PDE10A

PDE10A
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2OUN, 2OUP, 2OUQ, 2OUR, 2OUS, 2OUU, 2OUV, 2OUY, 2WEY, 2Y0J, 2ZMF, 3SN7, 3SNI, 3SNL, 3UI7, 3UUO, 3WI2, 3WS8, 3WS9, 3WYK, 3WYL, 3WYM, 4AEL, 4AJD, 4AJF, 4AJG, 4AJM, 4BBX, 4DDL, 4DFF, 4FCB, 4FCD, 4HEU, 4HF4, 4LKQ, 4LLJ, 4LLK, 4LLP, 4LLX, 4LM0, 4LM1, 4LM2, 4LM3, 4LM4, 4MRW, 4MRZ, 4MS0, 4MSA, 4MSC, 4MSE, 4MSH, 4MSN, 4MUW, 4MVH, 4P0N, 4P1R, 4PHW, 4TPM, 4TPP, 4WN1, 4XY2, 4YQH, 4YS7, 4ZO5, 5C1W, 5C28, 5C29, 5C2A, 5C2H, 5DH5, 5AXQ, 5DH4, 5AXP, 5C2E, 5EDH, 5EDI, 5EDG, 5EDE, 5I2R, 5B4L, 5B4K
Identifiers
Aliases	PDE10A, HSPDE10A19, ADSD2, IOLOD, phosphodiesterase 10A, LINC00473
External IDs	OMIM: 610652 MGI: 1345143 HomoloGene: 4852 GeneCards: PDE10A
Gene location (Human)
Chr.	Chromosome 6 (human)[1]
End	165,988,078 bp[1]
Gene location (Mouse)
Chr.	Chromosome 17 (mouse)[2]
End	8,986,648 bp[2]
RNA expression pattern
	; ; ; ;
	More reference expression data
Gene ontology
Molecular function	• nucleotide binding; • 3',5'-cyclic-nucleotide phosphodiesterase activity; • cAMP binding; • cGMP binding; • metal ion binding; • cGMP-stimulated cyclic-nucleotide phosphodiesterase activity; • cyclic-nucleotide phosphodiesterase activity; • catalytic activity; • drug binding; • phosphoric diester hydrolase activity; • hydrolase activity; • 3',5'-cyclic-AMP phosphodiesterase activity; • 3',5'-cyclic-GMP phosphodiesterase activity;
Cellular component	• cytoplasm; • cytosol; • perikaryon; • membrane; • neuronal cell body;
Biological process	• cAMP catabolic process; • regulation of protein kinase A signaling; • cGMP catabolic process; • regulation of cAMP-mediated signaling; • metabolism; • signal transduction; • G-protein coupled receptor signaling pathway; • negative regulation of cGMP-mediated signaling; • negative regulation of cAMP-mediated signaling;
	Sources:Amigo / QuickGO
Orthologs
	10846
	23984
	ENSG00000112541
	ENSMUSG00000023868
	Q9Y233
	Q8CA95
	NM_001130690; NM_006661
	NM_001290707; NM_011866; NM_001347321
	NP_001124162; NP_006652
	NP_001277636; NP_001334250; NP_035996
	Wikidata
View/Edit Human	View/Edit Mouse

cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A is an enzyme that in humans is encoded by the PDE10A gene.[5][6]

Various cellular responses are regulated by the second messengers cAMP and cGMP. Phosphodiesterases, such as PDE10A, eliminate cAMP- and cGMP-mediated intracellular signaling by hydrolyzing the cyclic nucleotide to the corresponding nucleoside 5-prime monophosphate.[6][7]

Inhibitors

3d model of compound #96 (Malamas, 2011)[8]

Compound 96: IC₅₀ = 700 pM, high selectivity against all other members of the PDE family[8]
Papaverine[9]
PF-2545920[10]
TAK-063: IC₅₀ = 300 pM[11]
AMG 579[12]

Research

Preliminary evidence indicates a possible link between PDE10A expression and obesity in mice and humans.[13]

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References

GRCh38: Ensembl release 89: ENSG00000112541 - Ensembl, May 2017
GRCm38: Ensembl release 89: ENSMUSG00000023868 - Ensembl, May 2017
"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
Fujishige K, Kotera J, Michibata H, Yuasa K, Takebayashi S, Okumura K, Omori K (Jul 1999). "Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A)". J Biol Chem. 274 (26): 18438–45. doi:10.1074/jbc.274.26.18438. PMID 10373451.
"Entrez Gene: PDE10A phosphodiesterase 10A".
Fujishige K, Kotera J, Yuasa K, Omori K (October 2000). "The human phosphodiesterase PDE10A gene genomic organization and evolutionary relatedness with other PDEs containing GAF domains". Eur. J. Biochem. 267 (19): 5943–51. doi:10.1046/j.1432-1327.2000.01661.x. PMID 10998054.
Malamas, MS; et al. (2011). "Highly potent, selective, and orally active phosphodiesterase 10A inhibitors". J. Med. Chem. 54 (21): 7621–38. doi:10.1021/jm2009138. PMID 21988093.
Siuciak JA, Chapin DS, Harms JF, et al. (August 2006). "Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis". Neuropharmacology. 51 (2): 386–96. doi:10.1016/j.neuropharm.2006.04.013. PMID 16780899.
Verhoest PR, Chapin DS, Corman M, et al. (August 2009). "Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the treatment of schizophrenia". J. Med. Chem. 52 (16): 5188–96. doi:10.1021/jm900521k. PMID 19630403.
Kunitomo J, Yoshikawa M, Fushimi M, et al. (2014). "Discovery of 1-[2-Fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (TAK-063), a Highly Potent, Selective, and Orally Active Phosphodiesterase 10A (PDE10A) Inhibitor". J. Med. Chem. 57 (22): 9627–43. doi:10.1021/jm5013648. PMID 25384088.
Hu; et al. (2014). "Discovery of Clinical Candidate 1-(4-(3-(4-(1Hbenzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (AMG 579), a Potent, Selective, and Efficacious Inhibitor of Phosphodiesterase 10A (PDE10A)"". J Med Chem. 57 (15): 6632–41. doi:10.1021/jm500713j. PMID 25062128.
Hankir, Mohammed K; et al. (2016). "A novel thermoregulatory role for PDE10A in mouse and human adipocytes". EMBO Molecular Medicine. 8 (7): 796–812. doi:10.15252/emmm.201506085. PMC 4931292. PMID 27247380.

