Streptococcus pneumoniae isoprenoid biosynthesis is downregulated by diphosphomevalonate: An antimicrobial target

John L. Andreassi, Kristina Dabovic, Thomas S. Leyh

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The toll that Streptococcus pneumoniae exacts on the welfare of humanity is enormous. This organism claims the lives of ∼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 (Kd = 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.

Original languageEnglish (US)
Pages (from-to)16461-16466
Number of pages6
JournalBiochemistry
Volume43
Issue number51
DOIs
StatePublished - Dec 28 2004

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Allosteric Site
Biosynthesis
Terpenes
mevalonate kinase
Streptococcus pneumoniae
Down-Regulation
Mevalonic Acid
Substrates
Anti-Infective Agents
Binding Sites
Switches
Anti-Bacterial Agents
Incidence
Enzymes

ASJC Scopus subject areas

  • Biochemistry

Cite this

Streptococcus pneumoniae isoprenoid biosynthesis is downregulated by diphosphomevalonate : An antimicrobial target. / Andreassi, John L.; Dabovic, Kristina; Leyh, Thomas S.

In: Biochemistry, Vol. 43, No. 51, 28.12.2004, p. 16461-16466.

Research output: Contribution to journalArticle

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