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School of Medicine
Jorge Escalante-Semerena, Ph.D.
The Escalante laboratory is interested in prokaryotic metabolism and physiology. Our group takes a comprehensive approach to our research problems. We do in vivo and in vitro genetics, enzymology, small-molecule biochemistry, metabolic pathway integration, and general physiology. Structural work is performed in collaboration with Ivan Rayment and Hazel Holden (UW-Madison), and Andrew Gulick (SUNY-Buffalo), spectroscopy analysis is performed in collaboration with Thomas Brunold (UW-Madison). Much of the work we do is performed in the Gram-negative enteropathogen Salmonella enterica because we can do sophisticated in vivo and in vitro genetic analysis of strains. Our work spans bacteria and archaea in the following areas.
Metabolic pathway integration/Posttranslational control of metabolic enzymes.
In 1998, we identified the cobB gene of Salmonella enterica as a new member of the SIR2 family regulatory proteins in eukaryotes whose activities are needed for gene silencing and cell aging. Our report was an important contribution to this field of research and led to the identification of two enzymatic activities associated with these proteins. Knowledge of these activities is essential to better understand the exciting process of cell aging. We recently established a link between sirtuins and central metabolism. We showed that the acetyl-CoA synthetase enzyme (Acs, AMP-forming) is under the control of the sirtuin-dependent acetylation/deacetylation system (SDPADS). We (in collaboration with Jef Boeke and Bob Cole/Johns Hopkins University) demonstrated that residue Lys609 of Acs is the site of acetylation, and that acetylated Acs is inactive. It is likely that the SDPADS controls the activity of many other proteins in the cell. We are using a proteomics approach to identify SDPADS substrates in S. enterica and other prokaryotes of interest to us, including archaea. Very recently, we identified the gene encoding the acetyltransferase of the SDPADS in S. enterica. This protein (we call it Pat for protein acetyltransferase), is encoded by a gene of previously unknown function. Genetic and biochemical data unequivocally show that Pat and CobB comprise the SDPADS.
A second focus of our work centers on the catabolism of poor carbon sources such as propionate and acetate, two short-chain fatty acids that are very abundant in soil and the gut. These compounds are used by many prokaryotes of relevance to the environment and health. Catabolism of these short-chain fatty acids has profound physiological implications for the cell. Both acetate and propionate are toxic to the cell as evidenced by the fact that the breakdown of propionate requires functional editing DNA polymerase, glutathione, and mismatch repair functions. We are investigating why these functions are need during growth on propionate. We would like to know why is propionate such a metabolic risk to the cell. Propionate catabolism is also a great model system to investigate strategies used by the cell to integrate its metabolic pathways.
Complex Metabolic Pathway Analysis.
We are studying multiple aspects of adenosylcobalamin (AdoCbl, coenzyme B12) biosynthesis. This coenzyme is the largest non-polymeric molecule with biological activity. At least 24 genes of the Salmonella enterica genome are dedicated to the synthesis of coenzyme B12. Twenty of the twenty-four known cobalamin biosynthetic (cob) genes comprise a 17-kb superoperon. In Salmonella enterica, de novo synthesis of AdoCbl occurs only under anoxic growth conditions. This fact raises very interesting questions regarding gene regulation and oxygen liability of intermediates/enzymes. Transcriptional regulation of this superoperon is complex and requires the interplay of local as well as global regulatory proteins.