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CYP5122A1 encodes an essential sterol C4-methyl oxidase in Leishmania donovani and determines the antileishmanial activity of antifungal azoles
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CYP5122A1 encodes an essential sterol C4-methyl oxidase in Leishmania donovani and determines the antileishmanial activity of antifungal azoles
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Journal Article
CYP5122A1 encodes an essential sterol C4-methyl oxidase in Leishmania donovani and determines the antileishmanial activity of antifungal azoles
2024
Overview
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.
CYP5122A1 is a sterol C4-methyl oxidase that catalyzes the sequential oxidation of lanosterol, is essential for both
Leishmania donovani
promastigotes in culture and intracellular amastigotes in infected mice, and provides a new target for antileishmanial drug discovery.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 140/58
/ 45/77
/ 64/60
/ 82/80
/ 82/83
/ Animals
/ Antifungal Agents - pharmacology
/ Antiprotozoal Agents - pharmacology
/ Azoles
/ Cytochrome P-450 Enzyme System - genetics
/ Cytochrome P-450 Enzyme System - metabolism
/ Drugs
/ Enzymes
/ Female
/ Humanities and Social Sciences
/ Lanosterol - analogs & derivatives
/ Leishmania donovani - drug effects
/ Leishmania donovani - enzymology
/ Leishmania donovani - genetics
/ Leishmaniasis, Visceral - drug therapy
/ Leishmaniasis, Visceral - parasitology
/ Mice
/ Oxidase
/ Protozoan Proteins - antagonists & inhibitors
/ Protozoan Proteins - genetics
/ Protozoan Proteins - metabolism
/ Science
/ Sterols
