PUBLICATION
Identification of zebrafish fumarate hydratase active site by molecular docking and simulation studies
- Authors
- Hemagowri, V., Selvaraj, V., Jesu Jaya Sudan, R., Chinnappan, S., Bhuvan, A., Santhakumar, K.
- ID
- ZDB-PUB-201002-144
- Date
- 2020
- Source
- Journal of biomolecular structure & dynamics 40(3): 1260-1272 (Journal)
- Registered Authors
- Santhakumar, Kiran
- Keywords
- in silico, Fumarate hydratase, TCA cycle, citrate, molecular dynamics, zebrafish
- MeSH Terms
-
- Animals
- Catalytic Domain
- Fumarate Hydratase*/chemistry
- Fumarate Hydratase*/genetics
- Molecular Docking Simulation
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins/chemistry*
- Zebrafish Proteins/genetics
- PubMed
- 32969324 Full text @ J. Biomol. Struct. Dyn.
Citation
Hemagowri, V., Selvaraj, V., Jesu Jaya Sudan, R., Chinnappan, S., Bhuvan, A., Santhakumar, K. (2020) Identification of zebrafish fumarate hydratase active site by molecular docking and simulation studies. Journal of biomolecular structure & dynamics. 40(3):1260-1272.
Abstract
Fumarate hydratase (FH), one of the members of TCA cycle, acts as a catalyte for the synthesis of malate from fumarate. FH has been proposed to play as a tumour suppressor leading to the pathogenicity of leiomyomas, renal cell carcinoma and paraganglioma. Mutations in the active site of FH lead to alteration in the protein structure. Similarly, binding of several chemical inhibitors to the active site also leads to the disruption of protein structural integrity thereby leading to protein dysfunction. Therefore, in order to address this mechanism leading to cancer, the binding efficiency of potential human FH inhibitor citrate to zebrafish fh has been extensively analysed in this study by molecular docking and simulation experiments followed by quantification of fumarate hydratase enzyme activity to validate and confirm the findings. Molecular docking revealed stronger interaction of zebrafish fh protein with inhibitor citrate when compared to natural substrate fumarate. Study on the dynamics of docked structures further confirmed that citrate was found to possess more binding affinity than fumarate. In vitro biochemical analysis also revealed concentration dependent potential inhibitory effect of citrate on zebrafish fh, thus confirming the findings of the in-silico experiments. Communicated by Ramaswamy H. Sarma.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping