Biology:Autotaxin

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Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (E-NPP 2), is an enzyme that in humans is encoded by the ENPP2 gene.[1][2]

Structure

Autotaxin is a multi-domain protein with a modular architecture. From the N- to the C-terminus, it comprises two consecutive N-terminal cysteine-rich somatomedin B-like (SMB) domains, followed by a central catalytic phosphodiesterase (PDE) domain and a C-terminal nuclease-like (NUC) domain. The two SMB domains mediate protein–protein interactions, particularly through integrin-dependent binding to cell surfaces. The catalytic PDE domain, which is structurally related to alkaline phosphatases, harbors the enzyme’s lysophospholipase D activity responsible for converting lysophosphatidylcholine into lysophosphatidic acid (LPA). The C-terminal NUC domain, although catalytically inactive, is structurally linked to the PDE domain and contributes to substrate binding and overall protein stability. A region at the extreme C-terminus, sometimes referred to as the MORFO domain, overlaps with the NUC region and has been associated with oligodendrocyte remodeling. Thus, the domain organization from N- to C-terminus is: SMB1–SMB2–PDE–NUC, with the MORFO domain often considered part of or overlapping with the NUC domain.[3][4]

The crystal structures of rat and mouse autotaxin have been determined,[5] including both apo and ligand-bound forms. Each structure reveals four domains: two N-terminal somatomedin-B-like domains likely involved in cell-surface localization, the catalytic PDE domain containing a deep hydrophobic pocket for lipid substrate binding, and the C-terminal inactive NUC domain, which appears to stabilize the overall structure.

Function

Autotaxin is a secreted enzyme important for generating the lipid signaling molecule lysophosphatidic acid (LPA). Autotaxin has lysophospholipase D activity that converts lysophosphatidylcholine into LPA.

Autotaxin was originally identified as a tumor cell-motility-stimulating factor; later it was shown to be LPA (which signals through lysophospholipid receptors), the lipid product of the reaction catalyzed by autotaxin, which is responsible for its effects on cell-proliferation.

The protein encoded by this gene functions as a phosphodiesterase. Autotaxin is secreted and further processed to make the biologically active form. Several alternatively spliced transcript variants have been identified. Autotaxin is able to cleave the phosphodiester bond between the α and the β position of triphosphate nucleotides, acting as an ectonucleotide phosphodiesterase producing pyrophosphate, as most members of the ENPP family[6]. Importantly, autotaxin also acts as phospholipase, catalyzing the removal of the head group of various lysolipids. The physiological function of autotaxin is the production of the signalling lipid lysophosphatidic acid (LPA) in extracellular fluids. LPA evokes growth factor-like responses including stimulation of cell proliferation and chemotaxis. This gene product stimulates the motility of tumor cells, has angiogenic properties, and its expression is up-regulated in several kinds of tumours.[2] Also, autotaxin and LPA are involved in numerous inflammatory-driven diseases such as asthma and arthritis.[7] Physiologically, LPA helps promote wound healing responses to tissue damage. Under normal circumstances, LPA negatively regulates autotaxin transcription, but in the context of wound repair, cytokines induce autotaxin expression to increase overall LPA concentrations.[8]

As a drug target

Autotaxin contains a tripartite binding site composed of a zinc-dependent catalytic center, a hydrophilic groove, and a hydrophobic pocket[9]. Based on how inhibitors interact with this site, ATX inhibitors can be classified into six types: Type I compounds occupy the orthosteric site, mimicking the LPC substrate binding[10][11]; Type II inhibitors bind solely to the hydrophobic pocket, blocking LPC accommodation[12][13]; Type III inhibitors occupy the allosteric regulatory tunnel, modulating ATX activity non-competitively[14][15]; Type IV compounds occupy both the binding pocket and the tunnel without contacting the catalytic site[16][17]; Type V inhibitors occupy the allosteric tunnel and the orthosteric site[18]; and Type VI compounds engage all three regions—the orthosteric site, allosteric tunnel, and hydrophobic pocket[19].

A type IV inhibitor, Ziritaxestat (GLPG1690), against idiopathic pulmonary fibrosis[17] showed promising results in a phase II trial that ended in May 2018[20]. It has been shown that THC is also a partial autotaxin inhibitor, with an apparent IC50 of 407 ± 67 nM for the ATX-gamma isoform.[21] THC was also co-crystallized with autotaxin, deciphering the binding interface of the complex. These results might explain some of the effects of THC on inflammation and neurological diseases, since autotaxin is responsible of LPA generation, a key lipid mediator involved in numerous diseases and physiological processes. However, clinical trials need to be performed in order to assess the importance of ATX inhibition by THC during medicinal cannabis consumption. Development of cannabinoid inspired autotaxin inhibitors could also be an option in the future. A DNA aptamer inhibitor of Autotaxin has also been described.[22]

