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Discovering disease-associated enzymes by proteome reactivity profiling
Katherine T Barglow1, Benjamin F Cravatt
1The Skaggs Institute for Chemical Biology and Department of Cell Biology and Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Chemistry & Biology
|November 24, 2004
Summary
This study developed novel activity-based proteomic probes to profile protein function, revealing altered enzyme activity in obesity. Hydroxypyruvate reductase was upregulated in obese mice, potentially contributing to glucose production.
Area of Science:
- Biochemistry
- Proteomics
- Metabolomics
Background:
- Proteomics seeks disease markers and therapeutic targets by profiling protein function, not just abundance.
- Novel methods are required to analyze protein activity for accurate disease association.
Purpose of the Study:
- To develop and evaluate a strategy for creating diverse activity-based proteomic probes.
- To identify differentially expressed enzyme activities in lean versus obese mouse models.
Main Methods:
- Synthesis and evaluation of structurally diverse activity-based proteomic probe libraries.
- Quantitative screening of probe-proteome interactions.
- Bioinformatic analysis to select an optimal probe set with complementary reactivity.
Main Results:
- An optimal set of activity-based proteomic probes was selected.
- Several enzyme activities were found to be differentially expressed between lean and obese mice.
- Hydroxypyruvate reductase was identified as significantly upregulated (6-fold) in obese mouse livers.
Conclusions:
- The developed probes enable functional profiling of proteomes.
- Upregulation of hydroxypyruvate reductase in obesity suggests a role in altered serine-to-glucose metabolism.
- This metabolic pathway may contribute to obesity-associated gluconeogenesis.