title: Streptococcus pneumoniae isoprenoid biosynthesis is downregulated by diphosphomevalonate: an antimicrobial target.
abstract: The toll that Streptococcus pneumoniae exacts on the welfare of humanity is enormous. This organism claims the lives of approximately 3700 people daily, the majority of whom are children below the age of 5, and the situation could worsen due to the increasing incidence of pernicious, multiple-antibiotic-resistant strains. Here we report the discovery and characterization of a new allosteric site, shown to be absent in humans, that can be used to switch off an essential pathway in S. pneumoniae, the mevalonate pathway. Diphosphomevalonate (DPM), an intermediate in the pathway, binds with high affinity (K(d) = 530 nM) to mevalonate kinase, the first enzyme in the pathway, and inactivates it. Steady-state and equilibrium binding measurements reveal that DPM binding is noncompetitive versus substrates. DPM binds at an allosteric site, and inhibition cannot be overcome by an increasing substrate concentration. The DPM-binding site is a promising target for the development of new antimicrobial agents.
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461-1926, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Andreassi
authors.forename: Kristina
authors.initials: K
authors.lastname: Dabovic
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Leyh
mesh_terms: D000494:Allosteric Regulation / Q000502:physiology; D000495:Allosteric Site / Q000502:physiology*; D015536:Down-Regulation; D006801:Humans; D007700:Kinetics; D008798:Mevalonic Acid / Q000031:analogs & derivatives* / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D011485:Protein Binding / Q000502:physiology; D013296:Streptococcus pneumoniae / Q000378:metabolism*; D013729:Terpenes / Q000378:metabolism*
chemical_list: D013729:Terpenes; C046285:5-diphosphomevalonic acid; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; D008798:Mevalonic Acid