Farnesyl pyrophosphate synthase is essential for the promastigote and amastigote stages in Leishmania major.
Amastigote
Drug
Essentiality
Isoprenoid
Leishmania
Lipid
Target
Journal
Molecular and biochemical parasitology
ISSN: 1872-9428
Titre abrégé: Mol Biochem Parasitol
Pays: Netherlands
ID NLM: 8006324
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
10
02
2019
revised:
01
03
2019
accepted:
05
03
2019
pubmed:
31
3
2019
medline:
29
4
2020
entrez:
31
3
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30926449
pii: S0166-6851(19)30021-0
doi: 10.1016/j.molbiopara.2019.03.001
pmc: PMC6529949
mid: NIHMS1525447
pii:
doi:
Substances chimiques
Polyisoprenyl Phosphates
0
Sesquiterpenes
0
farnesyl pyrophosphate
79W6B01D07
Geranyltranstransferase
EC 2.5.1.10
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
8-15Subventions
Organisme : NIAID NIH HHS
ID : R01 AI099380
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.
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