Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9X261C)

• DOT Name: Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A (PDE11A)
• Synonyms: EC 3.1.4.35; EC 3.1.4.53; cAMP and cGMP phosphodiesterase 11A
• Gene Name: PDE11A
• Related Disease:
  Pigmented nodular adrenocortical disease, primary, 2
  Primary pigmented nodular adrenocortical disease
• UniProt ID: PDE11_HUMAN
• EC Number: 3.1.4.35; 3.1.4.53
• Pfam ID: PF01590 ; PF00233
• Sequence:
  MAASRLDFGEVETFLDRHPELFEDYLMRKGKQEMVEKWLQRHSQGQGALGPRPSLAGTSS
  LAHSTCRGGSSVGGGTGPNGSAHSQPLPGGGDCGGVPLSPSWAGGSRGDGNLQRRASQKE
  LRKSFARSKAIHVNRTYDEQVTSRAQEPLSSVRRRALLRKASSLPPTTAHILSALLESRV
  NLPRYPPTAIDYKCHLKKHNERQFFLELVKDISNDLDLTSLSYKILIFVCLMVDADRCSL
  FLVEGAAAGKKTLVSKFFDVHAGTPLLPCSSTENSNEVQVPWGKGIIGYVGEHGETVNIP
  DAYQDRRFNDEIDKLTGYKTKSLLCMPIRSSDGEIIGVAQAINKIPEGAPFTEDDEKVMQ
  MYLPFCGIAISNAQLFAASRKEYERSRALLEVVNDLFEEQTDLEKIVKKIMHRAQTLLKC
  ERCSVLLLEDIESPVVKFTKSFELMSPKCSADAENSFKESMEKSSYSDWLINNSIAELVA
  STGLPVNISDAYQDPRFDAEADQISGFHIRSVLCVPIWNSNHQIIGVAQVLNRLDGKPFD
  DADQRLFEAFVIFCGLGINNTIMYDQVKKSWAKQSVALDVLSYHATCSKAEVDKFKAANI
  PLVSELAIDDIHFDDFSLDVDAMITAALRMFMELGMVQKFKIDYETLCRWLLTVRKNYRM
  VLYHNWRHAFNVCQLMFAMLTTAGFQDILTEVEILAVIVGCLCHDLDHRGTNNAFQAKSG
  SALAQLYGTSATLEHHHFNHAVMILQSEGHNIFANLSSKEYSDLMQLLKQSILATDLTLY
  FERRTEFFELVSKGEYDWNIKNHRDIFRSMLMTACDLGAVTKPWEISRQVAELVTSEFFE
  QGDRERLELKLTPSAIFDRNRKDELPRLQLEWIDSICMPLYQALVKVNVKLKPMLDSVAT
  NRSKWEELHQKRLLASTASSSPASVMVAKEDRN
• Function: Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides cAMP and cGMP. Catalyzes the hydrolysis of both cAMP and cGMP to 5'-AMP and 5'-GMP, respectively.
• Tissue Specificity: Isoform 1 is present in prostate, pituitary, heart and liver. It is however not present in testis nor in penis, suggesting that weak inhibition by Tadalafil (Cialis) is not relevant (at protein level). Isoform 2 may be expressed in testis. Isoform 4 is expressed in adrenal cortex.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Metabolic pathways (hsa01100)
  Cushing syndrome (hsa04934)
  Morphine addiction (hsa05032)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  cGMP effects (R-HSA-418457)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pigmented nodular adrenocortical disease, primary, 2	DISESGQ5	Strong	Autosomal dominant	[1]
Primary pigmented nodular adrenocortical disease	DISXCNDR	Supportive	Autosomal dominant	[1]

This DOT Affected the Biotransformations of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
[3H]cAMP	DMZRQU7	Investigative	Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A (PDE11A) increases the hydrolysis of [3H]cAMP.	[12]
Cyclic guanosine monophosphate	DMOU93V	Investigative	Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A (PDE11A) increases the hydrolysis of Cyclic guanosine monophosphate.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A (PDE11A).	[2]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A (PDE11A).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A (PDE11A).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A (PDE11A).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A (PDE11A).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A (PDE11A).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A (PDE11A).	[5]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A (PDE11A).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A (PDE11A).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A (PDE11A).	[10]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A (PDE11A).	[11]

References

• [1] A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia. Nat Genet. 2006 Jul;38(7):794-800. doi: 10.1038/ng1809. Epub 2006 Jun 11.
• [2] 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.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [8] 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.
• [9] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [10] 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.
• [11] Evaluation of estrogen receptor alpha activation by glyphosate-based herbicide constituents. Food Chem Toxicol. 2017 Oct;108(Pt A):30-42.
• [12] Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A. Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3702-7. doi: 10.1073/pnas.97.7.3702.