Autotaxin

Jump to: navigation, search

Template:Infobox gene 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]

Function

Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (NPP2 or ENPP2), 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.[2] Also, autotaxin and LPA are involved in numerous inflammatory-driven diseases such as asthma and arthritis.[3] 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.[4]

It has been shown that autotaxin's function can be regulated by certain steroids, namely bile acids.[5]

As a drug target

Various small molecule inhibitors of autotaxin have been developed for clinical applications. A specific inhibitor against idiopathic pulmonary fibrosis is under phase II trials.[6] A DNA aptamer inhibitor of Autotaxin has also been described.[7]

Structure

The crystal structures rat[8] and mouse autotaxin[9] have been solved. In each case, the apo structure have been solved along with product or inhibitor bound complexes. Both proteins consist of 4 domains, 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

References

  1. Kawagoe H, Soma O, Goji J, Nishimura N, Narita M, Inazawa J, Nakamura H, Sano K (November 1995). "Molecular cloning and chromosomal assignment of the human brain-type phosphodiesterase I/nucleotide pyrophosphatase gene (PDNP2)". Genomics. 30 (2): 380–4. PMID 8586446. doi:10.1006/geno.1995.0036. 
  2. 2.0 2.1 "Entrez Gene: ENPP2 ectonucleotide pyrophosphatase/phosphodiesterase 2 (autotaxin)". 
  3. 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. PMID 24560789. doi:10.1016/j.febslet.2014.02.009. 
  4. 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. PMC 4442871Freely accessible. PMID 25896349. doi:10.1194/jlr.M057661. 
  5. Keune WJ, Hausmann J, Bolier R, Tolenaars D, Kremer A, Heidebrecht T, Joosten RP, Sunkara M, Morris AJ, Matas-Rico E, Moolenaar WH, Oude Elferink RP, Perrakis A (April 2016). "Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling". Nature Communications. 7: 11248. PMC 4834639Freely accessible. PMID 27075612. doi:10.1038/ncomms11248. 
  6. ClinicalTrials.gov NCT02738801 Study to Assess Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Properties of GLPG1690
  7. Kato K, Ikeda H, Miyakawa S, Futakawa S, Nonaka Y, Fujiwara M, Okudaira S, Kano K, Aoki J, Morita J, Ishitani R, Nishimasu H, Nakamura Y, Nureki O (May 2016). "Structural basis for specific inhibition of Autotaxin by a DNA aptamer". Nature Structural & Molecular Biology. 23 (5): 395–401. PMID 27043297. doi:10.1038/nsmb.3200. 
  8. Hausmann J, Kamtekar S, Christodoulou E, Day JE, Wu T, Fulkerson Z, Albers HM, van Meeteren LA, Houben AJ, van Zeijl L, Jansen S, Andries M, Hall T, Pegg LE, Benson TE, Kasiem M, Harlos K, Kooi CW, Smyth SS, Ovaa H, Bollen M, Morris AJ, Moolenaar WH, Perrakis A (February 2011). "Structural basis of substrate discrimination and integrin binding by autotaxin". Nature Structural & Molecular Biology. 18 (2): 198–204. PMC 3064516Freely accessible. PMID 21240271. doi:10.1038/nsmb.1980. 
  9. Nishimasu H, Okudaira S, Hama K, Mihara E, Dohmae N, Inoue A, Ishitani R, Takagi J, Aoki J, Nureki O (February 2011). "Crystal structure of autotaxin and insight into GPCR activation by lipid mediators". Nature Structural & Molecular Biology. 18 (2): 205–12. PMID 21240269. doi:10.1038/nsmb.1998. 

Further reading

External links

Template:Portal bar


Linked-in.jpg