Isolevuglandin adducts in disease

Antioxid Redox Signal. 2015 Jun 20;22(18):1703-18. doi: 10.1089/ars.2014.6154. Epub 2015 Feb 18.

Abstract

Significance: A diverse family of lipid-derived levulinaldehydes, isolevuglandins (isoLGs), is produced by rearrangement of endoperoxide intermediates generated through both cyclooxygenase (COX) and free radical-induced cyclooxygenation of polyunsaturated fatty acids and their phospholipid esters. The formation and reactions of isoLGs with other biomolecules has been linked to alcoholic liver disease, Alzheimer's disease, age-related macular degeneration, atherosclerosis, cardiac arythmias, cancer, end-stage renal disease, glaucoma, inflammation of allergies and infection, mitochondrial dysfunction, multiple sclerosis, and thrombosis. This review chronicles progress in understanding the chemistry of isoLGs, detecting their production in vivo and understanding their biological consequences.

Critical issues: IsoLGs have never been isolated from biological sources, because they form adducts with primary amino groups of other biomolecules within seconds. Chemical synthesis enabled investigation of isoLG chemistry and detection of isoLG adducts present in vivo.

Recent advances: The first peptide mapping and sequencing of an isoLG-modified protein present in human retina identified the modification of a specific lysyl residue of the sterol C27-hydroxylase Cyp27A1. This residue is preferentially modified by iso[4]LGE2 in vitro, causing loss of function. Adduction of less than one equivalent of isoLG can induce COX-associated oligomerization of the amyloid peptide Aβ1-42. Adduction of isoLGE2 to phosphatidylethanolamines causes gain of function, converting them into proinflammatory isoLGE2-PE agonists that foster monocyte adhesion to endothelial cells.

Future directions: Among the remaining questions on the biochemistry of isoLGs are the dependence of biological activity on isoLG isomer structure, the structures and mechanism of isoLG-derived protein-protein and DNA-protein cross-link formation, and its biological consequences.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Amyloid / chemistry
  • Amyloid / metabolism
  • Animals
  • Blood-Brain Barrier / pathology
  • DNA-Binding Proteins / metabolism
  • Fatty Acids, Unsaturated / metabolism*
  • Humans
  • Inflammation / metabolism
  • Mitochondria / metabolism
  • Oxidative Stress*
  • Phosphatidylethanolamines / chemistry
  • Phosphatidylethanolamines / metabolism
  • Prostaglandin-Endoperoxide Synthases / metabolism
  • Prostaglandins E / chemistry*
  • Prostaglandins E / metabolism*
  • Protein Binding
  • Pyrrolidines / chemistry*
  • Pyrrolidines / metabolism*
  • Tubulin / chemistry
  • Tubulin / metabolism

Substances

  • Amyloid
  • DNA-Binding Proteins
  • Fatty Acids, Unsaturated
  • Phosphatidylethanolamines
  • Prostaglandins E
  • Pyrrolidines
  • Tubulin
  • Prostaglandin-Endoperoxide Synthases