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; OMA:PDE10A - orthologs
Gene location (Human)
Chr.	Chromosome 6 (human)
End	165,988,117 bp
Gene location (Mouse)
Chr.	Chromosome 17 (mouse)
End	9,205,480 bp
RNA expression pattern
	Top expressed in
	left uterine tube; ; cartilage tissue; ; left ovary; ; external globus pallidus; ; corpus epididymis; ; putamen; ; right ovary; ; anterior pituitary; ; stromal cell of endometrium; ; caudate nucleus;
	Top expressed in
	olfactory tubercle; ; nucleus accumbens; ; globus pallidus; ; superior frontal gyrus; ; Temporal Lobe; ; Amygdala; ; lobe of cerebellum; ; cerebellar vermis; ; anterior amygdaloid area; ; lateral septal nucleus;
	More reference expression data
	; ; ; ;
	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; phosphoric diester hydrolase activity; hydrolase activity; 3',5'-cyclic-AMP phosphodiesterase activity; 3',5'-cyclic-GMP phosphodiesterase activity;
Cellular component	cytoplasm; cytosol; perikaryon; membrane; soma;
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_001385079
	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]

AMG-579^[9]
Balipodect (TAK-063): IC₅₀ = 300 pM^[10]
Compound 96: IC₅₀ = 700 pM, high selectivity against all other members of the PDE family^[8]
CPL500036^[11]
Mardepodect (PF-2545920)^[12]
MK-8189
Papaverine^[13]
Tofisopam

Research

Preliminary evidence indicates a possible link between PDE10A expression and obesity in mice and humans.^[14] PDE10A is a regulatory protein involved in the signaling of the striatum, a region of the brain important for controlling movement and cognition. Dysfunction of the striatum has been linked to the development of schizophrenia. Inhibition of PDE10A has been identified as a potential treatment for the disorder, and an inhibitor compound (MK-8189) is as of February 2023 in Phase 2b clinical development for the treatment of schizophrenia.^[15]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000112541 – Ensembl, May 2017
^ ^a ^b ^c 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 (June 1999). "Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A)". The Journal of Biological Chemistry. 274 (26): 18438–18445. doi:10.1074/jbc.274.26.18438. PMID 10373451.
^ ^a ^b "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". European Journal of Biochemistry. 267 (19): 5943–5951. doi:10.1046/j.1432-1327.2000.01661.x. PMID 10998054.
^ ^a ^b Malamas MS, Ni Y, Erdei J, Stange H, Schindler R, Lankau HJ, et al. (November 2011). "Highly potent, selective, and orally active phosphodiesterase 10A inhibitors". Journal of Medicinal Chemistry. 54 (21): 7621–7638. doi:10.1021/jm2009138. PMID 21988093.
^ Hu E, Chen N, Bourbeau MP, Harrington PE, Biswas K, Kunz RK, et al. (August 2014). "Discovery of clinical candidate 1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (AMG 579), a potent, selective, and efficacious inhibitor of phosphodiesterase 10A (PDE10A)". Journal of Medicinal Chemistry. 57 (15): 6632–6641. doi:10.1021/jm500713j. PMID 25062128.
^ Kunitomo J, Yoshikawa M, Fushimi M, Kawada A, Quinn JF, Oki H, et al. (November 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". Journal of Medicinal Chemistry. 57 (22): 9627–9643. doi:10.1021/jm5013648. PMID 25384088.
^ Matloka M, Janowska S, Pankiewicz P, Kokhanovska S, Kos T, Hołuj M, et al. (2022). "A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects". Frontiers in Pharmacology. 13: 999685. doi:10.3389/fphar.2022.999685. PMC 9681820. PMID 36438799.
^ Verhoest PR, Chapin DS, Corman M, Fonseca K, Harms JF, Hou X, 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". Journal of Medicinal Chemistry. 52 (16): 5188–5196. doi:10.1021/jm900521k. PMID 19630403.
^ Siuciak JA, Chapin DS, Harms JF, Lebel LA, McCarthy SA, Chambers L, et al. (August 2006). "Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis". Neuropharmacology. 51 (2): 386–396. doi:10.1016/j.neuropharm.2006.04.013. PMID 16780899. S2CID 13447370.
^ Hankir MK, Kranz M, Gnad T, Weiner J, Wagner S, Deuther-Conrad W, et al. (July 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.
^ Layton ME, Kern JC, Hartingh TJ, Shipe WD, Raheem I, Kandebo M, et al. (January 2023). "Discovery of MK-8189, a Highly Potent and Selective PDE10A Inhibitor for the Treatment of Schizophrenia". Journal of Medicinal Chemistry. 66 (2): 1157–1171. doi:10.1021/acs.jmedchem.2c01521. PMC 9884086. PMID 36624931.

