The ubiquitous conserved glycopeptidase Gcp prevents accumulation of toxic glycated proteins.
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.
Katz
Chen
C
Department of Molecular Microbiology and Biotechnology, Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Cohen-Or
Ifat
I
Gophna
Uri
U
Ron
Eliora Z
EZ
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*
D029968:Escherichia coli Proteins; D017127:Glycation End Products, Advanced; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
Prog Clin Biol Res. 1989;304:43-67
2675036
Mol Cell. 2008 Oct 24;32(2):259-75
18951093
J Biol Chem. 1997 Feb 7;272(6):3437-43
9013588
Gene. 1977;2(2):75-93
344136
J Bacteriol. 1991 Sep;173(18):5597-603
1885539
J Mol Biol. 1999 Apr 16;287(5):1023-40
10222208
Biochem Soc Trans. 2008 Oct;36(Pt 5):1045-50
18793186
Chem Rev. 2002 Feb;102(2):439-69
11841250
Biosci Biotechnol Biochem. 1995 Mar;59(3):487-91
7766189
Curr Pharm Des. 2008;14(10):979-86
18473849
Mol Cell. 2003 Mar;11(3):671-83
12667450
J Alzheimers Dis. 2009;16(4):845-58
19387117
Environ Microbiol. 2008 Feb;10(2):281-8
18199122
Nucleic Acids Res. 2009 Sep;37(16):5343-52
19578062
FEMS Microbiol Ecol. 2001 May;35(3):277-285
11311438
J Clin Endocrinol Metab. 2008 Apr;93(4):1143-52
18182449
J Neural Transm (Vienna). 1998;105(8-9):1005-15
9869332
Nature. 2005 Feb 3;433(7025):531-7
15690043
J Biol Chem. 1981 Jan 25;256(2):815-22
7005225
Invest Ophthalmol Vis Sci. 2003 Aug;44(8):3663-8
12882821
Anal Biochem. 1982 Jan 15;119(2):325-9
6176144
Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6640-5
10829079
Curr Pharm Des. 2008;14(10):969-72
18473847
J Biol Chem. 2002 Nov 8;277(45):42523-9
12147680
Cell. 2005 Jul 29;122(2):209-20
16051146
Mol Microbiol. 2001 Feb;39(4):1061-8
11251824
Anal Biochem. 1991 Jan;192(1):109-11
1646571
Biochim Biophys Acta. 2001 Feb 14;1535(2):110-9
11341999
J Pept Sci. 2004 Mar;10(3):119-37
15113085
Prog Clin Biol Res. 1989;304:85-107
2675037
Nucleic Acids Res. 2004 Oct 12;32(18):5452-63
15479782
J Bacteriol. 2005 Jun;187(12):4207-13
15937182
J Bacteriol. 2009 Aug;191(15):4732-49
19376873
Biochem Soc Trans. 2003 Dec;31(Pt 6):1406-8
14641075
Gene. 1977;2(2):95-113
344137
J Biotechnol. 2006 Mar 23;122(2):254-66
16310273
Curr Pharm Des. 2008;14(10):973-8
18473848
Biotechnol Lett. 2007 Aug;29(8):1169-78
17479221
Diabetologia. 2001 Feb;44(2):129-46
11270668
Biochem Soc Trans. 2009 Feb;37(Pt 1):29-35
19143597
Nucleic Acids Res. 2007;35(18):6042-51
17766251
J Bacteriol. 2004 Oct;186(20):6768-74
15466028
J Bacteriol. 1995 Jul;177(14):4121-30
7608087
Cell. 2006 Mar 24;124(6):1155-68
16564010