Genome sequencing projects have revealed that eukaryotic and prokaryotic organisms universally possess a huge number of uncharacterized enzymes. The functional annotation of uncharacterized enzymatic pathways, thus, represents a grand challenge for researchers in the postgenomic era. To address this problem, global molecular profiling methods hold great promise, as they provide a relatively unbiased portrait of the biochemical composition of cells and tissues and can reveal unanticipated

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... ions in their metabolic and signaling networks. Nonetheless, the identification and functional characterization of enzymatic pathways that support human physiology and pathology have, to date, been hindered by a lack of "systems biology" techniques that can evaluate their activity in complex biological samples. To address this problem, we have introduced functional proteomic and metabolomic technologies that record dynamics in enzyme activity in directly in native biological systems. For example, the activity-based protein profiling (ABPP) technology utilizes active site-directed chemical probes to determine the functional state of large numbers of enzymes in proteomes. In this presentation, I will describe the integrated application of ABPP and complementary functional proteomic/ metabolomic methods to discover and functionally annotate enzyme activities in mammalian (patho)physiological processes, including cancer and nervous system signaling. The long-term goal of these studies is to map new biochemical pathways that play important roles in human disease and develop selective chemical tools to perturb these pathways in living systems.