Farnesyl pyrophosphate synthase is essential for the promastigote and amastigote stages in Leishmania major

Sumit Mukherjee, Somrita Basu, Kai Zhang

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Isoprenoid synthesis provides a diverse class of biomolecules including sterols, dolichols, ubiquinones and prenyl groups. The enzyme farnesyl pyrophosphate synthase (FPPS) catalyzes the formation of farnesyl pyrophosphate, a key intermediate for the biosynthesis of all isoprenoids. In Leishmania, FPPS is considered the main target of nitrogen containing bisphosphonates, yet the essentiality of this enzyme remains untested. Using a facilitated knockout approach, we carried out the genetic analysis of FPPS in Leishmania major. Our data indicated that chromosomal null mutants for FPPS could only be generated in presence of an episomally expressed FPPS. Long-term retention of the episome by the chromosomal FPPS-null mutants in culture and in infected BALB/c mice suggests that FPPS is indispensable. In addition, applying negative selection pressure failed to induce the loss of ectopic FPPS in the chromosomal FPPS-null mutants, although it led to significant growth delay in culture and in mice. Together, our findings have confirmed the essentiality of FPPS in both promastigotes and amastigotes in L. major and thus validate its potential as a drug target for the treatment of cutaneous leishmaniasis.

Original languageEnglish
Pages (from-to)8-15
Number of pages8
JournalMolecular and Biochemical Parasitology
Volume230
DOIs
StatePublished - Jun 2019

Keywords

  • Amastigote
  • Drug
  • Essentiality
  • Isoprenoid
  • Leishmania
  • Lipid
  • Target

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