Enzymes can be post-translationally modified, leading to isoforms with different properties. The phenotypic consequences of the quantitative variability of isoforms have never been studied. We used quantitative proteomics to dissect the relationships between the abundances of the enzymes and isoforms of alcoholic fermentation, metabolic traits, and growth-related traits in Saccharomyces cerevisiae. Although the enzymatic pool allocated to the fermentation proteome was constant over the culture media and the strains considered, there was variation in abundance of individual enzymes and sometimes much more of their isoforms, which suggests the existence of selective constraints on total protein abundance and trade-offs between isoforms. Variations in abundance of some isoforms were significantly associated to metabolic traits and growth-related traits. In particular, cell size and maximum population size were highly correlated to the degree of N-terminal acetylation of the alcohol dehydrogenase. The fermentation proteome was found to be shaped by human selection, through the differential targeting of a few isoforms for each food-processing origin of strains. These results highlight the importance of posttranslational modifications in the diversity of metabolic and life-history traits. Molecular & Cellular Proteomics 12: 10.1074/mcp.M112.024349, 720 -735, 2013.The key problem in understanding genotype-phenotype relationships is the complexity arising from multiple levels of cellular functioning. Among them, metabolic networks involve series of interconnected chemical reactions catalyzed by enzymes, allowing the transformation of input substrates into intermediate or final metabolites. These networks play an essential role in an organism's growth, reproduction, and ability to maintain cell integrity and to respond to environmental changes (1, 2). The metabolic fluxes, as well as the metabolite concentrations, are governed by the activity of the enzymes, which depends on three types of factors: kinetic parameters, enzyme abundance, and activation state of the enzyme. The kinetic parameters are determined by the sequence and the three-dimensional structure of the protein (3). The abundance of the enzymes is the result of numerous molecular processes taking place from the transcriptional to the translational level, including epigenetic modifications of the DNA and chromatin (4), transcriptional regulation by transcription factors (5), mRNA capping and splicing and small RNA regulation (6), protein turnover (7), etc. The enzyme activation state is primarily because of post-translational modifications of the native protein, themselves highly regulated (8, 9). Other mechanisms involved in enzyme activity are proteinprotein interactions and allosteric regulation, such mechanisms being sometimes mediated through post-translational modifications (10, 11). The resulting isoforms can display differences in activity, affinity for partners (protein or effectors), and stability (12). The most studied modification is the reversibl...