Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHO2TO0)

• DOT Name: Hydroxyproline dehydrogenase (PRODH2)
• Synonyms: HYPDH; EC 1.5.5.3; Kidney and liver proline oxidase 1; HsPOX1; Probable proline dehydrogenase 2; EC 1.5.5.2; Probable proline oxidase 2
• Gene Name: PRODH2
• Related Disease:
  Primary hyperoxaluria
  Intellectual disability
  Hydroxyprolinemia
  Schizophrenia
• UniProt ID: HYPDH_HUMAN
• EC Number: 1.5.5.2; 1.5.5.3
• Pfam ID: PF01619
• Sequence:
  MLRTCYVLCSQAGPPSRGWQSLSFDGGAFHLKGTGELTRALLVLRLCAWPPLVTHGLLLQ
  AWSRRLLGSRLSGAFLRASVYGQFVAGETAEEVKGCVQQLRTLSLRPLLAVPTEEEPDSA
  AKSGEAWYEGNLGAMLRCVDLSRGLLEPPSLAEASLMQLKVTALTSTRLCKELASWVRRP
  GASLELSPERLAEAMDSGQNLQVSCLNAEQNQHLRASLSRLHRVAQYARAQHVRLLVDAE
  YTSLNPALSLLVAALAVRWNSPGEGGPWVWNTYQACLKDTFERLGRDAEAAHRAGLAFGV
  KLVRGAYLDKERAVAQLHGMEDPTQPDYEATSQSYSRCLELMLTHVARHGPMCHLMVASH
  NEESVRQATKRMWELGIPLDGTVCFGQLLGMCDHVSLALGQAGYVVYKSIPYGSLEEVIP
  YLIRRAQENRSVLQGARREQELLSQELWRRLLPGCRRIPH
• Function: Dehydrogenase that converts trans-4-L-hydroxyproline to delta-1-pyrroline-3-hydroxy-5-carboxylate (Hyp) using ubiquinone-10 as the terminal electron acceptor. Can also use proline as a substrate but with a very much lower efficiency. Does not react with other diastereomers of Hyp: trans-4-D-hydroxyproline and cis-4-L-hydroxyproline. Ubiquininone analogs such as menadione, duroquinone and ubiquinone-1 react more efficiently than oxygen as the terminal electron acceptor during catalysis.
• KEGG Pathway:
  Arginine and proline metabolism (hsa00330)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Proline catabolism (R-HSA-70688)
  Glyoxylate metabolism and glycine degradation (R-HSA-389661)
• BioCyc Pathway: MetaCyc:MONOMER66-34410

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Primary hyperoxaluria	DIS0L16N	Strong	Biomarker	[1]
Intellectual disability	DISMBNXP	Disputed	Biomarker	[2]
Hydroxyprolinemia	DISL6XCL	Limited	Autosomal recessive	[3]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Hydroxyproline dehydrogenase (PRODH2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Hydroxyproline dehydrogenase (PRODH2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Hydroxyproline dehydrogenase (PRODH2).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Hydroxyproline dehydrogenase (PRODH2).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Hydroxyproline dehydrogenase (PRODH2).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Hydroxyproline dehydrogenase (PRODH2).	[9]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Hydroxyproline dehydrogenase (PRODH2).	[10]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Hydroxyproline dehydrogenase (PRODH2).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Hydroxyproline dehydrogenase (PRODH2).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Hydroxyproline dehydrogenase (PRODH2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Hydroxyproline dehydrogenase (PRODH2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Hydroxyproline dehydrogenase (PRODH2).	[15]

References

• [1] The effects of the inactivation of Hydroxyproline dehydrogenase on urinary oxalate and glycolate excretion in mouse models of primary hyperoxaluria.Biochim Biophys Acta Mol Basis Dis. 2020 Mar 1;1866(3):165633. doi: 10.1016/j.bbadis.2019.165633. Epub 2019 Dec 7.
• [2] Whole exome sequencing reveals inherited and de novo variants in autism spectrum disorder: a trio study from Saudi families.Sci Rep. 2017 Jul 18;7(1):5679. doi: 10.1038/s41598-017-06033-1.
• [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] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [10] Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling. Int J Cancer. 2004 Nov 1;112(2):200-12. doi: 10.1002/ijc.20401.
• [11] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [14] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [15] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.