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Farnesyl pyrophosphate synthase is essential for the promastigote and amastigote stages in Leishmania major.
- Source :
-
Molecular and biochemical parasitology [Mol Biochem Parasitol] 2019 Jun; Vol. 230, pp. 8-15. Date of Electronic Publication: 2019 Mar 26. - Publication Year :
- 2019
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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.<br /> (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Gene Knockout Techniques
Leishmania major genetics
Leishmaniasis, Cutaneous parasitology
Mice, Inbred BALB C
Genes, Essential
Genes, Protozoan
Geranyltranstransferase genetics
Geranyltranstransferase metabolism
Leishmania major enzymology
Leishmania major growth & development
Polyisoprenyl Phosphates metabolism
Sesquiterpenes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1872-9428
- Volume :
- 230
- Database :
- MEDLINE
- Journal :
- Molecular and biochemical parasitology
- Publication Type :
- Academic Journal
- Accession number :
- 30926449
- Full Text :
- https://doi.org/10.1016/j.molbiopara.2019.03.001