4.5 Article

Low-density lipoprotein has an enormous capacity to bind (E)-4-Hydroxynon-2-enal (HNE):: Detection and characterization of lysyl and histidyl adducts containing multiple molecules of HNE

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CHEMICAL RESEARCH IN TOXICOLOGY
卷 21, 期 7, 页码 1384-1395

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AMER CHEMICAL SOC
DOI: 10.1021/tx8000303

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  1. NEI NIH HHS [R01 EY014239, EY 014239] Funding Source: Medline
  2. NHLBI NIH HHS [HL53315, R01 HL053315] Funding Source: Medline
  3. NIGMS NIH HHS [R01 GM021249, GM 21249] Funding Source: Medline

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(E)-4-Hydroxynon-2-enal (HNE), an electrophilic bifunctional cytotoxic lipid peroxidation product, forms covalent adducts with nucleophilic side chains of amino acid residues. HNE-derived adducts have been implicated in many pathophysiological processes including atherosclerosis, diabetes, and Alzheimer's disease. Tritium- and deuterium-labeled HNE (d(4)-HNE) were used orthogonally to study adduction with proteins and individual nucleophilic groups of histidyl, lysyl, and cysteine residues. Using tritium-labeled HNE, we detected the binding of 486 molecules of HNE per low-density lipoprotein (LDL) particle, significantly more than the total number of all reactive nucleophiles in the LDL particle. This suggests the formation of adducts that incorporate multiple molecules of HNE with some nucleophilic amino acid side chains. We also found that the reaction of a 1:1 mixture of d4-HNE and d(0)-HNE with N-acetylhistidine, N-acetyl-Gly-Lys-OMe, or N-acetyl cysteine generates 1:1, 2:1, and 3:1 adducts, which exhibit unique mass spectral signatures that aid in structural characterization. A domino-like reaction of initial 1:1 HNE Michael adducts of histidyl or lysyl nucleophiles with multiple additional HNE molecules forms 2:1 and 3:1 adducts that were structurally characterized by tandem mass spectrometry.

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