title: 2-aminoadipic acid is a marker of protein carbonyl oxidation in the aging human skin: effects of diabetes, renal failure and sepsis.
abstract: We hypothesized that the epsilon-amino group of lysine residues in longlived proteins oxidatively deaminates with age forming the carbonyl compound, allysine (alpha-aminoadipic acid-delta-semialdehyde), which can further oxidize into 2-aminoadipic acid. In the present study, we measured both products in insoluble human skin collagen from n=117 individuals of age range 10-90 years, of which n=61 and n=56 were non-diabetic and diabetic respectively, and a total of n=61 individuals had either acute or chronic renal failure. Allysine was reduced by borohydride into 6-hydroxynorleucine and both products were measured in acid hydrolysates by selective ion monitoring gas chromatography (GC)-MS. The results showed that 2-aminoadipic acid (P<0.0001), but not 6-hydroxynorleucine (P=0.14), significantly increased with age reaching levels of 1 and 0.3 mmol/mol lysine at late age respectively. Diabetes in the absence of renal failure significantly (P<0.0001) increased 2-aminoadipic acid up to <3 mmol/mol, but not 6-hydroxynorleucine (levels<0.4 mmol/mol, P=0.18). Renal failure even in the absence of diabetes markedly increased levels reaching up to <0.5 and 8 mmol/mol for 6-hydroxynorleucine and 2-aminoadipic acid respectively. Septicaemia significantly (P<0.0001) elevated 2-aminoadipic acid in non-diabetic, but not diabetic individuals, and mildly correlated with other glycoxidation markers, carboxymethyl-lysine and the methylglyoxal-derived products, carboxyethyl-lysine, argpyrimidine and MODIC (methylglyoxal-derived imidazolium cross-link). These results provide support for the presence of metal-catalysed oxidation (the Suyama pathway) in diabetes and the possible activation of myeloperoxidase during sepsis. We conclude that 2-aminoadipic acid is a more reliable marker for protein oxidation than its precursor, allysine. Its mechanism of formation in each of these conditions needs to be elucidated.
authors.affiliation: Department of Pathology, Case Western Reserve University, Wolstein Research Building, 2103 Cornell Road, Cleveland, OH 44106, USA. drs7@po.cwru.edu
authors.forename: David R
authors.initials: DR
authors.lastname: Sell
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Strauch
authors.forename: Wei
authors.initials: W
authors.lastname: Shen
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Monnier
mesh_terms: D015074:2-Aminoadipic Acid / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism*; D002648:Child; D003094:Collagen / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D011506:Proteins / Q000378:metabolism*; D051437:Renal Insufficiency / Q000378:metabolism*; D018805:Sepsis / Q000378:metabolism*; D012867:Skin / Q000378:metabolism*; D015595:Skin Aging
chemical_list: D015415:Biomarkers; D011506:Proteins; D015074:2-Aminoadipic Acid; D003094:Collagen