Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (E-NPP 2), is an enzyme that in humans is encoded by the ENPP2gene.[5][6]
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. 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.[6] 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
Various small molecule inhibitors of autotaxin have been developed for clinical applications. A specific inhibitor against idiopathic pulmonary fibrosis showed promising results in a phase II trial that ended in May 2018.[9] A DNA aptamer inhibitor of Autotaxin has also been described.[10]
Recently, 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.[11] 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.
Structure
The crystal structures of rat and mouse autotaxin[12] have been solved. In each case, the apo structure has been solved along with those of product- or inhibitor-bound complexes. Both proteins consist of 4 domains, including 2 N-terminal somatomedin-B-like (SMB) domains which may be involved in cell-surface localisation. The catalytic domain follows and contains a deep hydrophobic pocket in which the lipid substrate binds. At the C-terminus is the inactive nuclease domain which may function to aid protein stability.
^"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.
^Kawagoe H, Soma O, Goji J, Nishimura N, Narita M, Inazawa J, et al. (November 1995). "Molecular cloning and chromosomal assignment of the human brain-type phosphodiesterase I/nucleotide pyrophosphatase gene (PDNP2)". Genomics. 30 (2): 380–4. doi:10.1006/geno.1995.0036. hdl:20.500.14094/D1001481. PMID8586446.
^Benesch MG, Ko YM, McMullen TP, Brindley DN (August 2014). "Autotaxin in the crosshairs: taking aim at cancer and other inflammatory conditions". FEBS Letters. 588 (16): 2712–27. doi:10.1016/j.febslet.2014.02.009. PMID24560789. S2CID35544825.
^Clinical trial number NCT02738801 for "Study to Assess Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Properties of GLPG1690" at ClinicalTrials.gov
^Kato K, Ikeda H, Miyakawa S, Futakawa S, Nonaka Y, Fujiwara M, et al. (May 2016). "Structural basis for specific inhibition of Autotaxin by a DNA aptamer". Nature Structural & Molecular Biology. 23 (5): 395–401. doi:10.1038/nsmb.3200. PMID27043297. S2CID24948842.
^Nishimasu H, Okudaira S, Hama K, Mihara E, Dohmae N, Inoue A, et al. (February 2011). "Crystal structure of autotaxin and insight into GPCR activation by lipid mediators". Nature Structural & Molecular Biology. 18 (2): 205–12. doi:10.1038/nsmb.1998. PMID21240269. S2CID6336916.
Nam SW, Clair T, Kim YS, McMarlin A, Schiffmann E, Liotta LA, et al. (September 2001). "Autotaxin (NPP-2), a metastasis-enhancing motogen, is an angiogenic factor". Cancer Research. 61 (18): 6938–44. PMID11559573.
Yang SY, Lee J, Park CG, Kim S, Hong S, Chung HC, et al. (2003). "Expression of autotaxin (NPP-2) is closely linked to invasiveness of breast cancer cells". Clinical & Experimental Metastasis. 19 (7): 603–8. doi:10.1023/A:1020950420196. PMID12498389. S2CID25181446.
Gijsbers R, Aoki J, Arai H, Bollen M (March 2003). "The hydrolysis of lysophospholipids and nucleotides by autotaxin (NPP2) involves a single catalytic site". FEBS Letters. 538 (1–3): 60–4. doi:10.1016/S0014-5793(03)00133-9. PMID12633853. S2CID38206060.
Koh E, Clair T, Woodhouse EC, Schiffmann E, Liotta L, Stracke M (May 2003). "Site-directed mutations in the tumor-associated cytokine, autotaxin, eliminate nucleotide phosphodiesterase, lysophospholipase D, and motogenic activities". Cancer Research. 63 (9): 2042–5. PMID12727817.
Kehlen A, Englert N, Seifert A, Klonisch T, Dralle H, Langner J, et al. (May 2004). "Expression, regulation and function of autotaxin in thyroid carcinomas". International Journal of Cancer. 109 (6): 833–8. doi:10.1002/ijc.20022. PMID15027116. S2CID25281125.
