Autotaxin
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Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase family member 2 (E-NPP 2), is an
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that in humans is encoded by the ''ENPP2''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.


Function

Autotaxin is a secreted enzyme important for generating the
lipid signaling Lipid signaling, broadly defined, refers to any biological cell signaling event involving a lipid messenger that binds a protein target, such as a receptor (biochemistry), receptor, kinase or phosphatase, which in turn mediate the effects of these ...
molecule lysophosphatidic acid (LPA). Autotaxin has lyso
phospholipase D Phospholipase D (PLD) (EC 3.1.4.4; also known as lipophosphodiesterase II, lecithinase D, choline phosphatase; systematic name: phosphatidylcholine phosphatidohydrolase) is an anesthetic-sensitive and mechanosensitive enzyme of the phospholipa ...
activity that converts lyso
phosphatidylcholine Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can easily be obtained from a variety of readily available sources, such as egg yolk or soyb ...
into LPA. Autotaxin was originally identified as a tumor cell-motility-stimulating factor; later it was shown to be LPA (which signals through
lysophospholipid receptor 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 receptor (biochemistry), receptors, each encode ...
s), the
lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...
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 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 oth ...
. 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 In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate () and tetrasodium pyrophosphate (), among others. Often pyrophosphates a ...
, as most members of the ENPP family. Importantly, autotaxin also acts as
phospholipase A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C, and D, which are distinguished by the type of reaction which they catalyze: *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 Chemotaxis (from ''chemical substance, chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell organism, single-cell or multicellular organisms direct thei ...
. This gene product stimulates the motility of tumor cells, has angiogenic properties, and its expression is up-regulated in several kinds of tumours. Also, autotaxin and LPA are involved in numerous inflammatory-driven diseases such as asthma and arthritis. 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.


As a drug target

Various small molecule inhibitors of autotaxin have been developed for clinical applications. A specific inhibitor against
idiopathic pulmonary fibrosis Idiopathic pulmonary fibrosis (IPF) synonymous with cryptogenic fibrosing alveolitis is a rare, progressive illness of the respiratory system, characterized by the thickening and stiffening of lung tissue, associated with the formation of scar ...
showed promising results in a phase II trial that ended in May 2018. A DNA
aptamer Aptamers are oligomers of artificial ssDNA, RNA, Xeno nucleic acid, XNA, or peptide that ligand, bind a specific target molecule, or family of target molecules. They exhibit a range of affinities (Dissociation constant, KD in the pM to μM rang ...
inhibitor of Autotaxin has also been described. 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. 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 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 The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...
is the inactive nuclease domain which may function to aid protein stability.


See also

* Lysophosphatidic acid *
Lysophospholipid receptor 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 receptor (biochemistry), receptors, each encode ...
s *
Lipid signaling Lipid signaling, broadly defined, refers to any biological cell signaling event involving a lipid messenger that binds a protein target, such as a receptor (biochemistry), receptor, kinase or phosphatase, which in turn mediate the effects of these ...
*
Phospholipase A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C, and D, which are distinguished by the type of reaction which they catalyze: *Phospholipase ...
s


References


Further reading

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External links

* {{Portal bar, Biology, border=no EC 3.1.4