title: The ubiquitous conserved glycopeptidase Gcp prevents accumulation of toxic glycated proteins.
abstract: Amadori-modified proteins (AMPs) are the products of nonenzymatic glycation formed by reaction of reducing sugars with primary amine-containing amino acids and can develop into advanced glycated end products (AGEs), highly stable toxic compounds. AGEs are known to participate in many age-related human diseases, including cardiovascular, neurological, and liver diseases. The metabolism of these glycated proteins is not yet understood, and the mechanisms that reduce their accumulation are not known so far. Here, we show for Escherichia coli that a conserved glycopeptidase (Gcp, also called Kae1), which is encoded by nearly every sequenced genome in the three domains of life, prevents the accumulation of Amadori products and AGEs. Using mutants, we show that Gcp depletion results in accumulation of AMPs and eventually leads to the accumulation of AGEs. We demonstrate that Gcp binds to glycated proteins, including pyruvate dehydrogenase, previously shown to be a glycation-prone enzyme. Our experiments also show that the severe phenotype of Gcp depletion can be relieved under conditions of low intracellular glycation. As glycated proteins are ubiquitous, the involvement of Gcp in the metabolism of AMPs and AGEs is likely to have been conserved in evolution, suggesting a universal involvement of Gcp in cellular aging and explaining the essentiality of Gcp in many organisms.
authors.affiliation: Department of Molecular Microbiology and Biotechnology, Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Chen
authors.initials: C
authors.lastname: Katz
authors.forename: Ifat
authors.initials: I
authors.lastname: Cohen-Or
authors.forename: Uri
authors.initials: U
authors.lastname: Gophna
authors.forename: Eliora Z
authors.initials: EZ
authors.lastname: Ron
mesh_terms: D005075:Biological Evolution; D004926:Escherichia coli / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism* / Q000633:toxicity; D006031:Glycosylation; D006801:Humans; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / Q000235:genetics / Q000378:metabolism*
chemical_list: D029968:Escherichia coli Proteins; D017127:Glycation End Products, Advanced; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
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