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.
c02
aka 7-DHC
abundant in SLOS.
aka 7-OC
Elevated levels found in Wolman's disease
aka 3b,5a-Dihydroxycholestan-6-one
radical
Bile Acid CoA ligase (or synthetase)
microsomal protein mostly expressed in liver [PMID:24309898, 25409824(mouse)]
d46
very-long chain acyl-CoA synthetase
expressed mostly in liver and kidney, and present in ER and peroxisome [PMID:24309898, 25409824(mouse)]
d46
alpha-methylacyl-CoA racemase
broadly expressed [PMID:24309898, 25409824(mouse)]
d46
D-biofinctional protein; aka MFE2, HSD17B4
D-biofinctional protein; aka MFE2, HSD17B4
amino acid N-acyl transferase
acyl-CoA thioesterase are a group of enzymes
"originally thought to be in peroxisome [PMID:10944470)], later found to be mitochondrial [PMID:16940157]" [https://www.uniprot.org/uniprot/P49753]
f07
a7b
"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]
a7b
"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]
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)"
ae1
Bile Acid CoA ligase (or synthetase)
microsomal protein mostly expressed in liver [PMID:24309898, 25409824(mouse)]
d46
very-long chain acyl-CoA synthetase
expressed mostly in liver and kidney, and present in ER and peroxisome [PMID:24309898, 25409824(mouse)]
d46
alpha-methylacyl-CoA racemase
broadly expressed [PMID:24309898, 25409824(mouse)]
d46
D-biofinctional protein; aka MFE2, HSD17B4
D-biofinctional protein; aka MFE2, HSD17B4
amino acid N-acyl transferase
acyl-CoA thioesterase are a group of enzymes
"originally thought to be in peroxisome [PMID:10944470)], later found to be mitochondrial [PMID:16940157]" [https://www.uniprot.org/uniprot/P49753]
f07
a7b
"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]
a7b
"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]
radical (deoxidised)
radical
"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]
afa
"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]
afa
Mechanism of transport to ER and plasma membrane has yet to be established [PMID: 24664998]
c07
c02
c7e
c02
c02
c02
c02
c02
c02
c02
c02
c02
c02
c02
c02
c02
c02
c02
c02
c02
ec0
c02
c02
c02
c02
c02
c02
c02
c02
cb4
f2f
ffa
c02
c02
c02
c02
c02
c02
c02
c02
c02
c02
c02
c02
c02
c02
transport to membrane bound NPC1
Biomarker for
Biomarker for
Biomarker for
Biomarker for
Biomarker for
Biomarker for
21229319
PubMed
Disorders of bile acid synthesis.
J Inherit Metab Dis
2011
Clayton PT
30340023
PubMed
Cilia-Associated Oxysterols Activate Smoothened.
Mol Cell
2018
Raleigh DR
Sever N
Choksi PK
Sigg MA
Hines KM
Thompson BM
Elnatan D
Jaishankar P
Bisignano P
Garcia-Gonzalo FR
Krup AL
Eberl M
Byrne EFX
Siebold C
Wong SY
Renslo AR
Grabe M
McDonald JG
Xu L
Beachy PA
Reiter JF
Niemann-Pick disease type A
DOID:0070111
Disease
21048217
PubMed
Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease.
Sci Transl Med
2010
Porter FD
Scherrer DE
Lanier MH
Langmade SJ
Molugu V
Gale SE
Olzeski D
Sidhu R
Dietzen DJ
Fu R
Wassif CA
Yanjanin NM
Marso SP
House J
Vite C
Schaffer JE
Ory DS
24309898
PubMed
Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics.
Mol Cell Proteomics
2014
Fagerberg L
Hallström BM
Oksvold P
Kampf C
Djureinovic D
Odeberg J
Habuka M
Tahmasebpoor S
Danielsson A
Edlund K
Asplund A
Sjöstedt E
Lundberg E
Szigyarto CA
Skogs M
Takanen JO
Berling H
Tegel H
Mulder J
Nilsson P
Schwenk JM
Lindskog C
Danielsson F
Mardinoglu A
Sivertsson A
von Feilitzen K
Forsberg M
Zwahlen M
Olsson I
Navani S
Huss M
Nielsen J
Ponten F
Uhlén M
31698146
PubMed
Oxysterols as lipid mediators: Their biosynthetic genes, enzymes and metabolites.
Prostaglandins Other Lipid Mediat
2020
Griffiths WJ
Wang Y
24664998
PubMed
Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin.
J Lipid Res
2014
Vance JE
Karten B
23673625
PubMed
Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties.
Nat Commun
2013
de Medina P
Paillasse MR
Segala G
Voisin M
Mhamdi L
Dalenc F
Lacroix-Triki M
Filleron T
Pont F
Saati TA
Morisseau C
Hammock BD
Silvente-Poirot S
Poirot M
10944470
PubMed
Identification of PTE2, a human peroxisomal long-chain acyl-CoA thioesterase.
Biochem Biophys Res Commun
2000
Jones JM
Gould SJ
Smith-Lemli-Opitz Syndrome pathway
PW:0001650
Pathway Ontology
20615952
PubMed
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
de Medina P
Paillasse MR
Segala G
Poirot M
Silvente-Poirot S
23415904
PubMed
11β-Hydroxysteroid dehydrogenase type 1 contributes to the balance between 7-keto- and 7-hydroxy-oxysterols in vivo.
Biochem Pharmacol
2013
Mitić T
Shave S
Semjonous N
McNae I
Cobice DF
Lavery GG
Webster SP
Hadoke PW
Walker BR
Andrew R
21813643
PubMed
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
Shinkyo R
Xu L
Tallman KA
Cheng Q
Porter NA
Guengerich FP
21874273
PubMed
Role of a disordered steroid metabolome in the elucidation of sterol and steroid biosynthesis.
Lipids
2012
Shackleton CH
Niemann-Pick disease type B
DOID:0070112
Disease
Niemann-Pick disease type C2
DOID:0070114
Disease
16940157
PubMed
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
Hunt MC
Rautanen A
Westin MA
Svensson LT
Alexson SE
25819840
PubMed
LC-MS/MS based assay and reference intervals in children and adolescents for oxysterols elevated in Niemann-Pick diseases.
Clin Biochem
2015
Klinke G
Rohrbach M
Giugliani R
Burda P
Baumgartner MR
Tran C
Gautschi M
Mathis D
Hersberger M
Smith-Lemli-Opitz syndrome
DOID:14692
Disease
14973125
PubMed
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
Schweizer RA
Zürcher M
Balazs Z
Dick B
Odermatt A
classic metabolic pathway
PW:0000002
Pathway Ontology
Niemann-Pick disease type C1
DOID:0070113
Disease
15095019
PubMed
Human and rodent type 1 11beta-hydroxysteroid dehydrogenases are 7beta-hydroxycholesterol dehydrogenases involved in oxysterol metabolism.
Cell Mol Life Sci
2004
Hult M
Elleby B
Shafqat N
Svensson S
Rane A
Jörnvall H
Abrahmsen L
Oppermann U
cholesterol metabolic pathway
PW:0001304
Pathway Ontology