Rison, Stuart Christopher Gorthorn; (2003) Of proteins and pathways: Investigating protein functional classifications and the small molecule metabolism of Escherichia coli. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In this thesis, proteins are considered in two ways: (i) as entities requiring functional classification, and (ii) as participants in the small molecule metabolism (SMM) of Escherichia coli. The first consideration prompts an investigation of functional classification schemes applicable to gene products. The concepts of depth, breadth and resolution are used as descriptors of the schemes' scope and architecture, and selected classifications compared on that basis. A "Combination Scheme" (CS) is generated, and a range of representative classifications are mapped against the CS. For comparison, FuncWheels (graphical representations of hierarchical classification schemes) are generated - these illustrate differences in functional space coverage. The survey highlights many issues related to the design and implementation of gene product functional classifications, which are discussed in the light of emerging second- generation schemes such as the "Gene Ontology". The thesis then focuses on the structural anatomy of E. coli SMM. Domain reuse within and between enzymes, as well as within and between pathways, is considered. Special cases such as the "serial recruitment" of blocks of enzymes, and homology in "parallel enzymes", are studied. A network view of pathways is then taken, and correlations between four contexts are analysed: the metabolic context (i.e. the spatial organisation of enzymes in the SMM network); the genomic context (i.e. the location of enzyme encoding genes on the E. coli chromosome); the evolutionary context (i.e. homologies between SMM enzymes); and the functional context (i.e. the catalytic activity of enzymes). In addition, incidences of "inline reuse" of enzymes (i.e. the use of the same enzyme at different steps of a metabolic pathway) and of isozymes (homologous proteins participating in the same metabolic step) are investigated. Taken together, these analyses suggest a chemistry-driven patchwork model of pathway evolution, but other localised mechanisms, as well as regulatory constraints, are likely to be involved.

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