Loughney K, Snyder PB, Uher L, Rosman GJ, Ferguson K, Florio VA (June 1999). "Isolation and characterization of PDE10A, a novel human 3', 5'-cyclic nucleotide phosphodiesterase". Gene. 234 (1): 109–117. doi:10.1016/S0378-1119(99)00171-7. PMID 10393245.
Kotera J, Fujishige K, Yuasa K, Omori K (August 1999). "Characterization and phosphorylation of PDE10A2, a novel alternative splice variant of human phosphodiesterase that hydrolyzes cAMP and cGMP". Biochemical and Biophysical Research Communications. 261 (3): 551–557. doi:10.1006/bbrc.1999.1013. PMID 10441464.
Zauli G, Milani D, Mirandola P, Mazzoni M, Secchiero P, Miscia S, Capitani S (February 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 Journal. 15 (2): 483–491. doi:10.1096/fj.00-0354com. PMID 11156964. S2CID 26315564.
Frame M, Wan KF, Tate R, Vandenabeele P, Pyne NJ (October 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". Cellular Signalling. 13 (10): 735–741. doi:10.1016/S0898-6568(01)00193-0. PMID 11602184.
Gross-Langenhoff M, Hofbauer K, Weber J, Schultz A, Schultz JE (February 2006). "cAMP is a ligand for the tandem GAF domain of human phosphodiesterase 10 and cGMP for the tandem GAF domain of phosphodiesterase 11". The Journal of Biological Chemistry. 281 (5): 2841–2846. doi:10.1074/jbc.M511468200. PMID 16330539.
Chappie TA, Helal CJ, Hou X (September 2012). "Current landscape of phosphodiesterase 10A (PDE10A) inhibition". Journal of Medicinal Chemistry. 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.

This article on a gene on human chromosome 6 is a stub. You can help Wikipedia by expanding it.

[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 (June 1999). "Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A)". The Journal of Biological Chemistry. 274 (26): 18438–18445. 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". European Journal of Biochemistry. 267 (19): 5943–5951. doi:10.1046/j.1432-1327.2000.01661.x. PMID 10998054.

[Malamas-8] Malamas MS, Ni Y, Erdei J, Stange H, Schindler R, Lankau HJ, et al. (November 2011). "Highly potent, selective, and orally active phosphodiesterase 10A inhibitors". Journal of Medicinal Chemistry. 54 (21): 7621–7638. doi:10.1021/jm2009138. PMID 21988093.

[9] Hu E, Chen N, Bourbeau MP, Harrington PE, Biswas K, Kunz RK, et al. (August 2014). "Discovery of clinical candidate 1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (AMG 579), a potent, selective, and efficacious inhibitor of phosphodiesterase 10A (PDE10A)". Journal of Medicinal Chemistry. 57 (15): 6632–6641. doi:10.1021/jm500713j. PMID 25062128.

[pmid25384088-10] Kunitomo J, Yoshikawa M, Fushimi M, Kawada A, Quinn JF, Oki H, et al. (November 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". Journal of Medicinal Chemistry. 57 (22): 9627–9643. doi:10.1021/jm5013648. PMID 25384088.

[11] Matloka M, Janowska S, Pankiewicz P, Kokhanovska S, Kos T, Hołuj M, et al. (2022). "A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects". Frontiers in Pharmacology. 13: 999685. doi:10.3389/fphar.2022.999685. PMC 9681820. PMID 36438799.

[12] Verhoest PR, Chapin DS, Corman M, Fonseca K, Harms JF, Hou X, 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". Journal of Medicinal Chemistry. 52 (16): 5188–5196. doi:10.1021/jm900521k. PMID 19630403.

[13] Siuciak JA, Chapin DS, Harms JF, Lebel LA, McCarthy SA, Chambers L, et al. (August 2006). "Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis". Neuropharmacology. 51 (2): 386–396. doi:10.1016/j.neuropharm.2006.04.013. PMID 16780899. S2CID 13447370.

[14] Hankir MK, Kranz M, Gnad T, Weiner J, Wagner S, Deuther-Conrad W, et al. (July 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.

[15] Layton ME, Kern JC, Hartingh TJ, Shipe WD, Raheem I, Kandebo M, et al. (January 2023). "Discovery of MK-8189, a Highly Potent and Selective PDE10A Inhibitor for the Treatment of Schizophrenia". Journal of Medicinal Chemistry. 66 (2): 1157–1171. doi:10.1021/acs.jmedchem.2c01521. PMC 9884086. PMID 36624931.

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v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme 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)

Inhibitors

Research

References

Further reading