Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHS41XM)

• DOT Name: Retinoid isomerohydrolase (RPE65)
• Synonyms: EC 3.1.1.64; All-trans-retinyl-palmitate hydrolase; Lutein isomerase; Meso-zeaxanthin isomerase; EC 5.3.3.22; Retinal pigment epithelium-specific 65 kDa protein; Retinol isomerase
• Gene Name: RPE65
• Related Disease:
  Leber congenital amaurosis 2
  Leber congenital amaurosis 9
  RPE65-related recessive retinopathy
  Retinitis pigmentosa 20
  RPE65-related dominant retinopathy
  Leber congenital amaurosis
  Retinitis pigmentosa
  Severe early-childhood-onset retinal dystrophy
• UniProt ID: RPE65_HUMAN
• EC Number: 3.1.1.64; 5.3.3.22
• Pfam ID: PF03055
• Sequence:
  MSIQVEHPAGGYKKLFETVEELSSPLTAHVTGRIPLWLTGSLLRCGPGLFEVGSEPFYHL
  FDGQALLHKFDFKEGHVTYHRRFIRTDAYVRAMTEKRIVITEFGTCAFPDPCKNIFSRFF
  SYFRGVEVTDNALVNVYPVGEDYYACTETNFITKINPETLETIKQVDLCNYVSVNGATAH
  PHIENDGTVYNIGNCFGKNFSIAYNIVKIPPLQADKEDPISKSEIVVQFPCSDRFKPSYV
  HSFGLTPNYIVFVETPVKINLFKFLSSWSLWGANYMDCFESNETMGVWLHIADKKRKKYL
  NNKYRTSPFNLFHHINTYEDNGFLIVDLCCWKGFEFVYNYLYLANLRENWEEVKKNARKA
  PQPEVRRYVLPLNIDKADTGKNLVTLPNTTATAILCSDETIWLEPEVLFSGPRQAFEFPQ
  INYQKYCGKPYTYAYGLGLNHFVPDRLCKLNVKTKETWVWQEPDSYPSEPIFVSHPDALE
  EDDGVVLSVVVSPGAGQKPAYLLILNAKDLSEVARAEVEINIPVTFHGLFKKS
• Function: Critical isomerohydrolase in the retinoid cycle involved in regeneration of 11-cis-retinal, the chromophore of rod and cone opsins. Catalyzes the cleavage and isomerization of all-trans-retinyl fatty acid esters to 11-cis-retinol which is further oxidized by 11-cis retinol dehydrogenase to 11-cis-retinal for use as visual chromophore. Essential for the production of 11-cis retinal for both rod and cone photoreceptors. Also capable of catalyzing the isomerization of lutein to meso-zeaxanthin an eye-specific carotenoid. The soluble form binds vitamin A (all-trans-retinol), making it available for LRAT processing to all-trans-retinyl ester. The membrane form, palmitoylated by LRAT, binds all-trans-retinyl esters, making them available for IMH (isomerohydrolase) processing to all-cis-retinol. The soluble form is regenerated by transferring its palmitoyl groups onto 11-cis-retinol, a reaction catalyzed by LRAT.
• Tissue Specificity: Retina (at protein level). Retinal pigment epithelium specific.
• KEGG Pathway:
  Retinol metabolism (hsa00830)
  Metabolic pathways (hsa01100)
• Reactome Pathway: The canonical retinoid cycle in rods (twilight vision) (R-HSA-2453902)
• BioCyc Pathway: MetaCyc:ENSG00000116745-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leber congenital amaurosis 2	DISF39MM	Definitive	Autosomal recessive	[1]
Leber congenital amaurosis 9	DIS35YGW	Definitive	Autosomal recessive	[2]
RPE65-related recessive retinopathy	DISY89Y2	Definitive	Autosomal recessive	[3]
Retinitis pigmentosa 20	DIS8J8VI	Strong	Autosomal recessive	[4]
RPE65-related dominant retinopathy	DISW4F1S	Strong	Autosomal dominant	[3]
Leber congenital amaurosis	DISMGH8F	Supportive	Autosomal dominant	[5]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[6]
Severe early-childhood-onset retinal dystrophy	DISFDRFO	Supportive	Autosomal recessive	[7]

This DOT Affected the Biotransformations of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vitamin A	DMJ2AH4	Approved	Retinoid isomerohydrolase (RPE65) increases the chemical synthesis of Vitamin A.	[11]
All-trans-retinal	DM6CEVB	Investigative	Retinoid isomerohydrolase (RPE65) increases the chemical synthesis of All-trans-retinal.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Retinoid isomerohydrolase (RPE65).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Retinoid isomerohydrolase (RPE65).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Retinoid isomerohydrolase (RPE65).	[10]

References

• [1] Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis. Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3088-93. doi: 10.1073/pnas.95.6.3088.
• [2] Mutations in RPE65 cause Leber's congenital amaurosis. Nat Genet. 1997 Oct;17(2):139-41. doi: 10.1038/ng1097-139.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Two point mutations of RPE65 from patients with retinal dystrophies decrease the stability of RPE65 protein and abolish its isomerohydrolase activity. J Biol Chem. 2006 Aug 4;281(31):21820-21826. doi: 10.1074/jbc.M603725200. Epub 2006 Jun 5.
• [5] RPE65 Mutations in Two Japanese Families with Leber Congenital Amaurosis. Ophthalmic Genet. 2016 Jun;37(2):161-9. doi: 10.3109/13816810.2014.991931. Epub 2014 Dec 12.
• [6] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [7] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [8] Down-regulation of RPE65 protein expression and promoter activity by retinoic acid. Mol Vis. 2003 Aug 5;9:345-54.
• [9] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [10] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [11] Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle. Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13658-63. doi: 10.1073/pnas.0504167102. Epub 2005 Sep 6.
• [12] Impacts of two point mutations of RPE65 from Leber's congenital amaurosis on the stability, subcellular localization and isomerohydrolase activity of RPE65. FEBS Lett. 2006 Jul 24;580(17):4200-4. doi: 10.1016/j.febslet.2006.06.078. Epub 2006 Jul 5.