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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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, 2024. "CYP5122A1 encodes an essential sterol C4-methyl oxidase in Leishmania donovani and determines the antileishmanial activity of antifungal azoles," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53790-5
    DOI: 10.1038/s41467-024-53790-5
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    References listed on IDEAS

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    1. Christian Ritz & Florent Baty & Jens C Streibig & Daniel Gerhard, 2015. "Dose-Response Analysis Using R," PLOS ONE, Public Library of Science, vol. 10(12), pages 1-13, December.
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