-Dihydroxy-7-oxocholest-5-en-(25R)26-oyl-CoA Metabolite lipidmaps:LMST04030262
3b,5a,6b,24R-Tetrahydroxycholestan-(25R)26-oyl-CoA Metabolite lipidmaps:LMST04030244
5a,6a-Epoxycholesterol Metabolite lipidmaps:LMST01010011
7b,(25R)26-Dihydroxycholesterol Metabolite lipidmaps:LMST04030178
3b,7b,24R-Trihydroxycholest-5-en-(25R)26-oyl-CoA Metabolite lipidmaps:LMST04030261
Cholesterol Metabolite lipidmaps:LMST01010001
Cholesterol Metabolite lipidmaps:LMST01010001
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 Bile Acid CoA ligase (or synthetase)
microsomal protein mostly expressed in liver [PMID:24309898, 25409824(mouse)]
VLCS (SLC27A2) GeneProduct hgnc.symbol:SLC27A2 very-long chain acyl-CoA synthetase
expressed mostly in liver and kidney, and present in ER and peroxisome [PMID:24309898, 25409824(mouse)]
AMACR GeneProduct hgnc.symbol:AMACR alpha-methylacyl-CoA racemase
broadly expressed [PMID:24309898, 25409824(mouse)]
ACOX2 GeneProduct hgnc.symbol:ACOX2
DBP GeneProduct hgnc.symbol:DBP D-biofinctional protein; aka MFE2, HSD17B4
SCPx (SCP2) GeneProduct hgnc.symbol:SCP2
DBP GeneProduct hgnc.symbol:DBP D-biofinctional protein; aka MFE2, HSD17B4
BAAT GeneProduct ncbigene:570 amino acid N-acyl transferase
CYP27A1 GeneProduct hgnc.symbol:CYP27A1
BACS (SLC27A5) GeneProduct hgnc.symbol:SLC27A5 Bile Acid CoA ligase (or synthetase)
microsomal protein mostly expressed in liver [PMID:24309898, 25409824(mouse)]
VLCS (SLC27A2) GeneProduct hgnc.symbol:SLC27A2 very-long chain acyl-CoA synthetase
expressed mostly in liver and kidney, and present in ER and peroxisome [PMID:24309898, 25409824(mouse)]
AMACR GeneProduct hgnc.symbol:AMACR alpha-methylacyl-CoA racemase
broadly expressed [PMID:24309898, 25409824(mouse)]
ACOX2 GeneProduct hgnc.symbol:ACOX2
DBP GeneProduct hgnc.symbol:DBP D-biofinctional protein; aka MFE2, HSD17B4
SCPx (SCP2) GeneProduct hgnc.symbol:SCP2
DBP GeneProduct hgnc.symbol:DBP D-biofinctional protein; aka MFE2, HSD17B4
BAAT GeneProduct hgnc.symbol:BAAT amino acid N-acyl transferase
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 acyl-CoA thioesterase are a group of enzymes
ACOT2 Protein uniprot:P49753 'originally thought to be in peroxisome [PMID:10944470)], later found to be mitochondrial [PMID:16940157]' [https://www.uniprot.org/uniprot/P49753]
ACOT4 Protein uniprot:Q8N9L9 'Compared to mouse peroxisomal succinyl-coenzyme A thioesterase/ACOT4, the human enzyme has a broad substrate specificity overlapping the activity of three mouse acyl-coenzyme A thioesterases, providing an explanation for the unexpectedly low number of acyl-coenzyme A thioesterase genes in the human genome [PMID:16940157]' [https://www.uniprot.org/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 'Could be the product of a pseudogene. The peptide used to produce antibodies against ACOT7L matches at 85% with ACOT7 and the antibodies may not be specific to ACOT7L.' [https://www.uniprot.org/uniprot/Q6ZUV0]
ACOT15 Protein uniprot:Q8N1Q8
ChEH Protein uniprot:P34913 AKA cholesterol epoxide hydrolase (ChEH); EC: 3.3.2.11
'ChEH is a dimer of 7-dehydrocholesterol reductase (DHCR7) and 3β-hydroxysteroid-Δ8-Δ7-isomerase (D8D7I)'
ACOT1 Protein uniprot:Q86TX2
ACOT Protein eccode:3.1.2.2 acyl-CoA thioesterase are a group of enzymes
ACOT2 Protein uniprot:P49753 'originally thought to be in peroxisome [PMID:10944470)], later found to be mitochondrial [PMID:16940157]' [https://www.uniprot.org/uniprot/P49753]
ACOT4 Protein uniprot:Q8N9L9 'Compared to mouse peroxisomal succinyl-coenzyme A thioesterase/ACOT4, the human enzyme has a broad substrate specificity overlapping the activity of three mouse acyl-coenzyme A thioesterases, providing an explanation for the unexpectedly low number of acyl-coenzyme A thioesterase genes in the human genome [PMID:16940157]' [https://www.uniprot.org/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 'Could be the product of a pseudogene. The peptide used to produce antibodies against ACOT7L matches at 85% with ACOT7 and the antibodies may not be specific to ACOT7L.' [https://www.uniprot.org/uniprot/Q6ZUV0]
ACOT15 Protein uniprot:Q8N1Q8
DHCR7 Protein uniprot:Q9UBM7 'ChEH is a dimer of 7-dehydrocholesterol reductase (DHCR7) and 3β-hydroxysteroid-Δ8-Δ7-isomerase (D8D7I)'
the 3beta-hydroxysteroid delta7 reductase (DHCR7), which is the regulatory subunit. [https://en.wikipedia.org/wiki/Cholesterol-5,6-oxide_hydrolase]
D8D7I Protein uniprot:Q15125 'ChEH is a dimer of 7-dehydrocholesterol reductase (DHCR7) and 3β-hydroxysteroid-Δ8-Δ7-isomerase (D8D7I)'
also known as the emopamyl binding protein (EBP), which is the catalytic subunit [https://en.wikipedia.org/wiki/Cholesterol-5,6-oxide_hydrolase]

References

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