This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project investigates a fascinating structure-function relationship in tagatose-1,6-biphosphate (TBP) aldolase from Streptococcus pyogenes. TBP aldolase can cleave, apart from its own substrate TBP, three other bisphosphorylated D-hexoses: fructose-1,6-bisphosphate, sorbose-1,6-bisphosphate and psicose-1,6-bisphosphate. These four sugars are diastereoisomers and differ only in stereochemistry at carbon 3 and at carbon 4 with respect to the configuration of their hydroxyl groups. It is the elucidation of this intriguing nonspecific cleavage mechanism that prompted our structural and enzymatic study of the TBP aldolase from S. pyogenes. A number of structures of various enzymatic intermediates have been solved and are being analyzed in the light of detailed kinetic studies.A second objective is to examine the role of a highly homologous orthologue of this enzyme that binds directly a regulator of virulence genes expression in S. pyogenes. The TBP aldolase orthologue is thought to be able to convey environmental cues to the gene expression regulation machinery via its binding to the regulator. The hypothesis is one of binding by the enzyme with its natural substrate dihydroxyacetone-P induces conformational changes in the enzyme's structure that allow sequestration of the regulator. Structural studies to examine this hypothesis of orthologue function are under way.
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