Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXBJ9W5)

• DOT Name: Phosphatidate cytidylyltransferase, mitochondrial (TAMM41)
• Synonyms: EC 2.7.7.41; CDP-diacylglycerol synthase; CDP-DAG synthase; Mitochondrial translocator assembly and maintenance protein 41 homolog; TAM41
• Gene Name: TAMM41
• Related Disease:
  Combined oxidative phosphorylation deficiency 56
  Disorder of orbital region
  Congenital heart disease
• UniProt ID: TAM41_HUMAN
• EC Number: 2.7.7.41
• Pfam ID: PF09139
• Sequence:
  MALQTLQSSWVTFRKILSHFPEELSLAFVYGSGVYRQAGPSSDQKNAMLDFVFTVDDPVA
  WHSKNLKKNWSHYSFLKVLGPKIITSIQNNYGAGVYYNSLIMCNGRLIKYGVISTNVLIE
  DLLNWNNLYIAGRLQKPVKIISVNEDVTLRSALDRNLKSAVTAAFLMLPESFSEEDLFIE
  IAGLSYSGDFRMVVGEDKTKVLNIVKPNIAHFRELYGSILQENPQVVYKSQQGWLEIDKS
  PEGQFTQLMTLPKTLQQQINHIMDPPGKNRDVEETLFQVAHDPDCGDVVRLGLSAIVRPS
  SIRQSTKGIFTAGKSFGNPCVTYLLTEWLPHSWLQCKALYLLGACEMLSFDGHKLGYCSK
  VQTGITAAEPGGRTMSDHWQCCWKLYCPSEFSETLPVCRVFPSYCFIYQSYRCIGLQKQQ
  HLCSPSSSPSLRQLLPSVLVGYFCCYCHFSKW
• Function: Catalyzes the conversion of phosphatidic acid (PA) to CDP-diacylglycerol (CDP-DAG), an essential intermediate in the synthesis of phosphatidylglycerol, cardiolipin and phosphatidylinositol.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Combined oxidative phosphorylation deficiency 56	DISM7NKI	Strong	Autosomal recessive	[1]
Disorder of orbital region	DISH0ECJ	Strong	Genetic Variation	[2]
Congenital heart disease	DISQBA23	Limited	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phosphatidate cytidylyltransferase, mitochondrial (TAMM41).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Phosphatidate cytidylyltransferase, mitochondrial (TAMM41).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phosphatidate cytidylyltransferase, mitochondrial (TAMM41).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phosphatidate cytidylyltransferase, mitochondrial (TAMM41).	[7]
Bicalutamide	DMZMSPF	Approved	Bicalutamide increases the expression of Phosphatidate cytidylyltransferase, mitochondrial (TAMM41).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Phosphatidate cytidylyltransferase, mitochondrial (TAMM41).	[9]

References

• [1] Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease. HGG Adv. 2022 Mar 4;3(2):100097. doi: 10.1016/j.xhgg.2022.100097. eCollection 2022 Apr 14.
• [2] Isolation and chromosomal localization of two human CDP-diacylglycerol synthase (CDS) genes.Genomics. 1998 Nov 15;54(1):140-4. doi: 10.1006/geno.1998.5547.
• [3] TAMM41 is required for heart valve differentiation via regulation of PINK-PARK2 dependent mitophagy.Cell Death Differ. 2019 Nov;26(11):2430-2446. doi: 10.1038/s41418-019-0311-z. Epub 2019 Mar 1.
• [4] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Differentially expressed genes in the prostate cancer cell line LNCaP after exposure to androgen and anti-androgen. Cancer Genet Cytogenet. 2006 Apr 15;166(2):130-8. doi: 10.1016/j.cancergencyto.2005.09.012.
• [9] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.