Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXXNQ5K)

• DOT Name: N-fatty-acyl-amino acid synthase/hydrolase PM20D1 (PM20D1)
• Synonyms: EC 3.5.1.114; EC 3.5.1.14; Peptidase M20 domain-containing protein 1
• Gene Name: PM20D1
• Related Disease:
  Acute myelogenous leukaemia
  Alzheimer disease
  Ornithine transcarbamylase deficiency
  Parkinson disease
  Obesity
  Asthma
• UniProt ID: P20D1_HUMAN
• EC Number: 3.5.1.114; 3.5.1.14
• Pfam ID: PF07687 ; PF01546
• Sequence:
  MAQRCVCVLALVAMLLLVFPTVSRSMGPRSGEHQRASRIPSQFSKEERVAMKEALKGAIQ
  IPTVTFSSEKSNTTALAEFGKYIHKVFPTVVSTSFIQHEVVEEYSHLFTIQGSDPSLQPY
  LLMAHFDVVPAPEEGWEVPPFSGLERDGIIYGRGTLDDKNSVMALLQALELLLIRKYIPR
  RSFFISLGHDEESSGTGAQRISALLQSRGVQLAFIVDEGGFILDDFIPNFKKPIALIAVS
  EKGSMNLMLQVNMTSGHSSAPPKETSIGILAAAVSRLEQTPMPIIFGSGTVVTVLQQLAN
  EFPFPVNIILSNPWLFEPLISRFMERNPLTNAIIRTTTALTIFKAGVKFNVIPPVAQATV
  NFRIHPGQTVQEVLELTKNIVADNRVQFHVLSAFDPLPVSPSDDKALGYQLLRQTVQSVF
  PEVNITAPVTSIGNTDSRFFTNLTTGIYRFYPIYIQPEDFKRIHGVNEKISVQAYETQVK
  FIFELIQNADTDQEPVSHLHKL
• Function: Secreted enzyme that regulates the endogenous N-fatty acyl amino acid (NAAs) tissue and circulating levels by functioning as a bidirectional NAA synthase/hydrolase. It condenses free fatty acids and free amino acids to generate NAAs and bidirectionally catalyzes the reverse hydrolysis reaction. Some of these NAAs stimulate oxidative metabolism via mitochondrial uncoupling, increasing energy expenditure in a UPC1-independent manner. Thereby, this secreted protein may indirectly regulate whole body energy expenditure. PM20D1 circulates in tight association with both low- and high-density (LDL and HDL,respectively) lipoprotein particles.
• Reactome Pathway: Oleoyl-phe metabolism (R-HSA-9673163)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Posttranslational Modification	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Ornithine transcarbamylase deficiency	DIS3DOIC	Strong	Altered Expression	[3]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[4]
Obesity	DIS47Y1K	moderate	Biomarker	[5]
Asthma	DISW9QNS	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of N-fatty-acyl-amino acid synthase/hydrolase PM20D1 (PM20D1).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of N-fatty-acyl-amino acid synthase/hydrolase PM20D1 (PM20D1).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of N-fatty-acyl-amino acid synthase/hydrolase PM20D1 (PM20D1).	[8]

References

• [1] Use of methylation profiling to identify significant differentially methylated genes in bone marrow mesenchymal stromal cells from acute myeloid leukemia.Int J Mol Med. 2018 Feb;41(2):679-686. doi: 10.3892/ijmm.2017.3271. Epub 2017 Nov 17.
• [2] PM20D1 is aquantitative trait locus associated with Alzheimer's disease.Nat Med. 2018 May;24(5):598-603. doi: 10.1038/s41591-018-0013-y. Epub 2018 May 7.
• [3] Genetic analysis of carbamoylphosphate synthetase I and ornithine transcarbamylase deficiency using fibroblasts.Eur J Pediatr. 2001 May;160(5):283-7. doi: 10.1007/s004310100725.
• [4] Comprehensive research synopsis and systematic meta-analyses in Parkinson's disease genetics: The PDGene database.PLoS Genet. 2012;8(3):e1002548. doi: 10.1371/journal.pgen.1002548. Epub 2012 Mar 15.
• [5] Inhibition of miR-324-5p increases PM20D1-mediated white and brown adipose loss and reduces body weight in juvenile mice.Eur J Pharmacol. 2019 Nov 15;863:172708. doi: 10.1016/j.ejphar.2019.172708. Epub 2019 Sep 27.
• [6] Differential DNA methylation profiles of infants exposed to maternal asthma during pregnancy.Pediatr Pulmonol. 2014 Sep;49(9):852-62. doi: 10.1002/ppul.22930. Epub 2013 Oct 25.
• [7] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [8] 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.
• [9] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.