title: How biochemical constraints of cellular growth shape evolutionary adaptations in metabolism.
abstract: Evolutionary adaptations in metabolic networks are fundamental to evolution of microbial growth. Studies on unneeded-protein synthesis indicate reductions in fitness upon nonfunctional protein synthesis, showing that cell growth is limited by constraints acting on cellular protein content. Here, we present a theory for optimal metabolic enzyme activity when cells are selected for maximal growth rate given such growth-limiting biochemical constraints. We show how optimal enzyme levels can be understood to result from an enzyme benefit minus cost optimization. The constraints we consider originate from different biochemical aspects of microbial growth, such as competition for limiting amounts of ribosomes or RNA polymerases, or limitations in available energy. Enzyme benefit is related to its kinetics and its importance for fitness, while enzyme cost expresses to what extent resource consumption reduces fitness through constraint-induced reductions of other enzyme levels. A metabolic fitness landscape is introduced to define the fitness potential of an enzyme. This concept is related to the selection coefficient of the enzyme and can be expressed in terms of its fitness benefit and cost.
authors.affiliation: Systems Bioinformatics, The Centre for Integrative Bioinformatics VU, VU University, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Berkhout
authors.forename: Evert
authors.initials: E
authors.lastname: Bosdriesz
authors.forename: Emrah
authors.initials: E
authors.lastname: Nikerel
authors.forename: Douwe
authors.initials: D
authors.lastname: Molenaar
authors.forename: Dick
authors.initials: D
authors.lastname: de Ridder
authors.forename: Bas
authors.initials: B
authors.lastname: Teusink
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Bruggeman
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D001419:Bacteria / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics*; D012321:DNA-Directed RNA Polymerases / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism; D004798:Enzymes / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D056084:Genetic Fitness; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008957:Models, Genetic; D014176:Protein Biosynthesis; D012270:Ribosomes / Q000378:metabolism; D012641:Selection, Genetic
chemical_list: D004798:Enzymes; D012321:DNA-Directed RNA Polymerases
keywords: constraints; cost–benefit analysis; fitness landscape; metabolic evolution
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