Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7SQ1C7)

• DOT Name: Proline dehydrogenase 1, mitochondrial (PRODH)
• Synonyms: EC 1.5.5.2; Proline oxidase; Proline oxidase 2; p53-induced gene 6 protein
• Gene Name: PRODH
• Related Disease: Hyperprolinemia type 1
• UniProt ID: PROD_HUMAN
• EC Number: 1.5.5.2
• Pfam ID: PF01619
• Sequence:
  MALRRALPALRPCIPRFVQLSTAPASREQPAAGPAAVPGGGSATAVRPPVPAVDFGNAQE
  AYRSRRTWELARSLLVLRLCAWPALLARHEQLLYVSRKLLGQRLFNKLMKMTFYGHFVAG
  EDQESIQPLLRHYRAFGVSAILDYGVEEDLSPEEAEHKEMESCTSAAERDGSGTNKRDKQ
  YQAHRAFGDRRNGVISARTYFYANEAKCDSHMETFLRCIEASGRVSDDGFIAIKLTALGR
  PQFLLQFSEVLAKWRCFFHQMAVEQGQAGLAAMDTKLEVAVLQESVAKLGIASRAEIEDW
  FTAETLGVSGTMDLLDWSSLIDSRTKLSKHLVVPNAQTGQLEPLLSRFTEEEELQMTRML
  QRMDVLAKKATEMGVRLMVDAEQTYFQPAISRLTLEMQRKFNVEKPLIFNTYQCYLKDAY
  DNVTLDVELARREGWCFGAKLVRGAYLAQERARAAEIGYEDPINPTYEATNAMYHRCLDY
  VLEELKHNAKAKVMVASHNEDTVRFALRRMEELGLHPADHQVYFGQLLGMCDQISFPLGQ
  AGYPVYKYVPYGPVMEVLPYLSRRALENSSLMKGTHRERQLLWLELLRRLRTGNLFHRPA
• Function: Converts proline to delta-1-pyrroline-5-carboxylate.
• Tissue Specificity: Expressed in lung, skeletal muscle and brain, to a lesser extent in heart and kidney, and weakly in liver, placenta and pancreas.
• KEGG Pathway:
  Arginine and proline metabolism (hsa00330)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Proline catabolism (R-HSA-70688)
• BioCyc Pathway: MetaCyc:HS01958-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperprolinemia type 1	DISSFNEV	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[11]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[12]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[14]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[15]
Fenofibrate	DMFKXDY	Approved	Fenofibrate decreases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[12]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[11]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[3]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[18]
UNC0379	DMD1E4J	Preclinical	UNC0379 increases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[19]
Ciglitazone	DMAPO0T	Preclinical	Ciglitazone increases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[14]
15-deoxy-Delta(12, 14)-prostaglandin J(2)	DM8VUX3	Investigative	15-deoxy-Delta(12, 14)-prostaglandin J(2) increases the expression of Proline dehydrogenase 1, mitochondrial (PRODH).	[14]

References

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• [8] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
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• [12] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [13] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [14] Apoptotic action of peroxisome proliferator-activated receptor-gamma activation in human non small-cell lung cancer is mediated via proline oxidase-induced reactive oxygen species formation. Mol Pharmacol. 2007 Sep;72(3):674-85.
• [15] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [16] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [17] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [18] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [19] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.