Biochem. J. (2007) 404
(269–277) (Printed in Great Britain)
2-Aminoadipic acid is a marker of protein carbonyl oxidation in the aging human skin: effects of diabetes, renal failure and sepsis
David R. SELL*2, Christopher M. STRAUCH*, Wei SHEN*1 and Vincent M. MONNIER*†
*Department of Pathology, Case Western Reserve University, Wolstein Research Building, 2103 Cornell Road, Cleveland, OH 44106, U.S.A., and †Department of Biochemistry, Case Western Reserve University, Wolstein Research Building, 2103 Cornell Road, Cleveland, OH 44106, U.S.A.
We hypothesized that the e-amino group of lysine residues in longlived proteins oxidatively deaminates with age forming the carbonyl compound, allysine (a-aminoadipic acid-d-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.
Key words: glycation, lysine, methylglyoxal, myeloperoxidase, redox-active metals, semicarbazide-sensitive amine oxidase.
Abbreviations used: AGE, advanced glycation end-product; CEL, Ne-carboxyethyl-lysine; CML, Ne-carboxymethyl-lysine; d4-CML, Ne-carboxymethyl-lysine-4,4,5,5-d4; d8-lysine, DL-lysine-3,3,4,4,5,5,6,6-d8; ECM, extracellular matrix; LC, liquid chromatography; LOX, lysyl oxidase; MCO, metal-catalysed oxidation; MODIC, methylglyoxal-derived imidazolium cross-link; MPO, myeloperoxidase; SKD, Strecker degradation; SSAO, semicarbazide-sensitive amine oxidase; VAP-1, vascular adhesion protein-1.
1Present address: TSLR Inc., Ann Arbor, MI 48108, U.S.A.
2To whom correspondence should be addressed (email drs7@po.cwru.edu).
Received 2 November 2006/31 January 2007; accepted 21 February 2007
Published as BJ Immediate Publication 21 February 2007, doi:10.1042/BJ20061645
© The Authors Journal compilation © 2007 Biochemical Society
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