title: Protein glycation and methylglyoxal metabolism in yeast: finding peptide needles in protein haystacks.
abstract: Metabolism, the set of all chemical transformations inside a living cell, comprises nonenzymatic processes that generate toxic products such as reactive oxygen species and 2-oxoaldehydes. Methylglyoxal, a highly reactive 2-oxoaldehyde by-product of glycolysis, is able to react irreversibly and nonenzymatically with proteins, forming methylglyoxal advanced glycation end-products, which alter protein structure, stability and function. Therefore, protein glycation may influence cell metabolism and its physiology in a way beyond what can be predicted based on the implicit codification used in systems biology. Genome-wide approaches and transcriptomics, two mainstays of systems biology, are powerless to tackle the problems caused by nonenzymatic reactions that are part of cell metabolism and biochemistry. The effects of methylglyoxal-derived protein glycation and the cell's response to this unspecific posttranslational modification were investigated in Saccharomyces cerevisiae as a model organism. Specific protein glycation phenotypes were identified using yeast null-mutants for methylglyoxal catabolism and the existence of specific protein glycation targets by peptide mass fingerprint was discovered. Enolase, the major target, endures a glycation-dependent activity loss caused by dissociation of the active dimer upon glycation at a specific arginine residue, identified using the hidden information of peptide mass fingerprint. Once glycation occurs, a cellular response involving heat shock proteins from the refolding chaperone pathway is elicited and Hsp26p is activated by glycation.
authors: Departamento de Química e Bioquimica, Centro de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Edifício, Lisboa, Portugal.
authors: Ricardo Anjos
authors: RA
authors: Gomes
authors: Hugo
authors: H
authors: Vicente Miranda
authors: Marta
authors: M
authors: Sousa Silva
authors: Gonçalo
authors: G
authors: Graça
authors: Ana Varela
authors: AV
authors: Coelho
authors: António Eduardo
authors: AE
authors: do Nascimento Ferreira
authors: Carlos
authors: C
authors: Cordeiro
authors: Ana Ponces
authors: AP
authors: Freire
mesh_terms: D017127:Glycation End Products, Advanced; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D011765:Pyruvaldehyde / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism*; D049490:Systems Biology
chemical_list: D017127:Glycation End Products, Advanced; C499528:HSP26 protein, S cerevisiae; D006360:Heat-Shock Proteins; D010455:Peptides; D029701:Saccharomyces cerevisiae Proteins; D011765:Pyruvaldehyde