Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT649C01)

• DOT Name: Sterol 26-hydroxylase, mitochondrial (CYP27A1)
• Synonyms: EC 1.14.15.15; 5-beta-cholestane-3-alpha,7-alpha,12-alpha-triol 26-hydroxylase; Cytochrome P-450C27/25; Cytochrome P450 27; Sterol 27-hydroxylase; Vitamin D(3) 25-hydroxylase
• Gene Name: CYP27A1
• Related Disease: Cerebrotendinous xanthomatosis
• UniProt ID: CP27A_HUMAN
• EC Number: 1.14.15.15
• Pfam ID: PF00067
• Sequence:
  MAALGCARLRWALRGAGRGLCPHGARAKAAIPAALPSDKATGAPGAGPGVRRRQRSLEEI
  PRLGQLRFFFQLFVQGYALQLHQLQVLYKAKYGPMWMSYLGPQMHVNLASAPLLEQVMRQ
  EGKYPVRNDMELWKEHRDQHDLTYGPFTTEGHHWYQLRQALNQRLLKPAEAALYTDAFNE
  VIDDFMTRLDQLRAESASGNQVSDMAQLFYYFALEAICYILFEKRIGCLQRSIPEDTVTF
  VRSIGLMFQNSLYATFLPKWTRPVLPFWKRYLDGWNAIFSFGKKLIDEKLEDMEAQLQAA
  GPDGIQVSGYLHFLLASGQLSPREAMGSLPELLMAGVDTTSNTLTWALYHLSKDPEIQEA
  LHEEVVGVVPAGQVPQHKDFAHMPLLKAVLKETLRLYPVVPTNSRIIEKEIEVDGFLFPK
  NTQFVFCHYVVSRDPTAFSEPESFQPHRWLRNSQPATPRIQHPFGSVPFGYGVRACLGRR
  IAELEMQLLLARLIQKYKVVLAPETGELKSVARIVLVPNKKVGLQFLQRQC
• Function: Cytochrome P450 monooxygenase that catalyzes regio- and stereospecific hydroxylation of cholesterol and its derivatives. Hydroxylates (with R stereochemistry) the terminal methyl group of cholesterol side-chain in a three step reaction to yield at first a C26 alcohol, then a C26 aldehyde and finally a C26 acid. Regulates cholesterol homeostasis by catalyzing the conversion of excess cholesterol to bile acids via both the 'neutral' (classic) and the 'acid' (alternative) pathways. May also regulate cholesterol homeostasis via generation of active oxysterols, which act as ligands for NR1H2 and NR1H3 nuclear receptors, modulating the transcription of genes involved in lipid metabolism. Plays a role in cholestanol metabolism in the cerebellum. Similarly to cholesterol, hydroxylates cholestanol and may facilitate sterol diffusion through the blood-brain barrier to the systemic circulation for further degradation. Also hydroxylates retinal 7-ketocholesterol, a noxious oxysterol with pro-inflammatory and pro-apoptotic effects, and may play a role in its elimination from the retinal pigment epithelium. May play a redundant role in vitamin D biosynthesis. Catalyzes 25-hydroxylation of vitamin D3 that is required for its conversion to a functionally active form.
• Tissue Specificity: Expressed in the neural retina and underlying retinal pigment epithelium (at protein level) . Expressed in the gray and white matter of cerebellum (at protein level) .
• KEGG Pathway:
  Primary bile acid biosynthesis (hsa00120)
  Metabolic pathways (hsa01100)
  PPAR sig.ling pathway (hsa03320)
  Cholesterol metabolism (hsa04979)
• Reactome Pathway:
  Synthesis of bile acids and bile salts via 24-hydroxycholesterol (R-HSA-193775)
  Synthesis of bile acids and bile salts via 27-hydroxycholesterol (R-HSA-193807)
  Endogenous sterols (R-HSA-211976)
  Defective CYP27A1 causes CTX (R-HSA-5578996)
  Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol (R-HSA-193368)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cerebrotendinous xanthomatosis	DIST9FNK	Definitive	Autosomal recessive	[1]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
ANW-32821	DMMJOZD	Phase 2	Sterol 26-hydroxylase, mitochondrial (CYP27A1) decreases the chemical synthesis of ANW-32821.	[28]

This DOT Affected the Regulation of Drug Effects of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
27-hydroxycholesterol	DM2L6OZ	Investigative	Sterol 26-hydroxylase, mitochondrial (CYP27A1) increases the abundance of 27-hydroxycholesterol.	[29]
24(S)-hydroxycholesterol	DMGMWA6	Investigative	Sterol 26-hydroxylase, mitochondrial (CYP27A1) decreases the abundance of 24(S)-hydroxycholesterol.	[29]
Desmosterol	DMV8SUM	Investigative	Sterol 26-hydroxylase, mitochondrial (CYP27A1) increases the metabolism of Desmosterol.	[30]
Lanosterol	DMHN74V	Investigative	Sterol 26-hydroxylase, mitochondrial (CYP27A1) increases the metabolism of Lanosterol.	[30]

28 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[11]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[13]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[14]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[15]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[16]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[13]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[17]
Clavulanate	DM2FGRT	Approved	Clavulanate decreases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[18]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[19]
Atorvastatin	DMF28YC	Phase 3 Trial	Atorvastatin decreases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[22]
Eugenol	DM7US1H	Patented	Eugenol decreases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[23]
NS398	DMINUWH	Terminated	NS398 decreases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[24]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug decreases the activity of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[25]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid decreases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[13]
Linalool	DMGZQ5P	Investigative	Linalool increases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[26]
2-arachidonoylglycerol	DMM0KOJ	Investigative	2-arachidonoylglycerol increases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[27]
2-chloro-5-nitro-N-phenylbenzamide	DMUGQIV	Investigative	2-chloro-5-nitro-N-phenylbenzamide decreases the expression of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[19]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Sterol 26-hydroxylase, mitochondrial (CYP27A1).	[21]

References

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