Autotaxin structure-activity relationships revealed through lysophosphatidylcholine analogs

E. Jeffrey North, Daniel A. Osborne, Peter K. Bridson, Daniel L. Baker, Abby L. Parrill

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Autotaxin (ATX) catalyzes the hydrolysis of lysophosphatidylcholine (LPC) to form the bioactive lipid lysophosphatidic acid (LPA). LPA stimulates cell proliferation, cell survival, and cell migration and is involved in obesity, rheumatoid arthritis, neuropathic pain, atherosclerosis and various cancers, suggesting that ATX inhibitors have broad therapeutic potential. Product feedback inhibition of ATX by LPA has stimulated structure-activity studies focused on LPA analogs. However, LPA displays mixed mode inhibition, indicating that it can bind to both the enzyme and the enzyme-substrate complex. This suggests that LPA may not interact solely with the catalytic site. In this report we have prepared LPC analogs to help map out substrate structure-activity relationships. The structural variances include length and unsaturation of the fatty tail, choline and polar linker presence, acyl versus ether linkage of the hydrocarbon chain, and methylene and nitrogen replacement of the choline oxygen. All LPC analogs were assayed in competition with the synthetic substrate, FS-3, to show the preference ATX has for each alteration. Choline presence and methylene replacement of the choline oxygen were detrimental to ATX recognition. These findings provide insights into the structure of the enzyme in the vicinity of the catalytic site as well as suggesting that ATX produces rate enhancement, at least in part, by substrate destabilization.

Original languageEnglish
Pages (from-to)3433-3442
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number9
DOIs
StatePublished - May 1 2009
Externally publishedYes

Fingerprint

Lysophosphatidylcholines
Structure-Activity Relationship
Choline
Substrates
Catalytic Domain
Enzymes
Oxygen
Cell proliferation
Neuralgia
Hydrocarbons
Ether
Cell Movement
lysophosphatidic acid
Hydrolysis
Rheumatoid Arthritis
Cell Survival
Atherosclerosis
Nitrogen
Obesity
Display devices

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Autotaxin structure-activity relationships revealed through lysophosphatidylcholine analogs. / North, E. Jeffrey; Osborne, Daniel A.; Bridson, Peter K.; Baker, Daniel L.; Parrill, Abby L.

In: Bioorganic and Medicinal Chemistry, Vol. 17, No. 9, 01.05.2009, p. 3433-3442.

Research output: Contribution to journalArticle

North, E. Jeffrey ; Osborne, Daniel A. ; Bridson, Peter K. ; Baker, Daniel L. ; Parrill, Abby L. / Autotaxin structure-activity relationships revealed through lysophosphatidylcholine analogs. In: Bioorganic and Medicinal Chemistry. 2009 ; Vol. 17, No. 9. pp. 3433-3442.
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