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Membrane-dependent Activities of Human 15-LOX-2 and Its Murine Counterpart: IMPLICATIONS FOR MURINE MODELS OF ATHEROSCLEROSIS.

Abstract
The enzyme encoded by the ALOX15B gene has been linked to the development of atherosclerotic plaques in humans and in a mouse model of hypercholesterolemia. In vitro, these enzymes, which share 78% sequence identity, generate distinct products from their substrate arachidonic acid: the human enzyme, a 15-S-hydroperoxy product; and the murine enzyme, an 8-S-product. We probed the activities of these enzymes with nanodiscs as membrane mimics to determine whether they can access substrate esterified in a bilayer and characterized their activities at the membrane interface. We observed that both enzymes transform phospholipid-esterified arachidonic acid to a 15-S-product. Moreover, when expressed in transfected HEK cells, both enzymes result in significant increases in the amounts of 15-hydroxyderivatives of eicosanoids detected. In addition, we show that 15-LOX-2 is distributed at the plasma membrane when the HEK293 cells are stimulated by the addition Ca(2+) ionophore and that cellular localization is dependent upon the presence of a putative membrane insertion loop. We also report that sequence differences between the human and mouse enzymes in this loop appear to confer distinct mechanisms of enzyme-membrane interaction for the homologues.
AuthorsGunes Bender, Erin E Schexnaydre, Robert C Murphy, Charis Uhlson, Marcia E Newcomer
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 291 Issue 37 Pg. 19413-24 (09 09 2016) ISSN: 1083-351X [Electronic] United States
PMID27435673 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
Chemical References
  • Arachidonic Acids
  • Calcium Ionophores
  • ALOX15B protein, human
  • Arachidonate 15-Lipoxygenase
Topics
  • Animals
  • Arachidonate 15-Lipoxygenase (chemistry, genetics, metabolism)
  • Arachidonic Acids (chemistry, genetics, metabolism)
  • Atherosclerosis (enzymology, genetics)
  • Calcium Ionophores (pharmacology)
  • Cell Membrane (chemistry, enzymology, genetics)
  • Disease Models, Animal
  • HEK293 Cells
  • Humans
  • Mice
  • Protein Structure, Secondary
  • Protein Transport (drug effects)

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