Mechanistic insight into the role of mevalonate kinase by a natural fatty acid-mediated killing of Leishmania donovani
Abstract 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 wi...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-09-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-20509-9 |
| _version_ | 1828222353107058688 |
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| author | Surendra Rajit Prasad Prakash Kumar Saptarshi Mandal Anu Mohan Radhika Chaurasia Ashish Shrivastava Pallaprolu Nikhil Dande Aishwarya P. Ramalingam Rahul Gajbhiye Shriya Singh Arunava Dasgupta Mukesh Chourasia V. Ravichandiran Prolay Das Debabrata Mandal |
| author_facet | Surendra Rajit Prasad Prakash Kumar Saptarshi Mandal Anu Mohan Radhika Chaurasia Ashish Shrivastava Pallaprolu Nikhil Dande Aishwarya P. Ramalingam Rahul Gajbhiye Shriya Singh Arunava Dasgupta Mukesh Chourasia V. Ravichandiran Prolay Das Debabrata Mandal |
| author_sort | Surendra Rajit Prasad |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-12T16:54:05Z |
| format | Article |
| id | doaj.art-a1c1e3cab80342288fdf372b1c2054b0 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-12T16:54:05Z |
| publishDate | 2022-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-a1c1e3cab80342288fdf372b1c2054b02022-12-22T03:24:19ZengNature PortfolioScientific Reports2045-23222022-09-0112111910.1038/s41598-022-20509-9Mechanistic insight into the role of mevalonate kinase by a natural fatty acid-mediated killing of Leishmania donovaniSurendra Rajit Prasad0Prakash Kumar1Saptarshi Mandal2Anu Mohan3Radhika Chaurasia4Ashish Shrivastava5Pallaprolu Nikhil6Dande Aishwarya7P. Ramalingam8Rahul Gajbhiye9Shriya Singh10Arunava Dasgupta11Mukesh Chourasia12V. Ravichandiran13Prolay Das14Debabrata Mandal15Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Export Promotions Industrial Park (EPIP)Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Export Promotions Industrial Park (EPIP)Department of Chemistry, Indian Institute of TechnologyDepartment of Biotechnology, National Institute of Pharmaceutical Education and Research, Export Promotions Industrial Park (EPIP)Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Export Promotions Industrial Park (EPIP)Translational Bioinformatics and Computational Genomics Research Lab, Department of Life Sciences, Shiv Nadar UniversityDepartment of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and ResearchDepartment of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and ResearchDepartment of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and ResearchDepartment of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and ResearchMolecular Microbiology and Immunology Division, CSIR-Central Drug Research InstituteMolecular Microbiology and Immunology Division, CSIR-Central Drug Research InstituteAmity Institute of Biotechnology, Amity UniversityDepartment of Biotechnology, National Institute of Pharmaceutical Education and Research, Export Promotions Industrial Park (EPIP)Department of Chemistry, Indian Institute of TechnologyDepartment of Biotechnology, National Institute of Pharmaceutical Education and Research, Export Promotions Industrial Park (EPIP)Abstract 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.https://doi.org/10.1038/s41598-022-20509-9 |
| spellingShingle | Surendra Rajit Prasad Prakash Kumar Saptarshi Mandal Anu Mohan Radhika Chaurasia Ashish Shrivastava Pallaprolu Nikhil Dande Aishwarya P. Ramalingam Rahul Gajbhiye Shriya Singh Arunava Dasgupta Mukesh Chourasia V. Ravichandiran Prolay Das Debabrata Mandal Mechanistic insight into the role of mevalonate kinase by a natural fatty acid-mediated killing of Leishmania donovani Scientific Reports |
| 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 |
| url | https://doi.org/10.1038/s41598-022-20509-9 |
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