Loughney K, Snyder PB, Uher L, et al. (1999). "Isolation and characterization of PDE10A, a novel human 3', 5'-cyclic nucleotide phosphodiesterase". Gene. 234 (1): 109–17. doi:10.1016/S0378-1119(99)00171-7. PMID 10393245.
Kotera J, Fujishige K, Yuasa K, Omori K (1999). "Characterization and phosphorylation of PDE10A2, a novel alternative splice variant of human phosphodiesterase that hydrolyzes cAMP and cGMP". Biochem. Biophys. Res. Commun. 261 (3): 551–7. doi:10.1006/bbrc.1999.1013. PMID 10441464.
Zauli G, Milani D, Mirandola P, et al. (2001). "HIV-1 Tat protein down-regulates CREB transcription factor expression in PC12 neuronal cells through a phosphatidylinositol 3-kinase/AKT/cyclic nucleoside phosphodiesterase pathway". FASEB J. 15 (2): 483–91. doi:10.1096/fj.00-0354com. PMID 11156964.
Frame M, Wan KF, Tate R, et al. (2001). "The gamma subunit of the rod photoreceptor cGMP phosphodiesterase can modulate the proteolysis of two cGMP binding cGMP-specific phosphodiesterases (PDE6 and PDE5) by caspase-3". Cell. Signal. 13 (10): 735–41. doi:10.1016/S0898-6568(01)00193-0. PMID 11602184.
Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
Mungall AJ, Palmer SA, Sims SK, et al. (2003). "The DNA sequence and analysis of human chromosome 6". Nature. 425 (6960): 805–11. doi:10.1038/nature02055. PMID 14574404.
Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
Gross-Langenhoff M, Hofbauer K, Weber J, et al. (2006). "cAMP is a ligand for the tandem GAF domain of human phosphodiesterase 10 and cGMP for the tandem GAF domain of phosphodiesterase 11". J. Biol. Chem. 281 (5): 2841–6. doi:10.1074/jbc.M511468200. PMID 16330539.
Chappie TA, Helal CJ, Hou X (2012). "Current Landscape of Phosphodiesterase 10A (PDE10A) Inhibition". J. Med. Chem. 55 (17): 7299–7331. doi:10.1021/jm3004976. PMID 22834877.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000112541 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000023868 - Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid10373451-5] Fujishige K, Kotera J, Michibata H, Yuasa K, Takebayashi S, Okumura K, Omori K (Jul 1999). "Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A)". J Biol Chem. 274 (26): 18438–45. doi:10.1074/jbc.274.26.18438. PMID 10373451.

[entrez-6] "Entrez Gene: PDE10A phosphodiesterase 10A".

[pmid10998054-7] Fujishige K, Kotera J, Yuasa K, Omori K (October 2000). "The human phosphodiesterase PDE10A gene genomic organization and evolutionary relatedness with other PDEs containing GAF domains". Eur. J. Biochem. 267 (19): 5943–51. doi:10.1046/j.1432-1327.2000.01661.x. PMID 10998054.

[Malamas-8] Malamas, MS; et al. (2011). "Highly potent, selective, and orally active phosphodiesterase 10A inhibitors". J. Med. Chem. 54 (21): 7621–38. doi:10.1021/jm2009138. PMID 21988093.

[9] Siuciak JA, Chapin DS, Harms JF, et al. (August 2006). "Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis". Neuropharmacology. 51 (2): 386–96. doi:10.1016/j.neuropharm.2006.04.013. PMID 16780899.

[10] Verhoest PR, Chapin DS, Corman M, et al. (August 2009). "Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the treatment of schizophrenia". J. Med. Chem. 52 (16): 5188–96. doi:10.1021/jm900521k. PMID 19630403.

[pmid25384088-11] Kunitomo J, Yoshikawa M, Fushimi M, et al. (2014). "Discovery of 1-[2-Fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (TAK-063), a Highly Potent, Selective, and Orally Active Phosphodiesterase 10A (PDE10A) Inhibitor". J. Med. Chem. 57 (22): 9627–43. doi:10.1021/jm5013648. PMID 25384088.

[12] Hu; et al. (2014). "Discovery of Clinical Candidate 1-(4-(3-(4-(1Hbenzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (AMG 579), a Potent, Selective, and Efficacious Inhibitor of Phosphodiesterase 10A (PDE10A)"". J Med Chem. 57 (15): 6632–41. doi:10.1021/jm500713j. PMID 25062128.

[13] Hankir, Mohammed K; et al. (2016). "A novel thermoregulatory role for PDE10A in mouse and human adipocytes". EMBO Molecular Medicine. 8 (7): 796–812. doi:10.15252/emmm.201506085. PMC 4931292. PMID 27247380.

Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)

PDE10A

Inhibitors

Research

References

Further reading