Mevalonate analogues as substrates of enzymes in the isoprenoid biosynthetic pathway of Streptococcus pneumoniae

Takashi Kudoh, Chan Sun Park, Scott T. Lefurgy, Meihao Sun, Theodore Michels, Thomas S. Leyh, Richard B. Silverman

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Survival of the human pathogen Streptococcus pneumoniae requires a functional mevalonate pathway, which produces isopentenyl diphosphate, the essential building block of isoprenoids. Flux through this pathway appears to be regulated at the mevalonate kinase (MK) step, which is strongly feedback-inhibited by diphosphomevalonate (DPM), the penultimate compound in the pathway. The human mevalonate pathway is not regulated by DPM, making the bacterial pathway an attractive antibiotic target. Since DPM has poor drug characteristics, being highly charged, we propose to use unphosphorylated, cell-permeable prodrugs based on mevalonate that will be phosphorylated in turn by MK and phosphomevalonate kinase (PMK) to generate the active compound in situ. To test the limits of this approach, we synthesized a series of C3-substituted mevalonate analogues to probe the steric and electronic requirements of the MK and PMK active sites. MK and PMK accepted substrates with up to two additional carbons, showing a preference for small substituents. This result establishes the feasibility of using a prodrug strategy for DPM-based antibiotics in S. pneumoniae and identified several analogues to be tested as inhibitors of MK. Among the substrates accepted by both enzymes were cyclopropyl, vinyl, and ethynyl mevalonate analogues that, when diphosphorylated, might be mechanism-based inactivators of the next enzyme in the pathway, diphosphomevalonate decarboxylase.

Original languageEnglish (US)
Pages (from-to)1124-1134
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume18
Issue number3
DOIs
StatePublished - Feb 1 2010

Fingerprint

mevalonate kinase
Mevalonic Acid
Biosynthetic Pathways
Terpenes
Streptococcus pneumoniae
Substrates
Enzymes
Prodrugs
pyrophosphomevalonate decarboxylase
Anti-Bacterial Agents
Pathogens
Catalytic Domain
Carbon
Fluxes
Feedback
Survival

Keywords

  • Diphosphomevalonate decarboxylase
  • Diphosphomevalonic acid
  • Isoprenoid pathway
  • Mevalonate kinase
  • Mevalonic acid
  • Phosphomevalonate kinase
  • Phosphomevalonic acid
  • Prodrug

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Mevalonate analogues as substrates of enzymes in the isoprenoid biosynthetic pathway of Streptococcus pneumoniae. / Kudoh, Takashi; Park, Chan Sun; Lefurgy, Scott T.; Sun, Meihao; Michels, Theodore; Leyh, Thomas S.; Silverman, Richard B.

In: Bioorganic and Medicinal Chemistry, Vol. 18, No. 3, 01.02.2010, p. 1124-1134.

Research output: Contribution to journalArticle

Kudoh, Takashi ; Park, Chan Sun ; Lefurgy, Scott T. ; Sun, Meihao ; Michels, Theodore ; Leyh, Thomas S. ; Silverman, Richard B. / Mevalonate analogues as substrates of enzymes in the isoprenoid biosynthetic pathway of Streptococcus pneumoniae. In: Bioorganic and Medicinal Chemistry. 2010 ; Vol. 18, No. 3. pp. 1124-1134.
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