Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR0OO41)

• DOT Name: rRNA N6-adenosine-methyltransferase METTL5 (METTL5)
• Synonyms: EC 2.1.1.-; Methyltransferase-like protein 5
• Gene Name: METTL5
• Related Disease:
  Intellectual developmental disorder, autosomal recessive 72
  Intellectual disability
  Isolated congenital microcephaly
  Autosomal recessive primary microcephaly
• UniProt ID: METL5_HUMAN
• PDB ID: 6H2U; 6H2V
• EC Number: 2.1.1.-
• Pfam ID: PF05175
• Sequence:
  MKKVRLKELESRLQQVDGFEKPKLLLEQYPTRPHIAACMLYTIHNTYDDIENKVVADLGC
  GCGVLSIGTAMLGAGLCVGFDIDEDALEIFNRNAEEFELTNIDMVQCDVCLLSNRMSKSF
  DTVIMNPPFGTKNNKGTDMAFLKTALEMARTAVYSLHKSSTREHVQKKAAEWKIKIDIIA
  ELRYDLPASYKFHKKKSVDIEVDLIRFSF
• Function: Catalytic subunit of a heterodimer with TRMT112, which specifically methylates the 6th position of adenine in position 1832 of 18S rRNA. N6-methylation of adenine(1832) in 18S rRNA resides in the decoding center of 18S rRNA and is required for translation and embryonic stem cells (ESCs) pluripotency and differentiation.
• Tissue Specificity: Expressed from very early development (8 post-conceptual weeks) and expression persists through adulthood in multiple substructures of the brain, including the cerebellar cortex, hippocampus, and striatum.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual developmental disorder, autosomal recessive 72	DISLCY02	Strong	Autosomal recessive	[1]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[2]
Isolated congenital microcephaly	DISUXHZ6	moderate	Biomarker	[2]
Autosomal recessive primary microcephaly	DIS29IE3	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of rRNA N6-adenosine-methyltransferase METTL5 (METTL5).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of rRNA N6-adenosine-methyltransferase METTL5 (METTL5).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of rRNA N6-adenosine-methyltransferase METTL5 (METTL5).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of rRNA N6-adenosine-methyltransferase METTL5 (METTL5).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of rRNA N6-adenosine-methyltransferase METTL5 (METTL5).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of rRNA N6-adenosine-methyltransferase METTL5 (METTL5).	[8]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of rRNA N6-adenosine-methyltransferase METTL5 (METTL5).	[9]

References

• [1] Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability. Mol Psychiatry. 2017 Nov;22(11):1604-1614. doi: 10.1038/mp.2016.109. Epub 2016 Jul 26.
• [2] Bi-allelic Variants in METTL5 Cause Autosomal-Recessive Intellectual Disability and Microcephaly. Am J Hum Genet. 2019 Oct 3;105(4):869-878. doi: 10.1016/j.ajhg.2019.09.007. Epub 2019 Sep 26.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] 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.
• [9] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.