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Mechanistic insight into the role of mevalonate kinase by a natural fatty acid-mediated killing of Leishmania donovani

We evaluated the anti-leishmanial efficacy of different saturated medium-chain fatty acids (FAs, C8–C18) where FA containing C8 chain, caprylic acid (CA), was found to be most potent against Leishmania donovani, the causative agent for visceral leishmaniasis (VL). Different analogs of CA with C8 lin...

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Autores principales: Prasad, Surendra Rajit, Kumar, Prakash, Mandal, Saptarshi, Mohan, Anu, Chaurasia, Radhika, Shrivastava, Ashish, Nikhil, Pallaprolu, Aishwarya, Dande, Ramalingam, P., Gajbhiye, Rahul, Singh, Shriya, Dasgupta, Arunava, Chourasia, Mukesh, Ravichandiran, V., Das, Prolay, Mandal, Debabrata
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9525708/
https://www.ncbi.nlm.nih.gov/pubmed/36180490
http://dx.doi.org/10.1038/s41598-022-20509-9
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author Prasad, Surendra Rajit
Kumar, Prakash
Mandal, Saptarshi
Mohan, Anu
Chaurasia, Radhika
Shrivastava, Ashish
Nikhil, Pallaprolu
Aishwarya, Dande
Ramalingam, P.
Gajbhiye, Rahul
Singh, Shriya
Dasgupta, Arunava
Chourasia, Mukesh
Ravichandiran, V.
Das, Prolay
Mandal, Debabrata
author_facet Prasad, Surendra Rajit
Kumar, Prakash
Mandal, Saptarshi
Mohan, Anu
Chaurasia, Radhika
Shrivastava, Ashish
Nikhil, Pallaprolu
Aishwarya, Dande
Ramalingam, P.
Gajbhiye, Rahul
Singh, Shriya
Dasgupta, Arunava
Chourasia, Mukesh
Ravichandiran, V.
Das, Prolay
Mandal, Debabrata
author_sort Prasad, Surendra Rajit
collection PubMed
description We evaluated the anti-leishmanial efficacy of different saturated medium-chain fatty acids (FAs, C8–C18) where FA containing C8 chain, caprylic acid (CA), was found to be most potent against Leishmania donovani, the causative agent for visceral leishmaniasis (VL). Different analogs of CA with C8 linear chain, but not higher, along with a carboxyl/ester group showed a similar anti-leishmanial effect. Ergosterol depletion was the major cause of CA-mediated cell death. Molecular docking and molecular dynamic simulation studies indicated the enzyme mevalonate kinase (MevK) of the ergosterol biosynthesis pathway as a possible target of CA. Enzyme assays with purified recombinant MevK and CA/CA analogs confirmed the target with a competitive inhibition pattern. Using biochemical and biophysical studies; strong binding interaction between MevK and CA/CA analogs was established. Further, using parasites with overexpressed MevK and proteomics studies of CA-treated parasites the direct role of MevK as the target was validated. We established the mechanism of the antileishmanial effect of CA, a natural product, against VL where toxicity and drug resistance with current chemotherapeutics demand an alternative. This is the first report on the identification of an enzymatic target with kinetic parameters and mechanistic insights against any organism for a natural medium-chain FA.
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spelling pubmed-95257082022-10-02 Mechanistic insight into the role of mevalonate kinase by a natural fatty acid-mediated killing of Leishmania donovani Prasad, Surendra Rajit Kumar, Prakash Mandal, Saptarshi Mohan, Anu Chaurasia, Radhika Shrivastava, Ashish Nikhil, Pallaprolu Aishwarya, Dande Ramalingam, P. Gajbhiye, Rahul Singh, Shriya Dasgupta, Arunava Chourasia, Mukesh Ravichandiran, V. Das, Prolay Mandal, Debabrata Sci Rep Article We evaluated the anti-leishmanial efficacy of different saturated medium-chain fatty acids (FAs, C8–C18) where FA containing C8 chain, caprylic acid (CA), was found to be most potent against Leishmania donovani, the causative agent for visceral leishmaniasis (VL). Different analogs of CA with C8 linear chain, but not higher, along with a carboxyl/ester group showed a similar anti-leishmanial effect. Ergosterol depletion was the major cause of CA-mediated cell death. Molecular docking and molecular dynamic simulation studies indicated the enzyme mevalonate kinase (MevK) of the ergosterol biosynthesis pathway as a possible target of CA. Enzyme assays with purified recombinant MevK and CA/CA analogs confirmed the target with a competitive inhibition pattern. Using biochemical and biophysical studies; strong binding interaction between MevK and CA/CA analogs was established. Further, using parasites with overexpressed MevK and proteomics studies of CA-treated parasites the direct role of MevK as the target was validated. We established the mechanism of the antileishmanial effect of CA, a natural product, against VL where toxicity and drug resistance with current chemotherapeutics demand an alternative. This is the first report on the identification of an enzymatic target with kinetic parameters and mechanistic insights against any organism for a natural medium-chain FA. Nature Publishing Group UK 2022-09-30 /pmc/articles/PMC9525708/ /pubmed/36180490 http://dx.doi.org/10.1038/s41598-022-20509-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Prasad, Surendra Rajit
Kumar, Prakash
Mandal, Saptarshi
Mohan, Anu
Chaurasia, Radhika
Shrivastava, Ashish
Nikhil, Pallaprolu
Aishwarya, Dande
Ramalingam, P.
Gajbhiye, Rahul
Singh, Shriya
Dasgupta, Arunava
Chourasia, Mukesh
Ravichandiran, V.
Das, Prolay
Mandal, Debabrata
Mechanistic insight into the role of mevalonate kinase by a natural fatty acid-mediated killing of Leishmania donovani
title Mechanistic insight into the role of mevalonate kinase by a natural fatty acid-mediated killing of Leishmania donovani
title_full Mechanistic insight into the role of mevalonate kinase by a natural fatty acid-mediated killing of Leishmania donovani
title_fullStr Mechanistic insight into the role of mevalonate kinase by a natural fatty acid-mediated killing of Leishmania donovani
title_full_unstemmed Mechanistic insight into the role of mevalonate kinase by a natural fatty acid-mediated killing of Leishmania donovani
title_short Mechanistic insight into the role of mevalonate kinase by a natural fatty acid-mediated killing of Leishmania donovani
title_sort mechanistic insight into the role of mevalonate kinase by a natural fatty acid-mediated killing of leishmania donovani
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9525708/
https://www.ncbi.nlm.nih.gov/pubmed/36180490
http://dx.doi.org/10.1038/s41598-022-20509-9
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