Academic journal article Genetics

How Biochemical Constraints of Cellular Growth Shape Evolutionary Adaptations in Metabolism

Academic journal article Genetics

How Biochemical Constraints of Cellular Growth Shape Evolutionary Adaptations in Metabolism

Article excerpt

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.

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ENVIRONMENTAL conditions set the selective pressures acting on unicellular organisms. Microbial fitness is often related to growth properties, such as biomass yield, growth rate, or antibiotic resistance. As a large part of the available resources is spent on the synthesis of metabolic machinery, regulation of the levels of metabolic enzymes can have large influences on fitness (Dean 1989; Dong et al. 1995; Dekel and Alon 2005; Stoebel et al. 2008). Selection on growth rate may then direct the evolution of microorganisms to optimal allocation of resources for fitness enhancement (Dekel and Alon 2005; Molenaar et al. 2009). Alternatively, evolution may be directed by metabolic trade-offs (Beardmore et al. 2011; Wenger et al. 2011), which may cause sympatric speciation (Friesen et al. 2004). To improve our understanding of the driving processes of metabolic evolution, the interplay between selective pressures and the biochemistry and organization of metabolic networks must be taken into account.

Studies on the growth effects of unneeded-protein expression, sometimes called gratuitous or nonfunctional protein expression, indicate significant reductions in growth rate in batch cultivations of Escherichia coli (Novick and Weiner 1957; Dong et al. 1995; Dekel and Alon 2005; Shachrai et al. 2010) and Zymomonas mobilis (Snoep et al. 1995) and strong selective disadvantages in chemostat cultivations using E. coli (Dean et al. 1986; Dean 1989; Lunzer et al. 2002; Stoebel et al. 2008). In Saccharomyces cerevisiae, a trade-offrelated to unneeded- protein expression was found (Lang et al. 2009). Dong, Nilsson, and Kurland found that unneeded protein can be expressed up to 30% of the total protein content before E. coli growth halts (Dong et al. 1995). They concluded that growth reduction was caused by competition for protein synthesis machinery between nonfunctional and growth-promoting proteins (cf. Vind et al. 1993). They also found significant reductions of ribosomal activity at high unneeded-protein expression, as if the cells experience a nutrient downshift(Dong et al. 1996). Stoebel et al. (2008) discovered that the costs of unneeded-protein synthesis of E. coli's lac operon in chemostat cultures is due to the transcription and translation process, e.g., the competition for RNA polymerases and ribosomes, rather than due to toxic effects or excessive usage of nucleotide or amino acid precursors. Other studies (Dong et al. 1995; Vind et al. 1993) also indicate that unneeded-protein synthesis is at the expense of the synthesis of other proteins that have growthrelated activities; hence, these are all experimental indications of the existence of a cellular constraint that limits the cellular protein content. …

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