Details of Drug Off-Target (DOT)

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

• DOT Name: Homogentisate 1,2-dioxygenase (HGD)
• Synonyms: EC 1.13.11.5; Homogentisate oxygenase; Homogentisic acid oxidase; Homogentisicase
• Gene Name: HGD
• Related Disease:
  Alkaptonuria
  Adenocarcinoma
  Adenoma
  Advanced cancer
  Barrett esophagus
  Bone disease
  Cataract
  Colorectal adenoma
  Esophageal adenocarcinoma
  Familial multiple trichoepithelioma
  Inflammatory bowel disease
  Intrahepatic cholangiocarcinoma
  Irritable bowel syndrome
  Matthew-Wood syndrome
  Neoplasm
  Squamous cell carcinoma
  Inborn error of metabolism
  Arthritis
  Colorectal carcinoma
  Congenital contractural arachnodactyly
• UniProt ID: HGD_HUMAN
• PDB ID: 1EY2; 1EYB
• EC Number: 1.13.11.5
• Pfam ID: PF04209 ; PF20510
• Sequence:
  MAELKYISGFGNECSSEDPRCPGSLPEGQNNPQVCPYNLYAEQLSGSAFTCPRSTNKRSW
  LYRILPSVSHKPFESIDEGQVTHNWDEVDPDPNQLRWKPFEIPKASQKKVDFVSGLHTLC
  GAGDIKSNNGLAIHIFLCNTSMENRCFYNSDGDFLIVPQKGNLLIYTEFGKMLVQPNEIC
  VIQRGMRFSIDVFEETRGYILEVYGVHFELPDLGPIGANGLANPRDFLIPIAWYEDRQVP
  GGYTVINKYQGKLFAAKQDVSPFNVVAWHGNYTPYKYNLKNFMVINSVAFDHADPSIFTV
  LTAKSVRPGVAIADFVIFPPRWGVADKTFRPPYYHRNCMSEFMGLIRGHYEAKQGGFLPG
  GGSLHSTMTPHGPDADCFEKASKVKLAPERIADGTMAFMFESSLSLAVTKWGLKASRCLD
  ENYHKCWEPLKSHFTPNSRNPAEPN
• Function: Catalyzes the conversion of homogentisate to maleylacetoacetate.
• Tissue Specificity: Highest expression in the prostate, small intestine, colon, kidney and liver.
• KEGG Pathway:
  Tyrosine metabolism (hsa00350)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Tyrosine catabolism (R-HSA-8963684)
• BioCyc Pathway: MetaCyc:HS03728-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alkaptonuria	DISXDZWS	Definitive	Autosomal recessive	[1]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[2]
Adenoma	DIS78ZEV	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Barrett esophagus	DIS416Y7	Strong	Biomarker	[4]
Bone disease	DISE1F82	Strong	Genetic Variation	[5]
Cataract	DISUD7SL	Strong	Genetic Variation	[6]
Colorectal adenoma	DISTSVHM	Strong	Biomarker	[7]
Esophageal adenocarcinoma	DISODWFP	Strong	Biomarker	[8]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Biomarker	[9]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[10]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Biomarker	[11]
Irritable bowel syndrome	DIS27206	Strong	Biomarker	[10]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[14]
Inborn error of metabolism	DISO5FAY	moderate	Genetic Variation	[15]
Arthritis	DIST1YEL	Limited	Biomarker	[16]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[17]
Congenital contractural arachnodactyly	DISOM1K7	Limited	Altered Expression	[18]

11 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 Homogentisate 1,2-dioxygenase (HGD).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Homogentisate 1,2-dioxygenase (HGD).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Homogentisate 1,2-dioxygenase (HGD).	[21]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Homogentisate 1,2-dioxygenase (HGD).	[23]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Homogentisate 1,2-dioxygenase (HGD).	[24]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Homogentisate 1,2-dioxygenase (HGD).	[25]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Homogentisate 1,2-dioxygenase (HGD).	[26]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Homogentisate 1,2-dioxygenase (HGD).	[27]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Homogentisate 1,2-dioxygenase (HGD).	[28]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Homogentisate 1,2-dioxygenase (HGD).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Homogentisate 1,2-dioxygenase (HGD).	[30]

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 Homogentisate 1,2-dioxygenase (HGD).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Homogentisate 1,2-dioxygenase (HGD).	[29]

References

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• [2] Systematic Selective Sampling of Cholecystectomy Specimens Is Adequate to Detect Incidental Gallbladder Adenocarcinoma.Am J Surg Pathol. 2019 Dec;43(12):1668-1673. doi: 10.1097/PAS.0000000000001351.
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• [5] Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on 'black bone disease' in Italy.Eur J Hum Genet. 2016 Jan;24(1):66-72. doi: 10.1038/ejhg.2015.60. Epub 2015 Mar 25.
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• [10] Long-term Risk of Advanced Neoplasia After Colonic Low-grade Dysplasia in Patients With Inflammatory Bowel Disease: A Nationwide Cohort Study.J Crohns Colitis. 2019 Dec 10;13(12):1485-1491. doi: 10.1093/ecco-jcc/jjz114.
• [11] A multi-organ cancer study of the classification performance using 2D and 3D image features in radiomics analysis.Phys Med Biol. 2019 Nov 4;64(21):215009. doi: 10.1088/1361-6560/ab489f.
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• [13] Malignant and Nonmalignant Complications of the Rectal Stump in Patients with Inflammatory Bowel Disease.Inflamm Bowel Dis. 2019 Jan 10;25(2):377-384. doi: 10.1093/ibd/izy253.
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• [15] Toward a generalized computational workflow for exploiting transient pockets as new targets for small molecule stabilizers: Application to the homogentisate 1,2-dioxygenase mutants at the base of rare disease Alkaptonuria.Comput Biol Chem. 2017 Oct;70:133-141. doi: 10.1016/j.compbiolchem.2017.08.008. Epub 2017 Aug 25.
• [16] Mutation and polymorphism analysis of the human homogentisate 1, 2-dioxygenase gene in alkaptonuria patients.Am J Hum Genet. 1998 Apr;62(4):776-84. doi: 10.1086/301805.
• [17] Utility of DNA Flow Cytometric Analysis of Paraffin-embedded Tissue in the Risk Stratification and Management of 'Indefinite for dysplasia' in Patients With Inflammatory Bowel Disease.J Crohns Colitis. 2019 Mar 30;13(4):472-481. doi: 10.1093/ecco-jcc/jjy193.
• [18] Altered Expression of Oxidative Metabolism Related Genes in Cholangiocarcinomas.Asian Pac J Cancer Prev. 2015;16(14):5875-81. doi: 10.7314/apjcp.2015.16.14.5875.
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• [20] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [23] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
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• [25] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
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• [27] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [28] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
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