Intrinsic toxicity of glucose, due to non-enzymatic glycation, is controlled in-vivo by deglycation systems including: FN3K-mediated deglycation of fructosamines and transglycation of aldosamines

Abstract

Along with oxygen, glucose is an essential macronutrient for most cells, a source of carbons for biosynthesis and energy. However, alongside this indispensable role for cell survival and growth, glucose is intrinsically toxic by reacting with primary amines such as lysine in proteins in a non-enzymatic glycation process (a.k.a. Maillard reaction) especially important in long-lived, homeothermic organisms where temperatures of 37-44 degrees C accelerate its rate. Products of Maillard reactions are known to have adverse effects on protein function and have been implicated in the development of diabetic complications and possibly in neurodegenerative diseases. Because of the unavoidable nature of non-enzymatic glycation and its deleterious effects, we propose that glucose-utilizing organisms, especially the homeothermic ones, possess mechanisms to control this process at its earliest stages. In the intracellular milieu two such mechanisms are apparent at present; a fructosamine-3-kinase(FN3K)-dependent process which is ubiquitous in all warm-blooded animals and a FN3K-independent deglycation pathway present in all animals, including ones which do not have FN3K, such as insects. We propose that of the two pathways, the FN3K-independent mechanism is more important due to the fact that it breaks down the very first intermediate of the Maillard reaction, the Schiff base (a.k.a aldosamine). We postulate that this, FN3K-independent, deglycation occurs by transglycation, in which carbohydrate moieties of glycated amines, such as glucoselysines on proteins, are removed by intracellular nucleophiles including free amino acids and peptides such as glutathione, carnosine and anserine. Furthermore, we hypothesize that one or more of these nucleophile-aldose adducts, formed as by-products of transglycation, are actively removed from cells by one or more of the multi-drug-resistance [MDR] proteins or similar pumps. In the extracellular space, non-enzymatic glycation and deglycation occur as well. We also postulate that, in that setting, transglycation products are removed from the system by the kidneys or similar excretory organs. Our hypothesis leads to several testable predictions including: The deglycation hypothesis offers new paradigm for thinking about non-enzymatic glycation and diabetic complications and offers possible strategies for intervention in this and possibly other degenerative conditions.