Autotaxin

Last updated
ENPP2
3nkr.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases ENPP2 , ATX, ATX-X, AUTOTAXIN, LysoPLD, NPP2, PD-IALPHA, PDNP2, ectonucleotide pyrophosphatase/phosphodiesterase 2
External IDs OMIM: 601060 MGI: 1321390 HomoloGene: 4526 GeneCards: ENPP2
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
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 Mb Chr 15: 54.84 – 54.95 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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]

Contents

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. 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.

See also

Related Research Articles

<span class="mw-page-title-main">Phosphodiesterase</span> Class of enzymes

A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, phosphodiesterase refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases.

Phosphodiesterase 1, PDE1, EC 3.1.4.1, systematic name oligonucleotide 5-nucleotidohydrolase) is a phosphodiesterase enzyme also known as calcium- and calmodulin-dependent phosphodiesterase. It is one of the 11 families of phosphodiesterase (PDE1-PDE11). Phosphodiesterase 1 has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms. The various isoforms exhibit different affinities for cAMP and cGMP.

<span class="mw-page-title-main">Phosphodiesterase 2</span> Class of enzymes

The PDE2 enzyme is one of 21 different phosphodiesterases (PDE) found in mammals. These different PDEs can be subdivided to 11 families. The different PDEs of the same family are functionally related despite the fact that their amino acid sequences show considerable divergence. The PDEs have different substrate specificities. Some are cAMP selective hydrolases, others are cGMP selective hydrolases and the rest can hydrolyse both cAMP and cGMP.

<span class="mw-page-title-main">Lysophosphatidic acid</span> Chemical compound

A lysophosphatidic acid (LPA) is a phospholipid derivative that can act as a signaling molecule.

The lysophospholipid receptor (LPL-R) group are members of the G protein-coupled receptor family of integral membrane proteins that are important for lipid signaling. In humans, there are eleven LPL receptors, each encoded by a separate gene. These LPL receptor genes are also sometimes referred to as "Edg".

<span class="mw-page-title-main">S1PR1</span> Protein and coding gene in humans

Sphingosine-1-phosphate receptor 1, also known as endothelial differentiation gene 1 (EDG1) is a protein that in humans is encoded by the S1PR1 gene. S1PR1 is a G-protein-coupled receptor which binds the bioactive signaling molecule sphingosine 1-phosphate (S1P). S1PR1 belongs to a sphingosine-1-phosphate receptor subfamily comprising five members (S1PR1-5). S1PR1 was originally identified as an abundant transcript in endothelial cells and it has an important role in regulating endothelial cell cytoskeletal structure, migration, capillary-like network formation and vascular maturation. In addition, S1PR1 signaling is important in the regulation of lymphocyte maturation, migration and trafficking.

<span class="mw-page-title-main">LPAR1</span> Protein

Lysophosphatidic acid receptor 1 also known as LPA1 is a protein that in humans is encoded by the LPAR1 gene. LPA1 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA).

<span class="mw-page-title-main">LPAR4</span> Protein-coding gene in the species Homo sapiens

Lysophosphatidic acid receptor 4 also known as LPA4 is a protein that in humans is encoded by the LPAR4 gene. LPA4 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA).

<span class="mw-page-title-main">LPAR2</span> Protein-coding gene in the species Homo sapiens

Lysophosphatidic acid receptor 2 also known as LPA2 is a protein that in humans is encoded by the LPAR2 gene. LPA2 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA).

<span class="mw-page-title-main">LPAR6</span> Protein-coding gene in the species Homo sapiens

Lysophosphatidic acid receptor 6, also known as LPA6, P2RY5 and GPR87, is a protein that in humans is encoded by the LPAR6 gene. LPA6 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA).

<span class="mw-page-title-main">LPAR5</span> Protein-coding gene in the species Homo sapiens

Lysophosphatidic acid receptor 5 also known as LPA5 is a protein that in humans is encoded by the LPAR5 gene. LPA5 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA).

<span class="mw-page-title-main">LPAR3</span> Protein-coding gene in the species Homo sapiens

Lysophosphatidic acid receptor 3 also known as LPA3 is a protein that in humans is encoded by the LPAR3 gene. LPA3 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA).

<span class="mw-page-title-main">Ectonucleotide pyrophosphatase/phosphodiesterase 1</span>

Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 is an enzyme that in humans is encoded by the ENPP1 gene.

<span class="mw-page-title-main">PPAP2B</span> Protein-coding gene in the species Homo sapiens

Lipid phosphate phosphohydrolase 3 (LPP3), also known as phospholipid phosphatase 3 (PLPP3) and phosphatidic acid phosphatase type 2B, is an enzyme that in humans is encoded by the PPAP2B gene on chromosome 1. It is ubiquitously expressed in many tissues and cell types. LPP3 is a cell-surface glycoprotein that hydrolyzes extracellular lysophosphatidic acid (LPA) and short-chain phosphatidic acid. Its function allows it to regulate vascular and embryonic development by inhibiting LPA signaling, which is associated with a wide range of human diseases, including cardiovascular disease and cancer, as well as developmental defects. The PPAP2B gene also contains one of 27 loci associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">AGK (gene)</span> Protein-coding gene in the species Homo sapiens

The human gene AGK encodes the enzyme mitochondrial acylglycerol kinase.

<span class="mw-page-title-main">LIPH (gene)</span> Protein-coding gene in the species Homo sapiens

Lipase member H is an enzyme that in humans is encoded by the LIPH gene.

<span class="mw-page-title-main">Neutral cholesterol ester hydrolase 1</span> Protein-coding gene in the species Homo sapiens

Neutral cholesterol ester hydrolase 1 (NCEH) also known as arylacetamide deacetylase-like 1 (AADACL1) or KIAA1363 is an enzyme that in humans is encoded by the NCEH1 gene.

<span class="mw-page-title-main">Gintonin</span> Protein found in ginseng

Gintonin is a glycolipoprotein fraction isolated from Panax ginseng. The non-saponin ingredient was designated as gintonin, where gin was derived from ginseng, ton from the tonic effects of ginseng, and in from protein. The main component of gintonin is a complex of lysophosphatidic acids (LPA) and ginseng proteins such as ginseng major latex-like protein151 (GLP151) and ginseng ribonuclease-like storage protein.

<span class="mw-page-title-main">Nucleotide pyrophosphatase/phosphodiesterase</span> Class of enzymes

Nucleotide pyrophosphatase/phosphodiesterase (NPP) is a class of dimeric enzymes that catalyze the hydrolysis of phosphate diester bonds. NPP belongs to the alkaline phosphatase (AP) superfamily of enzymes. Humans express seven known NPP isoforms, some of which prefer nucleotide substrates, some of which prefer phospholipid substrates, and others of which prefer substrates that have not yet been determined. In eukaryotes, most NPPs are located in the cell membrane and hydrolyze extracellular phosphate diesters to affect a wide variety of biological processes. Bacterial NPP is thought to localize to the periplasm.

<span class="mw-page-title-main">Lysophosphatidic acid phosphatase type 6</span> Protein-coding gene in the species Homo sapiens

Lysophosphatidic acid phosphatase type 6 is an acid phosphatase enzyme that is encoded in humans by the ACP6 gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000136960 - Ensembl, May 2017
  2. 1 2 3 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, 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. doi:10.1006/geno.1995.0036. hdl: 20.500.14094/D1001481 . PMID   8586446.
  6. 1 2 "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, 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. 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. ISSN   2575-1077. PMC   9834664 . PMID   36623871.
  12. 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. doi:10.1038/nsmb.1998. PMID   21240269. S2CID   6336916.

Further reading