Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9D9T2F)

• DOT Name: Pyruvate dehydrogenase E1 component subunit alpha, testis-specific form, mitochondrial (PDHA2)
• Synonyms: EC 1.2.4.1; PDHE1-A type II
• Gene Name: PDHA2
• Related Disease:
  Estrogen-receptor positive breast cancer
  Male infertility
  Pyruvate dehydrogenase complex deficiency
  Spermatogenic failure 70
• UniProt ID: ODPAT_HUMAN
• EC Number: 1.2.4.1
• Pfam ID: PF00676
• Sequence:
  MLAAFISRVLRRVAQKSARRVLVASRNSSNDATFEIKKCDLYLLEEGPPVTTVLTRAEGL
  KYYRMMLTVRRMELKADQLYKQKFIRGFCHLCDGQEACCVGLEAGINPSDHVITSYRAHG
  VCYTRGLSVRSILAELTGRRGGCAKGKGGSMHMYTKNFYGGNGIVGAQGPLGAGIALACK
  YKGNDEICLTLYGDGAANQGQIAEAFNMAALWKLPCVFICENNLYGMGTSTERAAASPDY
  YKRGNFIPGLKVDGMDVLCVREATKFAANYCRSGKGPILMELQTYRYHGHSMSDPGVSYR
  TREEIQEVRSKRDPIIILQDRMVNSKLATVEELKEIGAEVRKEIDDAAQFATTDPEPHLE
  ELGHHIYSSDSSFEVRGANPWIKFKSVS
• Function: The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links the glycolytic pathway to the tricarboxylic cycle.
• Tissue Specificity: Testis. Expressed in postmeiotic spermatogenic cells.
• KEGG Pathway:
  Glycolysis / Gluconeogenesis (hsa00010)
  Citrate cycle (TCA cycle) (hsa00020)
  Pyruvate metabolism (hsa00620)
  Lipoic acid metabolism (hsa00785)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  2-Oxocarboxylic acid metabolism (hsa01210)
  HIF-1 sig.ling pathway (hsa04066)
  Glucagon sig.ling pathway (hsa04922)
  Central carbon metabolism in cancer (hsa05230)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Glyoxylate metabolism and glycine degradation (R-HSA-389661)
  Signaling by Retinoic Acid (R-HSA-5362517)
  Pyruvate metabolism (R-HSA-70268)
  Regulation of pyruvate dehydrogenase (PDH) complex (R-HSA-204174)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[1]
Male infertility	DISY3YZZ	Strong	Biomarker	[2]
Pyruvate dehydrogenase complex deficiency	DIS8RZP9	Strong	Genetic Variation	[3]
Spermatogenic failure 70	DIS3CUS6	Limited	Unknown	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Pyruvate dehydrogenase E1 component subunit alpha, testis-specific form, mitochondrial (PDHA2).	[4]

1 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 Pyruvate dehydrogenase E1 component subunit alpha, testis-specific form, mitochondrial (PDHA2).	[5]

References

• [1] Tamoxifen therapy benefit predictive signature combining with prognostic signature in surgical-only ER-positive breast cancer.J Cell Physiol. 2019 Jul;234(7):11140-11148. doi: 10.1002/jcp.27756. Epub 2018 Dec 7.
• [2] Linked homozygous BMPR1B and PDHA2 variants in a consanguineous family with complex digit malformation and male infertility. Eur J Hum Genet. 2018 Jun;26(6):876-885. doi: 10.1038/s41431-018-0121-7. Epub 2018 Mar 26.
• [3] Complex genetic findings in a female patient with pyruvate dehydrogenase complex deficiency: Null mutations in the PDHX gene associated with unusual expression of the testis-specific PDHA2 gene in her somatic cells.Gene. 2016 Oct 15;591(2):417-24. doi: 10.1016/j.gene.2016.06.041. Epub 2016 Jun 22.
• [4] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [5] 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.