ArticleThe Journal of biological chemistry2018
Lysophosphatidic acid produced by autotaxin acts as an allosteric modulator of its catalytic efficiency.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 50 citations in OpenAlex.
- Species-selective plasma metabolism drives lysophosphatidylcholine depletion after cardiac arrest.The Journal of biological chemistry · 2026Article
- Differential effects of lysophospholipid headgroups, acyl chain length and saturation on vacuole acidification, CaFrontiers in cell and developmental biology · 2026Article
- Coupled Electrostatic and Hydrophobic Destabilisation of the Gelsolin-Actin Complex Enables Facile Detection of Ovarian Cancer Biomarker Lysophosphatidic Acid.Biomolecules · 2023Article
- Autotaxin inhibitor IOA-289 reduces gastrointestinal cancer progression in preclinical models.Journal of experimental & clinical cancer research : CR · 2023Article
- Adipokine chemerin overexpression in trophoblasts leads to dyslipidemia in pregnant mice: implications for preeclampsia.Lipids in health and disease · 2023Article
- A type IV Autotaxin inhibitor ameliorates acute liver injury and nonalcoholic steatohepatitis.EMBO molecular medicine · 2022Article
- Structure-Based Design of a Novel Class of Autotaxin Inhibitors Based on Endogenous Allosteric Modulators.Journal of medicinal chemistry · 2022Article
- AGE/Non-AGE Glycation: An Important Event in Rheumatoid Arthritis Pathophysiology.Inflammation · 2022Review
- Phospholipase A1 Member A Activates Fibroblast-like Synoviocytes through the Autotaxin-Lysophosphatidic Acid Receptor Axis.International journal of molecular sciences · 2021Article
- Design and Development of Autotaxin Inhibitors.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8Cell reports · 2021Article
- 2-Carba-lysophosphatidic acid is a novel β-lysophosphatidic acid analogue with high potential for lysophosphatidic acid receptor activation and autotaxin inhibition.Scientific reports · 2021Article
- Hepatitis B Virus Promotes Hepatocellular Carcinoma Progression Synergistically With Hepatic Stellate CellsFrontiers in molecular biosciences · 2021Article
- Structure-Based Discovery of Novel Chemical Classes of Autotaxin Inhibitors.International journal of molecular sciences · 2020Article
- Review
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Autotaxin (ATX) is a secreted glycoprotein and the only member of the ectonucleotide pyrophosphatase/phosphodiesterase family that converts lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA controls key responses, such as cell migration, proliferation, and survival, implicating ATX-LPA signaling in various (patho)physiological processes and establishing it as a drug target. ATX structural and functional studies have revealed an orthosteric and an allosteric site, called the "pocket" and the "tunnel," respectively. However, the mechanisms in allosteric modulation of ATX's activity as a lysophospholipase D are unclear. Here, using the physiological LPC substrate, a new fluorescent substrate, and diverse ATX inhibitors, we revisited the kinetics and allosteric regulation of the ATX catalytic cycle, dissecting the different steps and pathways leading to LPC hydrolysis. We found that ATX activity is stimulated by LPA and that LPA activates ATX lysophospholipase D activity by binding to the ATX tunnel. A consolidation of all experimental kinetics data yielded a comprehensive catalytic model supported by molecular modeling simulations and suggested a positive feedback mechanism that is regulated by the abundance of the LPA products activating hydrolysis of different LPC species. Our results complement and extend the current understanding of ATX hydrolysis in light of the allosteric regulation by ATX-produced LPA species and have implications for the design and application of both orthosteric and allosteric ATX inhibitors.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.