Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4U3QHF)

• DOT Name: High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A)
• Synonyms: EC 3.1.4.35
• Gene Name: PDE9A
• UniProt ID: PDE9A_HUMAN
• PDB ID: 2HD1; 2YY2; 3DY8; 3DYL; 3DYN; 3DYQ; 3DYS; 3JSI; 3JSW; 3K3E; 3K3H; 3N3Z; 3QI3; 3QI4; 4E90; 4G2J; 4G2L; 4GH6; 4Y86; 4Y87; 4Y8C; 6A3N; 6LZZ; 7F0I; 8BPY
• EC Number: 3.1.4.35
• Pfam ID: PF00233
• Sequence:
  MGSGSSSYRPKAIYLDIDGRIQKVIFSKYCNSSDIMDLFCIATGLPRNTTISLLTTDDAM
  VSIDPTMPANSERTPYKVRPVAIKQLSAGVEDKRTTSRGQSAERPLRDRRVVGLEQPRRE
  GAFESGQVEPRPREPQGCYQEGQRIPPEREELIQSVLAQVAEQFSRAFKINELKAEVANH
  LAVLEKRVELEGLKVVEIEKCKSDIKKMREELAARSSRTNCPCKYSFLDNHKKLTPRRDV
  PTYPKYLLSPETIEALRKPTFDVWLWEPNEMLSCLEHMYHDLGLVRDFSINPVTLRRWLF
  CVHDNYRNNPFHNFRHCFCVAQMMYSMVWLCSLQEKFSQTDILILMTAAICHDLDHPGYN
  NTYQINARTELAVRYNDISPLENHHCAVAFQILAEPECNIFSNIPPDGFKQIRQGMITLI
  LATDMARHAEIMDSFKEKMENFDYSNEEHMTLLKMILIKCCDISNEVRPMEVAEPWVDCL
  LEEYFMQSDREKSEGLPVAPFMDRDKVTKATAQIGFIKFVLIPMFETVTKLFPMVEEIML
  QPLWESRDRYEELKRIDDAMKELQKKTDSLTSGATEKSRERSRDVKNSEGDCA
• Function: Specifically hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes. Highly specific: compared to other members of the cyclic nucleotide phosphodiesterase family, has the highest affinity and selectivity for cGMP. Specifically regulates natriuretic-peptide-dependent cGMP signaling in heart, acting as a regulator of cardiac hypertrophy in myocytes and muscle. Does not regulate nitric oxide-dependent cGMP in heart. Additional experiments are required to confirm whether its ability to hydrolyze natriuretic-peptide-dependent cGMP is specific to heart or is a general feature of the protein (Probable). In brain, involved in cognitive function, such as learning and long-term memory.
• Tissue Specificity: Expressed in all tissues examined (testis, brain, small intestine, skeletal muscle, heart, lung, thymus, spleen, placenta, kidney, liver, pancreas, ovary and prostate) except blood . Highest levels in brain, heart, kidney, spleen, prostate and colon. Isoform PDE9A12 is found in prostate . In brain, present in the cortex, cerebellum, and subiculum (at protein level) . In heart, primarily localizes to myocytes .
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
• Reactome Pathway: cGMP effects (R-HSA-418457)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
[3H]cAMP	DMZRQU7	Investigative	High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A) increases the hydrolysis of [3H]cAMP.	[16]
Cyclic guanosine monophosphate	DMOU93V	Investigative	High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A) increases the hydrolysis of Cyclic guanosine monophosphate.	[16]

2 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 High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A).	[1]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A).	[4]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A).	[6]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A).	[8]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A).	[11]
Celastrol	DMWQIJX	Preclinical	Celastrol decreases the expression of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A).	[14]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of High affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A).	[15]

References

• [1] 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.
• [2] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [3] 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.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [6] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [7] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [10] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30.
• [13] 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.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [15] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [16] Isolation and characterization of PDE9A, a novel human cGMP-specific phosphodiesterase. J Biol Chem. 1998 Jun 19;273(25):15559-64.