Friday, January 30, 2015

Metabolic Modeling for Validation of Genome Annotations

A major advance in bioinformatics in the last decade is the rapidity with which we can now create quantitative metabolic models from sequenced genomes.  In this and future blog posts we will examine several applications of metabolic modeling.  This post introduces metabolic modeling, considers its use for validation of genome annotations, and proposes that construction of metabolic models can form a routine part of the genome annotation process.

Thursday, January 22, 2015

Searching for Metabolic Routes in Pathway Tools

The Metabolic Route Search Problem

Consider the problem of performing an in-depth exploration of the metabolic network of an organism that you study, to compare alternative paths within that network whereby the organism can transform a starting metabolite into an ending metabolite.  What are the lengths and properties of these alternative pathways? 

Consider now a broader problem, namely the metabolic-engineering problem of finding the most efficient modification to the biochemical network of an organism to allow the organism to synthesize a new metabolite from a feedstock compound.  One aspect of "most efficient" is minimize the number of reactions added from an external database of known reactions.

RouteSearch [1] is a Pathway Tools component that solves both of the preceding problems by computing optimal metabolic routes, that is, an optimal series of biochemical reactions that connects start and goal compounds, given various cost parameters to control the optimality of the routes found.  RouteSearch can display several of the best routes it finds using an interactive graphical web page.  When RouteSearch is used for metabolic engineering, it uses the MetaCyc database as its external reaction database.

In computing optimality, RouteSearch takes into account the conservation of nonhydrogen atoms from the start compound to the goal compound. Perhaps surprisingly, it is possible to devise reaction paths that conserve no atoms from start to goal compound!  The more atoms that are conserved, the more efficient the transformation from start to goal.  To compute the number of conserved atoms, RouteSearch uses precomputed atom mappings of reactions that are available in MetaCyc [2]. An atom mapping of a reaction gives a one to one correspondence of each nonhydrogen atom from reactants to products.

RouteSearch is available only in Web mode in Pathway Tools (since version 17.0, March 2013). It is also available at but without the possibility to add reactions from MetaCyc (that mode is available only for locally installed versions of Pathway Tools). More details on how to use MetaCyc with RouteSearch are given in the following section.