Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM2DHUR)

• DOT Name: Protein C-mannosyl-transferase DPY19L3 (DPY19L3)
• Synonyms: EC 2.4.1.-; Dpy-19-like protein 3; Protein dpy-19 homolog 3
• Gene Name: DPY19L3
• Related Disease:
  Major depressive disorder
  Mood disorder
• UniProt ID: D19L3_HUMAN
• EC Number: 2.4.1.-
• Pfam ID: PF10034
• Sequence:
  MMSIRQRREIRATEVSEDFPAQEENVKLENKLPSGCTSRRLWKILSLTIGGTIALCIGLL
  TSVYLATLHENDLWFSNIKEVEREISFRTECGLYYSYYKQMLQAPTLVQGFHGLIYDNKT
  ESMKTINLLQRMNIYQEVFLSILYRVLPIQKYLEPVYFYIYTLFGLQAIYVTALYITSWL
  LSGTWLSGLLAAFWYVTNRIDTTRVEFTIPLRENWALPFFAIQIAAITYFLRPNLQPLSE
  RLTLLAIFISTFLFSLTWQFNQFMMLMQALVLFTLDSLDMLPAVKATWLYGIQITSLLLV
  CILQFFNSMILGSLLISFNLSVFIARKLQKNLKTGSFLNRLGKLLLHLFMVLCLTLFLNN
  IIKKILNLKSDEHIFKFLKAKFGLGATRDFDANLYLCEEAFGLLPFNTFGRLSDTLLFYA
  YIFVLSITVIVAFVVAFHNLSDSTNQQSVGKMEKGTVDLKPETAYNLIHTILFGFLALST
  MRMKYLWTSHMCVFASFGLCSPEIWELLLKSVHLYNPKRICIMRYSVPILILLYLCYKFW
  PGMMDELSELREFYDPDTVELMNWINSNTPRKAVFAGSMQLLAGVKLCTGRTLTNHPHYE
  DSSLRERTRAVYQIYAKRAPEEVHALLRSFGTDYVILEDSICYERRHRRGCRLRDLLDIA
  NGHMMDGPGENDPDLKPADHPRFCEEIKRNLPPYVAYFTRVFQNKTFHVYKLSRNK
• Function: C-mannosyltransferase that mediates C-mannosylation of tryptophan residues on target proteins. The reaction occurs on the luminal side of the endoplasmic reticulum and involves the transfer of a mannose unit from a dolichylphosphate mannose (Dol-P-Man) donor to an acceptor protein containing a WxxW or WxxC consensus sequence. C-mannosylates RSPO1, a Wnt signaling regulator, preferentially at the first Trp residue in the sequence WxxW. C-mannosylates the netrin receptor UNC5A, preferentially at the third tryptophan of WxxWxxWxxC sequence; [Isoform 2]: Has no C-mannosyltransferase activity.
• Tissue Specificity: Widely expressed.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[1]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein C-mannosyl-transferase DPY19L3 (DPY19L3).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein C-mannosyl-transferase DPY19L3 (DPY19L3).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein C-mannosyl-transferase DPY19L3 (DPY19L3).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein C-mannosyl-transferase DPY19L3 (DPY19L3).	[5]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein C-mannosyl-transferase DPY19L3 (DPY19L3).	[6]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein C-mannosyl-transferase DPY19L3 (DPY19L3).	[7]

References

• [1] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.