Metabolism of AGEs – Bacterial AGEs Are Degraded by Metallo-Proteases

Ifat Cohen-Or,Eliora Z. Ron,Chen Katz,Dwayne Elias

doi:10.1371/journal.pone.0074970

Ifat Cohen-Or, Eliora Z. Ron + Show 2 more

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https://doi.org/10.1371/journal.pone.0074970

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Journal: PloS one	Publication Date: Oct 9, 2013
Citations: 4	License type: CC BY 4.0

Affiliation: Tel Aviv University, Migal - Galilee Technology Center

Abstract

Advanced Glycation End Products (AGEs) are the final products of non-enzymatic protein glycation that results in loss of protein structure and function. We have previously shown that in E. coli AGEs are continually formed as high-molecular weight protein complexes. Moreover, we showed that AGEs are removed from the cells by an active, ATP-dependent secretion and that these secreted molecules have low molecular weight. Taken together, these results indicate that E. coli contains a fraction of low molecular weight AGEs, in addition to the high-molecular weight AGEs. Here we show that the low-molecular weight AGEs originate from high-molecular weight AGEs by proteolytic degradation. Results of in-vitro and in vivo experiments indicated that this degradation is carried out not by the major ATP-dependent proteases that are responsible for the main part of bacterial protein quality control but by an alternative metal-dependent proteolysis. This proteolytic reaction is essential for the further secretion of AGEs from the cells. As the biochemical reactions involving AGEs are not yet understood, the implication of a metalloprotease in breakdown of high molecular weight AGEs and their secretion constitutes an important step in the understanding of AGEs metabolism.

Highlights

Advanced Glycation End-products (AGEs) are the final products of non-enzymatic glycation formed by the reaction of reactive carbonyls (e.g.- reducing sugars) with primary aminecontaining amino acids of proteins
In order to study the mechanism of AGEs degradation we developed an in-vitro assay in which we determined the kinetics of AGEs degradation under several experimental conditions
Similar results were obtained following the addition of a protease inhibitor cocktail, further supporting the assumption that proteolytic activity is responsible for the degradation of AGEs

Summary

Introduction

Advanced Glycation End-products (AGEs) are the final products of non-enzymatic glycation formed by the reaction of reactive carbonyls (e.g.- reducing sugars) with primary aminecontaining amino acids of proteins. One of the first steps in this glycation process is the formation of Amadori-modified proteins (AMPs) which are reversible intermediates. These AMPs can further developed, in an oxidation-dependent manner, to form advanced protein complexes, that contain irreversible, highly stable high molecular weight AGEs [1,2,3,4]. AGEs were shown to accumulate both intracellularly and extracellularly with age and to participate in the pathophysiology of several age-related diseases such as cardiovascular disease, Alzheimer’s disease and complications of diabetes mellitus [6,7,8,9,10]. They accumulate in many sites, including the kidney, retina, and atherosclerotic plaques [11]

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