Gene expression regulates metabolite homeostasis during the Crabtree effect: Implications for the adaptation and evolution of Metabolism

Abstract

A key issue in both molecular and evolutionary biology has been to define the roles of genes and phenotypes in the adaptation of organisms to environmental changes. The dominant view has been that an organism’s metabolic adaptations are driven by gene expression and that gene mutations, independent of the starting phenotype, are responsible for the evolution of new metabolic phenotypes. We propose an alternate hypothesis, in which the phenotype and genotype together determine metabolic adaptation both in the lifetime of the organism and in the evolutionary selection of adaptive metabolic traits. We tested this hypothesis by flux-balance and metabolic-control analysis of the relative roles of the starting phenotype and gene expression in regulating the metabolic adaptations during the Crabtree effect in yeast, when they are switched from a low- to high-glucose environment. Critical for successful short-term adaptation was the ability of the glycogen/trehalose shunt to balance the glycolytic pathway. The role of later gene expression of new isoforms of glycolytic enzymes, rather than flux control, was to provide additional homeostatic mechanisms allowing an increase in the amount and efficiency of adenosine triphosphate and product formation while maintaining glycolytic balance. We further showed that homeostatic mechanisms, by allowing increased phenotypic plasticity, could have played an important role in guiding the evolution of the Crabtree effect. Although our findings are specific to Crabtree yeast, they are likely to be broadly found because of the well-recognized similarities in glucose metabolism across kingdoms and phyla from yeast to humans.

The early days of ex vivo 1H, 13C, and 31P nuclear magnetic resonance in the laboratory of Dr. Robert G. Shulman from 1975 to 1995

“…This paradox was not resolved until a reanalysis 30 years later of the early 13 C and 31 P NMR yeast data, which found a novel mechanism in which the fluxes of the glycogen and trehalose synthesis pathways (that were later found to be blocked by the cif mutation) were coordinated with the glycolytic flux for maintaining glycolytic intermediate homoestasis. 10 This was a completely unexpected finding, with general significance for environmental adaptation by metabolic networks, and demonstrates the value even today of these early NMR studies. Another example of the use of ex vivo NMR to support in vivo studies was in the validation of the accuracy of the 13 C NMR-labeling patterns obtained in experiments of perfused mouse livers provided with 13 C-labeled substrates, such as glycerol and glucose, by comparison with results from the then standard 14 C analysis.…”

“…The studies of yeast focused on understanding the regulation of the glycolytic pathway during variations of the Pasteur effect. [7][8][9][10] Yeasts were the paradigmatic organism for understanding the control of the glycolytic flux, and were also a model for the Warburg effect in cancer because of their conversion of glucose to ethanol rather than complete oxidation. They were grown under conditions of low glucose in an oxygenated medium and then switched rapidly to a medium containing high levels of [1-13 C] glucose.…”

“…Another example of the use of ex vivo NMR to support in vivo studies was in the validation of the accuracy of the 13 C NMR-labeling patterns obtained in experiments of perfused mouse livers provided with 13 C-labeled substrates, such as glycerol and glucose, by comparison with results from the then standard 14 C analysis. 10 These studies were performed in collaboration with Dr. Sheila Cohen, who was then at Merck. Because of the larger size of the mouse liver and the requirement for a perfusion system in the magnet, the studies were performed on a wider inner diameter Bruker WH 360-MHz spectrometer in the laboratory of Dr. Alan C McLaughlin at Brookhaven National Laboratory.…”

Co‐option of stress mechanisms in the origin of evolutionary novelties

“…1B; Weber and Depew 2003;West-Eberhard 2003;Badyaev 2005b;Badyaev Alexander 2009;Ehrenreich and Pfennig 2016;Badyaev et al 2017). An environmentally induced trait becomes undergirded by heritable genetic variation, such as when individuals with different genotypes show different phenotypic responses or different degrees of plasticity (e.g., Rothman et al 2021), and then natural selection can preserve, augment, and refine these traits occurring in a beneficial direction or remove detrimental plasticity. Eventually, these phenotypes become anchored by genetic alterations and no longer require the distinctive environmental factor to trigger the relevant trait (Fig.…”

Analyses of lung cancer-derived volatiles in exhaled breath and in vitro models

“…Upregulation of a certain gene would reflect in increased synthesis of the product metabolite since increasing levels of the enzyme catalyzing the reaction would be present. 72 This would provide greater abundance for these compounds to transfer to exhaled breath. Thus, the detection of these compounds in breath could be used to reflect on the genetic anomalies in lung cancers and assist in identifying disease severity.…”