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Bioorganic & medicinal chemistry

Understanding non-enzymatic aminophospholipid glycation and its inhibition. Polar head features affect the kinetics of Schiff base formation.


PMID 21719301

Abstract

Non-enzymatic aminophospholipid glycation is an especially important process because it alters the stability of lipid bilayers and interferes with cell function and integrity as a result. However, the kinetic mechanism behind this process has scarcely been studied. As in protein glycation, the process has been suggested to involve the formation of a Schiff base as the initial, rate-determining step. In this work, we conducted a comparative kinetic study of Schiff base formation under physiological conditions in three low-molecular weight analogues of polar heads in the naturally occurring aminophospholipids O-phosphorylethanolamine (PEA), O-phospho-DL-serine (PSer) and 2-aminoethylphenethylphosphate (APP) with various glycating carbonyl compounds (glucose, arabinose and acetol) and the lipid glycation inhibitor pyridoxal 5'-phosphate (PLP). Based on the results, the presence of a phosphate group and a carboxyl group in α position respect to the amino group decrease the formation constant for the Schiff base relative to amino acids. On the other hand, esterifying the phosphate group with a non-polar substituent in APP increases the stability of its Schiff base. The observed kinetic formation constants of aminophosphates with carbonyl groups were smaller than those for PLP. Our results constitute an important contribution to understanding the competitive inhibition effect of PLP on aminophospholipid glycation.

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