Functional Genomics of the GHMP Kinase Superfamily

Albert Einstein Col Of Med Yeshiva Univ, Bronx NY

Investigators

Abstract

DESCRIPTION (provided by applicant): We propose the establishment of a functional genomics program whose goal is the creation of a database that assigns molecular function to highly conserved, solvent-accessible residues in each enzyme family. Proof of principle will be achieved by identifying highly conserved residues in the GHMP kinase superfamily and then mutating these residues within the framework of a representative GHMP protein. Mutation of highly conserved GHMP kinase residues in Phosphomevalonate kinase (PMK) from Streptococcus pneumoniae will be representative of function among all GHMP kinases. The PMK mutants will be analyzed by initial rate kinetics and the results presented in a web-accessible database. A large-scale database will ultimately provide crucial functional information for the study of enzyme systems. S. pneumoniae is a human pathogen responsible for the majority of worldwide cases of bacterial meningitis and sepsis. The PMK and mevalonate kinase (MK) genes are essential to S. pnuemoniae cell survival. Genomic studies have assigned S. pneumoniae and human PMK to different protein families. We will ascertain functional and structural information using enzymological and x-ray crystallographic techniques in order to make available data for the selective targeting of PMK and/or MK in S. pneumoniae cells.