Cover Picture: Proteomics – Clinical Applications 6/09

AbstractNow you see it, now you don't: a lipoprotein shell game (Mars vs. Venus)“Cause and Effect” is a difficult game to play when you don't know all the rules. It has been over 30 years since physicians first began to warn patients of potential problems on the basis of elevated lipoproteins and triglycerides. In this report, Karlsson et al. examined the LDL portion of the problem with proteomic tools and found more puzzling results: several LDL components were more abundant in obese men than normal men, but normal and obese women were unchanged; a previously unseen protein, transthyretin, was associated with obese male LDL, not female. Enough unexplained differences are seen that the authors warn against depending on cholesterol‐based markers and single value biomarkers. Who knows how many peas the conman has up his sleeves?Karlsson, H. et al., Proteomics Clin. Appl. 2009, 3, 663–671.Alzheimer's toxic aldehydes ‐ toxic assetsOne of the principal security weaknesses of the brain's chemical defense system is the redox situation. Mix low levels of antioxidants and high levels of polyunsaturated fatty acids in the presence of reactive oxygen species and you have a recipe for electrophilic aldehydes, which add to cysteine, lysine and histidine residues. The biggest hazard appears to be the peroxidation of lipids, which yields several products, including 4‐hydroxynonenol (HNE). HNE adducts are found in AD brains. Perluigi et al. used proteomic tools (2‐DE,MALDI‐TOF,Western blots, etc.) to look at HNE‐bound proteins in postmortem AD patients. They found them in the hippocampus and inferior parietal lobule where the mitochondrial, defensive and energy production enzymes were severely, but specifi‐cally, disordered. The good news ‐ we have more targets to aim for.Perluigi, M. et al., Proteomics Clin. Appl. 2009, 3, 682–693.Flucloxacillin: an antibiotic with a backlashFlucloxacillin is a penicillinase‐resistant antibiotic that is frequently used to control staphylococcal infections of the skin, respiratory and urinary tract, usually with no untoward effects. On occasion, however, often after a delay of several weeks following completion of a course of treatment, side effects become apparent and have a long recovery time. In some, mostly elderly, patients, fatal liver failure may occur. Jenkins et al. applied proteomic tools to look into the mechanism of this toxicity. The antibiotic and a metabolite are known to react with lysine. They confirmed these results in vitro and in vivo and further showed that the covalent drug binding to serum proteins was site specific, as was modification by a 5 ‐hydroxymethyl metabolite of the drug. The authors suggest that the modification of serum proteins may contribute to formation of neoantigens and immune hypersensitivity reactions.Jenkins, R. E. et al., Proteomics Clin. Appl. 2009, 3, 720–729.