ArticleNature communications2024
CYP5122A1 encodes an essential sterol C4-methyl oxidase in Leishmania donovani and determines the antileishmanial activity of antifungal azoles.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers, 1 of them a synthesis that pooled it.
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7 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Efficacy and safety of different drugs for the treatment of leishmaniasis: a systematic review and network meta-analysis.Frontiers in cellular and infection microbiology · 2025Pooled it
- Multiscale-Aware Graph Embedding Approach Uncovers LC-61, a Potent Anti-Journal of chemical information and modeling · 2026Article
- Role of ergosterol biosynthesis in growth, drug sensitivity, and host colonization of honey bee trypanosomatid parasite,FEMS microbes · 2026Article
- Antidermatophytic activity of Curcuma longa against Trichophyton spp.: compound identification and molecular docking to lanosterol 14α-demethylase.BMC complementary medicine and therapies · 2025Article
- N-substituted-4-(pyridin-4-ylalkyl)piperazine-1-carboxamides and related compounds as Leishmania CYP51 and CYP5122A1 inhibitors.Bioorganic & medicinal chemistry · 2024Article
- Molecular Characterization of Sterol C4-Methyl Oxidase inInternational journal of molecular sciences · 2024Article
- 1,2,4-Oxadiazole Derivatives: Physicochemical Properties, Antileishmanial Potential, Docking and Molecular Dynamic Simulations ofMolecules (Basel, Switzerland) · 2024Article
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Abstract
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.
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