Wikipedia

Autotaxin

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.[5][6]

ENPP2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesENPP2, ATX, ATX-X, AUTOTAXIN, LysoPLD, NPP2, PD-IALPHA, PDNP2, ectonucleotide pyrophosphatase/phosphodiesterase 2
External IDsOMIM: 601060; MGI: 1321390; HomoloGene: 4526; GeneCards: ENPP2; OMA:ENPP2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5168

18606

Ensembl

ENSG00000136960

ENSMUSG00000022425

UniProt

Q13822

Q9R1E6

RefSeq (mRNA)

NM_001040092
NM_001130863
NM_006209
NM_001330600

NM_001136077
NM_015744
NM_001285994
NM_001285995

RefSeq (protein)

NP_001035181
NP_001124335
NP_001317529
NP_006200

NP_001129549
NP_001272923
NP_001272924
NP_056559

Location (UCSC)Chr 8: 119.56 – 119.67 MbChr 15: 54.84 – 54.95 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

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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. 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

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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

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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.

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000136960 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022425 – 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.
  5. ^ 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. PMID 8586446.
  6. ^ a b "Entrez Gene: ENPP2 ectonucleotide pyrophosphatase/phosphodiesterase 2 (autotaxin)".
  7. ^ 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. PMID 24560789. S2CID 35544825.
  8. ^ Benesch MG, Zhao YY, Curtis JM, McMullen TP, Brindley DN (June 2015). "Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate". Journal of Lipid Research. 56 (6): 1134–44. doi:10.1194/jlr.M057661. PMC 4442871. PMID 25896349.
  9. ^ Clinical trial number NCT02738801 for "Study to Assess Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Properties of GLPG1690" at ClinicalTrials.gov
  10. ^ 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. PMID 27043297. S2CID 24948842.
  11. ^ Eymery MC, McCarthy AA, Hausmann J (February 2023). "Linking medicinal cannabis to autotaxin-lysophosphatidic acid signaling". Life Science Alliance. 6 (2): e202201595. doi:10.26508/lsa.202201595. PMC 9834664. PMID 36623871.
  12. ^ 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. PMID 21240269. S2CID 6336916.

Further reading

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