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Dissertation thesis: Scalable Computation and Analysis of Elementary Flux Modes in Steady State Metabolic Netwrks

Stoichiometry network analysis of metabolic networks can be performed using the methods of the constrained-based analysis. Enforcing the thermodynamics constraints on individual reactions, neglecting the largely unknown kinetic parameters of the cellular reactions and establishing the quasi-steady state on the individual metabolites leads to the major structural constraints on the metabolic network which are used by the constraint-based analysis methods. Two families of methods known as (1) pathway-based methods (2) optimization-based methods were proposed and used in the studies of cellular phenotype and metabolic capabilities. Elementary flux modes represent metabolic pathways in the network which beside satisfying the imposed constraints, also satisfy the constraint of minimality (i.e. genetic independence) whereas the number of reactions with non-zero flux in a mode is minimal. The algorithm for the computation of elementary flux modes, the Nullspace Algorithm, is derived from the Double Description Method, for the enumeration of rays in the bounded polyhedron whose complexity still remains an open problem. The elementary flux modes can be used for the 1) characterization of the cell phenotype 2) discovery of efficient gene/reaction targets for engineering of more efficent microorganism strains 3) estimation of the overall most likely reaction flux distribution in the metabolic network, 4) studies of the regulatory cellular behavior by means of computing control effective fluxes.

Publications:
  1. D. Jevremovic, D. Boley, C. Sosa, "Algorithms for enumeration of efficient reaction knockouts using elementary flux modes", submitted for review, 2013
  2. D. Jevremovic, D. Boley, "Finding minimal generating set for the metabolic network with reversible reactions", Volume 112, Issue 1, April 2013, Pages 31-36
  3. D. Jevremovic, D. Boley, "Parallel Computation of Elementary Flux Modes in Metabolic Networks using Global Array Toolkit", The 6th Conference on Partitioned Global Address Space Programming Models, Santa Barbara, CA, October, 2012
  4. D. Jevremovic, D. Boley, C. Sosa, "Divide-and-conquer approach to the parallel computation of elementary flux modes in metabolic networks", 2011 IEEE International Symposium on Parallel and Distributed Processing Workshops and PhD Forum, pp. 502-511
  5. D. Jevremovic, C. Trinh, F. Srienc, C. Sosa, D. Boley, "Parallelization of the Nullspace Algorithm for the Computation of Metabolic Pathways", Parallel Computing, vol. 37, no. 6-7, (2011), pp. 261-278
  6. D. Jevremovic, C. Trinh, F. Srienc, D. Boley, "On Algebraic Properties of Extreme Pathways in Metabolic Networks", Journal of Computational Biology, vol. 17, no. 2, (2010), pp. 107-119
  7. D. Jevremovic, C. Trinh, F. Srienc, D. Boley, "A Simple Rank Test to Distinguish Extreme Pathways from Elementary Modes in Metabolic Networks", technical report 08-029, 2008