Dataset Information

Integrative Computational Framework for Understanding Metabolic Modulation in Leishmania.

ABSTRACT: Background: The integration of computational and mathematical approaches is used to provide a key insight into the biological systems. Through systems biology approaches we seek to find detailed and more robust information on Leishmanial metabolic network. Forman/Forman-Ricci curvature measures were applied to identify important nodes in the network(s). This was followed by flux balance analysis (FBA) to decipher important drug targets. Results: Our results revealed several key high curvature nodes (metabolites) belonging to common yet crucial metabolic networks, thus, maintaining the integrity of the network which signifies its robustness. Further analysis revealed the presence of some of these metabolites, MGO, in redox metabolism of the parasite. Being a component in the glyoxalase pathway and highly cytotoxic, we further attempted to study the outcome of the deletion of the key enzyme (GLOI) mainly involved in the neutralization of MGO by utilizing FBA. The model and the objective function kept as simple as possible demonstrated an interesting emergent behavior. The non-functional GLOI in the model contributed to "zero" flux which signifies the key role of GLOI as a rate limiting enzyme. This has led to several fold increase production of MGO, thereby, causing an increased level of MGO•- generation. Conclusions: The integrated computational approaches have deciphered GLOI as a potential target both from curvature measures as well as FBA which could further be explored for kinetic modeling by implying various redox-dependent constraints on the model. Furthermore, a constraint-based FBA on a larger model could further be explored to get broader picture to understand the exact underlying mechanisms. Designing various in vitro experimental perspectives could churn the therapeutic importance of GLOI.

SUBMITTER: Chauhan N

PROVIDER: S-EPMC6877600 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Integrative Computational Framework for Understanding Metabolic Modulation in Leishmania.

Chauhan Nutan N Singh Shailza S

Frontiers in bioengineering and biotechnology 20191119

Background: The integration of computational and mathematical approaches is used to provide a key insight into the biological systems. Through systems biology approaches we seek to find detailed and more robust information on Leishmanial metabolic network. Forman/Forman-Ricci curvature measures were applied to identify important nodes in the network(s). This was followed by flux balance analysis (FBA) to decipher important drug targets. Results: Our results revealed several ...[more]

PMID: 31803732

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Project description:As a newly discovered post-translational modification (PTM), lysine malonylation (Kmal) regulates a myriad of cellular processes from prokaryotes to eukaryotes and has important implications in human diseases. Despite its functional significance, computational methods to accurately identify malonylation sites are still lacking and urgently needed. In particular, there is currently no comprehensive analysis and assessment of different features and machine learning (ML) methods that are required for constructing the necessary prediction models. Here, we review, analyze and compare 11 different feature encoding methods, with the goal of extracting key patterns and characteristics from residue sequences of Kmal sites. We identify optimized feature sets, with which four commonly used ML methods (random forest, support vector machines, K-nearest neighbor and logistic regression) and one recently proposed [Light Gradient Boosting Machine (LightGBM)] are trained on data from three species, namely, Escherichia coli, Mus musculus and Homo sapiens, and compared using randomized 10-fold cross-validation tests. We show that integration of the single method-based models through ensemble learning further improves the prediction performance and model robustness on the independent test. When compared to the existing state-of-the-art predictor, MaloPred, the optimal ensemble models were more accurate for all three species (AUC: 0.930, 0.923 and 0.944 for E. coli, M. musculus and H. sapiens, respectively). Using the ensemble models, we developed an accessible online predictor, kmal-sp, available at http://kmalsp.erc.monash.edu/. We hope that this comprehensive survey and the proposed strategy for building more accurate models can serve as a useful guide for inspiring future developments of computational methods for PTM site prediction, expedite the discovery of new malonylation and other PTM types and facilitate hypothesis-driven experimental validation of novel malonylated substrates and malonylation sites.

Dataset Information

Integrative Computational Framework for Understanding Metabolic Modulation in Leishmania.

Publications

Integrative Computational Framework for Understanding Metabolic Modulation in Leishmania.

Similar Datasets

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