Genetic investigation of purine nucleotide imbalance in Saccharomyces cerevisiae
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ORIGINAL ARTICLE
Genetic investigation of purine nucleotide imbalance in Saccharomyces cerevisiae Christelle Saint‑Marc1,2 · Johanna Ceschin1,2 · Claire Almyre1,2 · Benoît Pinson1,2 · Bertrand Daignan‑Fornier1,2 Received: 20 May 2020 / Revised: 21 July 2020 / Accepted: 6 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Because metabolism is a complex balanced process involving multiple enzymes, understanding how organisms compensate for transient or permanent metabolic imbalance is a challenging task that can be more easily achieved in simpler unicellular organisms. The metabolic balance results not only from the combination of individual enzymatic properties, regulation of enzyme abundance, but also from the architecture of the metabolic network offering multiple interconversion alternatives. Although metabolic networks are generally highly resilient to perturbations, metabolic imbalance resulting from enzymatic defect and specific environmental conditions can be designed experimentally and studied. Starting with a double amd1 aah1 mutant that severely and conditionally affects yeast growth, we carefully characterized the metabolic shuffle associated with this defect. We established that the GTP decrease resulting in an adenylic/guanylic nucleotide imbalance was responsible for the growth defect. Identification of several gene dosage suppressors revealed that TAT1, encoding an amino acid transporter, is a robust suppressor of the amd1 aah1 growth defect. We show that TAT1 suppression occurs through replenishment of the GTP pool in a process requiring the histidine biosynthesis pathway. Importantly, we establish that a tat1 mutant exhibits synthetic sickness when combined with an amd1 mutant and that both components of this synthetic phenotype can be suppressed by specific gene dosage suppressors. Together our data point to a strong phenotypic connection between amino acid uptake and GTP synthesis, a connection that could open perspectives for future treatment of related human defects, previously reported as etiologically highly conserved. Keywords Yeast metabolism · AMP deaminase · Adenine deaminase · GTP · Amino acid transport
Introduction
Communicated by M. Kupiec. Christelle Saint-Marc and Johanna Ceschin contributed equally to the work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00294-020-01101-y) contains supplementary material, which is available to authorized users. * Bertrand Daignan‑Fornier b.daignan‑[email protected] 1
IBGC, UMR 5095, Université de Bordeaux, Bordeaux, France
Centre National de la Recherche Scientifique IBGC, UMR 5095, Bordeaux, France
2
Metabolism is the highly integrated process of chemical interconversion in living organisms. It involves multiple enzymes organized in interconnected pathways. Although metabolic enzymes are generally highly specific and involved in a single pathway, mutations affecting metabolic enzymes can have multiple effects and result in complex phenotyp
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