Details of Drug Off-Target (DOT)

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

• DOT Name: 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD)
• Synonyms: EC 4.1.1.45; Picolinate carboxylase
• Gene Name: ACMSD
• Related Disease:
  Alzheimer disease
  Hepatocellular carcinoma
  Kidney failure
  Parkinson disease
  Parkinsonian disorder
  Asthma
  Epilepsy
  Nervous system disease
• UniProt ID: ACMSD_HUMAN
• PDB ID: 2WM1; 4IGM; 4IGN; 4IH3; 4OFC; 7PWY
• EC Number: 4.1.1.45
• Pfam ID: PF04909
• Sequence:
  MKIDIHSHILPKEWPDLKKRFGYGGWVQLQHHSKGEAKLLKDGKVFRVVRENCWDPEVRI
  REMDQKGVTVQALSTVPVMFSYWAKPEDTLNLCQLLNNDLASTVVSYPRRFVGLGTLPMQ
  APELAVKEMERCVKELGFPGVQIGTHVNEWDLNAQELFPVYAAAERLKCSLFVHPWDMQM
  DGRMAKYWLPWLVGMPAETTIAICSMIMGGVFEKFPKLKVCFAHGGGAFPFTVGRISHGF
  SMRPDLCAQDNPMNPKKYLGSFYTDALVHDPLSLKLLTDVIGKDKVILGTDYPFPLGELE
  PGKLIESMEEFDEETKNKLKAGNALAFLGLERKQFE
• Function: Converts alpha-amino-beta-carboxymuconate-epsilon-semialdehyde (ACMS) to alpha-aminomuconate semialdehyde (AMS). ACMS can be converted non-enzymatically to quinolate (QA), a key precursor of NAD, and a potent endogenous excitotoxin of neuronal cells which is implicated in the pathogenesis of various neurodegenerative disorders. In the presence of ACMSD, ACMS is converted to AMS, a benign catabolite. ACMSD ultimately controls the metabolic fate of tryptophan catabolism along the kynurenine pathway.
• KEGG Pathway:
  Tryptophan metabolism (hsa00380)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Tryptophan catabolism (R-HSA-71240)
• BioCyc Pathway: MetaCyc:HS14455-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
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[2]
Kidney failure	DISOVQ9P	Strong	Biomarker	[3]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[4]
Parkinsonian disorder	DISHGY45	Strong	Genetic Variation	[5]
Asthma	DISW9QNS	Limited	Genetic Variation	[6]
Epilepsy	DISBB28L	Limited	Autosomal dominant	[7]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD).	[9]

6 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 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD).	[13]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD).	[14]

References

• [1] Association of Parkinson's Disease GWAS-Linked Loci with Alzheimer's Disease in Han Chinese.Mol Neurobiol. 2017 Jan;54(1):308-318. doi: 10.1007/s12035-015-9649-5. Epub 2016 Jan 6.
• [2] Purification and molecular cloning of rat 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase.Biochem J. 2002 Feb 1;361(Pt 3):567-75. doi: 10.1042/0264-6021:3610567.
• [3] Mechanism of increases in L-kynurenine and quinolinic acid in renal insufficiency.Am J Physiol Renal Physiol. 2000 Sep;279(3):F565-72. doi: 10.1152/ajprenal.2000.279.3.F565.
• [4] Polymorphisms of ACMSD-TMEM163, MCCC1, and BCKDK-STX1B Are Not Associated with Parkinson's Disease in Taiwan.Parkinsons Dis. 2019 Jan 2;2019:3489638. doi: 10.1155/2019/3489638. eCollection 2019.
• [5] Is the Enzyme ACMSD a Novel Therapeutic Target in Parkinson's Disease?.J Parkinsons Dis. 2017;7(4):577-587. doi: 10.3233/JPD-171240.
• [6] Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma.Toxicol Sci. 2015 Jul;146(1):192-201. doi: 10.1093/toxsci/kfv084. Epub 2015 Apr 26.
• [7] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [8] Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21.Diabetes. 2013 Mar;62(3):977-86. doi: 10.2337/db12-0406. Epub 2012 Dec 3.
• [9] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [10] 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.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [13] 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.
• [14] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.