Comput Methods Programs Biomed - Development and application of efficient pathway enumeration algorithms for metabolic engineering applications.

Tópicos

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Resumo

Metabolic Engineering (ME) aims to design microbial cell factories towards the production of valuable compounds. In this endeavor, one important task relates to the search for the most suitable heterologous pathway(s) to add to the selected host. Different algorithms have been developed in the past towards this goal, following distinct approaches spanning constraint-based modeling, graph-based methods and knowledge-based systems based on chemical rules. While some of these methods search for pathways optimizing specific objective functions, here the focus will be on methods that address the enumeration of pathways that are able to convert a set of source compounds into desired targets and their posterior evaluation according to different criteria. Two pathway enumeration algorithms based on (hyper)graph-based representations are selected as the most promising ones and are analyzed in more detail: the Solution Structure Generation and the Find Path algorithms. Their capabilities and limitations are evaluated when designing novel heterologous pathways, by applying these methods on three case studies of synthetic ME related to the production of non-native compounds in E. coli and S. cerevisiae: 1-butanol, curcumin and vanillin. Some targeted improvements are implemented, extending both methods to address limitations identified that impair their scalability, improving their ability to extract potential pathways over large-scale databases. In all case-studies, the algorithms were able to find already described pathways for the production of the target compounds, but also alternative pathways that can represent novel ME solutions after further evaluation.

Resumo Limpo

metabol engin aim design microbi cell factori toward product valuabl compound endeavor one import task relat search suitabl heterolog pathway add select host differ algorithm develop past toward goal follow distinct approach span constraintbas model graphbas method knowledgebas system base chemic rule method search pathway optim specif object function focus will method address enumer pathway abl convert set sourc compound desir target posterior evalu accord differ criteria two pathway enumer algorithm base hypergraphbas represent select promis one analyz detail solut structur generat find path algorithm capabl limit evalu design novel heterolog pathway appli method three case studi synthet relat product nonnat compound e coli s cerevisia butanol curcumin vanillin target improv implement extend method address limit identifi impair scalabl improv abil extract potenti pathway largescal databas casestudi algorithm abl find alreadi describ pathway product target compound also altern pathway can repres novel solut evalu

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