CYP5122A1 encodes an essential sterol C4-methyl oxidase in Leishmania donovani and determines the antileishmanial activity of antifungal azoles

Yiru Jin, Somrita Basu, Mei Feng, Yu Ning, Indeewara Munasinghe, Arline M. Joachim, Junan Li, Lingli Qin, Robert Madden, Hannah Burks, Philip Gao, Judy Qiju Wu, Salma Waheed Sheikh, April C. Joice, Chamani Perera, Karl A. Werbovetz, Kai Zhang and Michael Zhuo Wang ()
Additional contact information
Yiru Jin: The University of Kansas
Somrita Basu: Texas Tech University
Mei Feng: The University of Kansas
Yu Ning: Texas Tech University
Indeewara Munasinghe: The University of Kansas
Arline M. Joachim: The Ohio State University
Junan Li: The Ohio State University
Lingli Qin: The University of Kansas
Robert Madden: Texas Tech University
Hannah Burks: Texas Tech University
Philip Gao: The University of Kansas
Judy Qiju Wu: The University of Kansas
Salma Waheed Sheikh: Texas Tech University
April C. Joice: The Ohio State University
Chamani Perera: The University of Kansas
Karl A. Werbovetz: The Ohio State University
Kai Zhang: Texas Tech University
Michael Zhuo Wang: The University of Kansas

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53790-5

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