title: The Impact of Non-Enzymatic Reactions and Enzyme Promiscuity on Cellular Metabolism during (Oxidative) Stress Conditions.
abstract: Cellular metabolism assembles in a structurally highly conserved, but functionally dynamic system, known as the metabolic network. This network involves highly active, enzyme-catalyzed metabolic pathways that provide the building blocks for cell growth. In parallel, however, chemical reactivity of metabolites and unspecific enzyme function give rise to a number of side products that are not part of canonical metabolic pathways. It is increasingly acknowledged that these molecules are important for the evolution of metabolism, affect metabolic efficiency, and that they play a potential role in human disease-age-related disorders and cancer in particular. In this review we discuss the impact of oxidative and other cellular stressors on the formation of metabolic side products, which originate as a consequence of: (i) chemical reactivity or modification of regular metabolites; (ii) through modifications in substrate specificity of damaged enzymes; and (iii) through altered metabolic flux that protects cells in stress conditions. In particular, oxidative and heat stress conditions are causative of metabolite and enzymatic damage and thus promote the non-canonical metabolic activity of the cells through an increased repertoire of side products. On the basis of selected examples, we discuss the consequences of non-canonical metabolic reactivity on evolution, function and repair of the metabolic network.
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Rd, Cambridge CB2 1GA, UK. gp394@cam.ac.uk.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Piedrafita
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Rd, Cambridge CB2 1GA, UK. mk747@cam.ac.uk.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Keller
authors.affiliation: Department of Biochemistry, University of Cambridge, 80 Tennis Court Rd, Cambridge CB2 1GA, UK. markus.ralser@crick.ac.uk.|The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, London NW1 7AA, UK. markus.ralser@crick.ac.uk.
authors.forename: Markus
authors.initials: M
authors.lastname: Ralser
mesh_terms: D005075:Biological Evolution; D006801:Humans; D053858:Metabolic Networks and Pathways; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D013379:Substrate Specificity
keywords: enzyme promiscuity; metabolic damage; metabolite repair; oxidative stress; reactive oxygen species; underground metabolism