Files in this item



application/pdfPRADHAN-THESIS-2019.pdf (4MB)
(no description provided)PDF


Title:Efficient enzyme coupling algorithms identify functional pathways in genome-scale metabolic models
Author(s):Pradhan, Dikshant
Advisor(s):Jensen, Paul A
Department / Program:Bioengineering
Degree Granting Institution:University of Illinois at Urbana-Champaign
metabolic engineering
genome-scale model
Abstract:Flux coupling identifies sets of reactions whose fluxes are “coupled" or correlated in genome-scale models. By identified sets of coupled reactions, modelers can 1.) reduce the dimensionality of genome-scale models, 2.) identify reactions that must be modulated together during metabolic engineering, and 3.) identify sets of important enzymes using high-throughput data. We present three computational tools to improve the efficiency, applicability, and biological interpretability of flux coupling analysis. The first algorithm (cachedFCF) uses information from intermediate solutions to decrease the runtime of standard flux coupling methods by 10-100 fold. Importantly, cached-FCF makes no assumptions regarding the structure of the underlying model, allowing efficient flux coupling analysis of models with non-convex constraints. We next developed a mathematical framework (FALCON) that incorporates enzyme activity as continuous variables in genome-scale models. Using data from gene expression and fitness assays, we verified that enzyme sets calculated directly from FALCON models are more functionally coherent than sets of enzymes collected from coupled reaction sets. Finally, we present a method (delete-and-couple) for expanding enzyme sets to allow redundancies and branches in the associated metabolic pathways. The expanded enzyme sets align with known biological pathways and retain functional coherence. The expanded enzyme sets allow pathway-level analyses of genome-scale metabolic models. Together, our algorithms extend flux coupling techniques to enzymatic networks and models with transcriptional regulation and other non-convex constraints. By expanding the efficiency and flexibility of flux coupling, we believe this technique will find new applications in metabolic engineering, microbial pathogenesis, and other fields that leverage network modeling.
Issue Date:2019-04-24
Rights Information:Copyright 2019 Dikshant Pradhan
Date Available in IDEALS:2019-08-23
Date Deposited:2019-05

This item appears in the following Collection(s)

Item Statistics