Integrative Computational Framework for Understanding Metabolic Modulation in Leishmania

The integration of computational and mathematical approaches is used to provide a key insight into the biological systems. Here, we seek to find detailed and more robust information on Leishmanial metabolic network by performing mathematical characterization in terms of Forman/Forman-Ricci curvature measures combined with flux balance analysis (FBA). The model prototype developed largely depends on its structure and topological components. The correlation of curvature measures with various network statistical properties revealed the structural-functional framework. The analyses helped us to identify the importance of several nodes and detect sub-networks. Our results revealed several key high curvature nodes (metabolites) belonging to common yet crucial metabolic, thus, maintaining the integrity of the network which signifies its robustness. Further analysis revealed the presence of some of these metabolites in redox metabolism of the parasite. MGO, an important node, has highly cytotoxic and mutagenic nature that can irreversibly modify DNA, proteins and enzymes, making them nonfunctional, leading to the formation of AGEs and MGO[bullet]-. Being a component in the glyoxalase pathway, 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 both kept as simple as possible, demonstrated an interesting emergent behavior. The nonfunctional 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[bullet]- generation. Hence, the integrated computational approaches has 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. Designing various in vitro experimental perspectives could churn the therapeutic importance of GLOI.\n\nAuthor SummaryLeishmaniasis, one of the most neglected tropical diseases in the world, is of primary concern due to the increased risk of emerging drug resistance. To design novel drugs and search effective molecular drug targets with therapeutic importance, it is important to decipher the relation among the components responsible for leishmanial parasite survival inside the host cell at the metabolic level. Here, we have attempted to get an insight in the leishmanial metabolic network and predict the importance of key metabolites by applying mathematical characterization in terms of curvature measures and flux balance analysis (FBA). Our results identified several metabolites playing significant role in parasites redox homeostasis. Among these MGO (methylglyoxal) caught our interest due to its highly toxic and reactive nature of irreversibly modifying DNA and proteins. FBA results helped us to look into the important role of GLOI (Glyoxalase I), the enzyme that catalyses the detoxification of MGO, in the pathway that, when non-functional, has resulted into increased level production of free radicals and AGEs (advanced glycation end products). Thus, our study has deciphered GLOI as a potential target which could further be explored for future in vitro experiments to design potential GLOI inhibitors.