autotaxin

Target id: 2901

Nomenclature: autotaxin

Family: LPA synthesis

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     autotaxin has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 915 8q24.12 ENPP2 ectonucleotide pyrophosphatase/phosphodiesterase 2
Mouse - 914 15 D2 Enpp2 ectonucleotide pyrophosphatase/phosphodiesterase 2
Rat - 862 7q31 Enpp2 ectonucleotide pyrophosphatase/phosphodiesterase 2
Gene and Protein Information Comments
The table provides information for human variant 1, which is the longest transcript and encodes the longest isoform (1, also known as alpha). Similarly for the mouse gene, which has 4 reported transcript variants, we provide information for the longest protein isoform.
In humans and mice variant 2, which is translated to isoform β, is the major isoform found in tissue expression studies [5].
Previous and Unofficial Names
ATX | PDNP2 | PD-IALPHA | lysoPLD
Database Links
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 3.1.4.39
Description Reaction Reference
Hydrolysis of lysophosphatidylcholine to form lysophosphatidic acid 1-alkyl-sn-glycero-3-phosphoethanolamine + H2O <=> 1-alkyl-sn-glycerol 3-phosphate + ethanolamine

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
GLPG1690 Hs Inhibition 7.8 pKi 3
pKi 7.8 (Ki 1.5x10-8 M) [3]
Description: Inhibition of substrate (LPC) conversion to LPA.
example 1.11 [WO2014139978] Hs Inhibition 9.0 pIC50 6
pIC50 9.0 (IC50 1x10-9 M) [6]
PF-8380 Hs Inhibition 8.6 – 8.8 pIC50 4
pIC50 8.6 – 8.8 (IC50 2.8x10-9 – 1.7x10-9 M) [4]
Description: Assessed using ATXβ isoform.
example 2 [WO2013054185] Hs Inhibition 8.6 pIC50 7
pIC50 8.6 (IC50 2.59x10-9 M) [7]
Inhibitor Comments
GLPG1690 (structure not disclosed) has completed a first-in-human Phase 1 clinical trial (NCT02179502). Phase 2 trial NCT02738801 is evaluating the safety, tolerability, PK and PD of GLPG1690 in patients with idiopathic pulmonary fibrosis (IPF). Autotaxin inhibitor develpoment and exemplar compounds are discussed in [1].
Immunopharmacology Comments
Autotaxin is up-regulated in many inflammatory conditions, including cancer, arthritis, and multiple sclerosis. The product of autotaxin activity, LPA, has proliferative, chemotactic and angiogenic actions. Inhibitors of the ATX-LPA axis are being investigated as novel pharmaceuticals [1].
Immuno Process Associations
Immuno Process:  Antigen presentation
Immuno Process ID:  3
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  scavenger receptor activity (GO:0005044) IEA
References: 
Tissue Distribution
Brain and peripheral tissues (human and mouse):
predominately ATXβ isoform. ATXα found at low levels in central and peripheral nervous systems, and ATXγ also at low levels in the CNS.
Species:  Human
Technique:  RT-PCR
References:  5
Physiological Functions
Converts sphingosylphosphorylcholine (SPC) to sphingosine 1-phosphate (S1P)
Species:  Human
Tissue:  In vitro cell culture
References:  2
Hydrolyzes lysophosphatidylcholine to form the bioactive lipid lysophosphatidic acid (LPA).
Species:  Human
Tissue: 
References:  5

References

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1. Castagna D, Budd DC, Macdonald SJ, Jamieson C, Watson AJ. (2016) Development of Autotaxin Inhibitors: An Overview of the Patent and Primary Literature. J. Med. Chem.59 (12): 5604-21. [PMID:26745766]

2. Clair T, Aoki J, Koh E, Bandle RW, Nam SW, Ptaszynska MM, Mills GB, Schiffmann E, Liotta LA, Stracke ML. (2003) Autotaxin hydrolyzes sphingosylphosphorylcholine to produce the regulator of migration, sphingosine-1-phosphate. Cancer Res.63 (17): 5446-53. [PMID:14500380]

3. Desroy N, Housseman C, Bock X, Joncour A, Bienvenu N, Cherel L, Labeguere V, Rondet E, Peixoto C, Grassot JM et al.. (2017) Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis. J. Med. Chem.,  [Epub ahead of print]. [PMID:28414242]

4. Gierse J, Thorarensen A, Beltey K, Bradshaw-Pierce E, Cortes-Burgos L, Hall T, Johnston A, Murphy M, Nemirovskiy O, Ogawa S et al.. (2010) A novel autotaxin inhibitor reduces lysophosphatidic acid levels in plasma and the site of inflammation. J. Pharmacol. Exp. Ther.334 (1): 310-7. [PMID:20392816]

5. Giganti A, Rodriguez M, Fould B, Moulharat N, Cogé F, Chomarat P, Galizzi JP, Valet P, Saulnier-Blache JS, Boutin JA et al.. (2008) Murine and human autotaxin alpha, beta, and gamma isoforms: gene organization, tissue distribution, and biochemical characterization. J. Biol. Chem.283 (12): 7776-89. [PMID:18175805]

6. Hert J, Hunziker D, Mattei P, Mauser H, Tang G, Wang L. (2014) New octahydro-pyrrolo[3,4-c]-pyrrole derivatives and analogs thereof as autotaxin inhibitors. Patent number: WO2014139978 A1. Assignee: Hoffmann-La Roche Inc.. Priority date: 12/03/2013. Publication date: 18/09/2014.

7. Long S, Thorarensen A, Schnute ME. (2013) Pyrimidine and pyridine derivatives useful in therapy. Patent number: WO2013054185 A1. Assignee: Pfizer, Inc.. Priority date: 13/10/2011. Publication date: 18/04/2013.

How to cite this page

LPA synthesis: autotaxin. Last modified on 08/05/2017. Accessed on 22/10/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2901.