See also

References

  1. ↑ "Molecular cloning and chromosomal assignment of the human brain-type phosphodiesterase I/nucleotide pyrophosphatase gene (PDNP2)". Genomics 30 (2): 380–384. November 1995. doi:10.1006/geno.1995.0036. PMID 8586446. 
  2. ↑ 2.0 2.1 "Entrez Gene: ENPP2 ectonucleotide pyrophosphatase/phosphodiesterase 2 (autotaxin)". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=5168. 
  3. ↑ "Autotaxin (ATX): a multi-functional and multi-modular protein possessing enzymatic lysoPLD activity and matricellular properties". Biochimica et Biophysica Acta 1781 (9): 525–30. September 2008. doi:10.1016/j.bbalip.2008.04.009. PMID 18485925. 
  4. ↑ "Structure-function relationships of autotaxin, a secreted lysophospholipase D". Advances in Biological Regulation 53 (1): 112–7. January 2013. doi:10.1016/j.jbior.2012.09.010. PMID 23069371. 
  5. ↑ "Crystal structure of autotaxin and insight into GPCR activation by lipid mediators". Nature Structural & Molecular Biology 18 (2): 205–212. February 2011. doi:10.1038/nsmb.1998. PMID 21240269. 
  6. ↑ "Structure and function of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family: Tidying up diversity" (in English). Journal of Biological Chemistry 298 (2). 2022-02-01. doi:10.1016/j.jbc.2021.101526. ISSN 0021-9258. PMID 34958798. 
  7. ↑ "Autotaxin in the crosshairs: taking aim at cancer and other inflammatory conditions". FEBS Letters 588 (16): 2712–2727. August 2014. doi:10.1016/j.febslet.2014.02.009. PMID 24560789. Bibcode: 2014FEBSL.588.2712B. 
  8. ↑ "Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate". Journal of Lipid Research 56 (6): 1134–1144. June 2015. doi:10.1194/jlr.M057661. PMID 25896349. 
  9. ↑ "The Structural Binding Mode of the Four Autotaxin Inhibitor Types that Differentially Affect Catalytic and Non-Catalytic Functions" (in en). Cancers 11 (10): 1577. 2019-10-16. doi:10.3390/cancers11101577. ISSN 2072-6694. PMID 31623219. 
  10. ↑ "Carba analogs of cyclic phosphatidic acid are selective inhibitors of autotaxin and cancer cell invasion and metastasis". The Journal of Biological Chemistry 281 (32): 22786–22793. 2006-08-11. doi:10.1074/jbc.M512486200. ISSN 0021-9258. PMID 16782709. Bibcode: 2006JBiCh.28122786B. 
  11. ↑ "A Metabolically-Stabilized Phosphonate Analog of Lysophosphatidic Acid Attenuates Collagen-Induced Arthritis" (in en). PLOS ONE 8 (7). 2013-07-29. doi:10.1371/journal.pone.0070941. ISSN 1932-6203. PMID 23923032. Bibcode: 2013PLoSO...870941N. 
  12. ↑ "Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding" (in English). Molecular Pharmacology 88 (6): 982–992. 2015-12-01. doi:10.1124/mol.115.100404. ISSN 0026-895X. PMID 26371182. https://molpharm.aspetjournals.org/article/S0026-895X(24)03209-7/abstract. 
  13. ↑ "Aromatic phosphonates inhibit the lysophospholipase D activity of autotaxin". Bioorganic & Medicinal Chemistry Letters. Tetrahedron Young Investigator Award 2011: Carolyn R. Bertozzi 21 (17): 5098–5101. 2011-09-01. doi:10.1016/j.bmcl.2011.03.068. ISSN 0960-894X. PMID 21489790. 
  14. ↑ "Structural Basis for Inhibition of Human Autotaxin by Four Potent Compounds with Distinct Modes of Binding" (in English). Molecular Pharmacology 88 (6): 982–992. 2015-12-01. doi:10.1124/mol.115.100404. ISSN 0026-895X. PMID 26371182. https://molpharm.aspetjournals.org/article/S0026-895X(24)03209-7/abstract. 
  15. ↑ "Structure–Activity Relationships of Small Molecule Autotaxin Inhibitors with a Discrete Binding Mode". Journal of Medicinal Chemistry 60 (2): 722–748. 2017-01-26. doi:10.1021/acs.jmedchem.6b01597. ISSN 0022-2623. PMID 27982588. 
  16. ↑ "Rational Design of Autotaxin Inhibitors by Structural Evolution of Endogenous Modulators". Journal of Medicinal Chemistry 60 (5): 2006–2017. 2017-03-09. doi:10.1021/acs.jmedchem.6b01743. ISSN 0022-2623. PMID 28165241. 
  17. ↑ 17.0 17.1 "Autotaxin facilitates selective LPA receptor signaling" (in English). Cell Chemical Biology 30 (1): 69–84.e14. 2023-01-19. doi:10.1016/j.chembiol.2022.12.006. ISSN 2451-9456. PMID 36640760. https://www.cell.com/cell-chemical-biology/abstract/S2451-9456(22)00456-1. 
  18. ↑ "Structure-Based Design of a Novel Class of Autotaxin Inhibitors Based on Endogenous Allosteric Modulators". Journal of Medicinal Chemistry 65 (8): 6338–6351. 2022-04-28. doi:10.1021/acs.jmedchem.2c00368. ISSN 0022-2623. PMID 35440138. 
  19. ↑ "Design, Synthesis, and Biological Implications of Autotaxin inhibitors with a Three-Point lock binding mode". Bioorganic & Medicinal Chemistry 124. 2025-07-01. doi:10.1016/j.bmc.2025.118181. ISSN 0968-0896. PMID 40233422. https://www.sciencedirect.com/science/article/pii/S0968089625001221. 
  20. ↑ Clinical trial number NCT02738801 for "Study to Assess Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Properties of GLPG1690" at ClinicalTrials.gov
  21. ↑ "Linking medicinal cannabis to autotaxin-lysophosphatidic acid signaling". Life Science Alliance 6 (2). February 2023. doi:10.26508/lsa.202201595. PMID 36623871. 
  22. ↑ "Structural basis for specific inhibition of Autotaxin by a DNA aptamer". Nature Structural & Molecular Biology 23 (5): 395–401. May 2016. doi:10.1038/nsmb.3200. PMID 27043297. 

Further reading



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