CYP5122A1 encodes an essential sterol C4-methyl oxidase in Leishmania donovani and determines the antileishmanial activity of antifungal azoles.
Leishmania donovani
/ drug effects
Animals
Antifungal Agents
/ pharmacology
Mice
Azoles
/ pharmacology
Leishmaniasis, Visceral
/ drug therapy
Antiprotozoal Agents
/ pharmacology
Protozoan Proteins
/ metabolism
Mice, Inbred BALB C
Cytochrome P-450 Enzyme System
/ metabolism
Lanosterol
/ pharmacology
Female
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
31 Oct 2024
31 Oct 2024
Historique:
received:
19
07
2023
accepted:
20
10
2024
medline:
1
11
2024
pubmed:
1
11
2024
entrez:
1
11
2024
Statut:
epublish
Résumé
Visceral leishmaniasis is a life-threatening parasitic disease, but current antileishmanial drugs have severe drawbacks. Antifungal azoles inhibit the activity of cytochrome P450 (CYP) 51 enzymes which are responsible for removing the C14α-methyl group of lanosterol, a key step in ergosterol biosynthesis in Leishmania. However, they exhibit varying degrees of antileishmanial activities in culture, suggesting the existence of unrecognized molecular targets. Our previous study reveals that, in Leishmania, lanosterol undergoes parallel C4- and C14-demethylation to form 4α,14α-dimethylzymosterol and T-MAS, respectively. In the current study, CYP5122A1 is identified as a sterol C4-methyl oxidase that catalyzes the sequential oxidation of lanosterol to form C4-oxidation metabolites. CYP5122A1 is essential for both L. donovani promastigotes in culture and intracellular amastigotes in infected mice. CYP5122A1 overexpression results in growth delay, increased tolerance to stress, and altered expression of lipophosphoglycan and proteophosphoglycan. CYP5122A1 also helps to determine the antileishmanial effect of antifungal azoles in vitro. Dual inhibitors of CYP51 and CYP5122A1 possess superior antileishmanial activity against L. donovani promastigotes whereas CYP51-selective inhibitors have little effect on promastigote growth. Our findings uncover the critical biochemical and biological role of CYP5122A1 in L. donovani and provide an important foundation for developing new antileishmanial drugs by targeting both CYP enzymes.
Identifiants
pubmed: 39482311
doi: 10.1038/s41467-024-53790-5
pii: 10.1038/s41467-024-53790-5
doi:
Substances chimiques
Antifungal Agents
0
Azoles
0
Antiprotozoal Agents
0
Protozoan Proteins
0
Cytochrome P-450 Enzyme System
9035-51-2
Lanosterol
1J05Z83K3M
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
9409Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
ID : R01AI139198
Informations de copyright
© 2024. The Author(s).
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