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.

由于新陈代谢是一个复杂的平衡过程，涉及多种酶，因此了解生物体如何补偿短暂或永久性代谢不平衡是一项艰巨的任务，在简单的单细胞生物中可以轻松实现。代谢平衡不仅是由于个体酶学特性，酶丰度的调节的结合，而且还取决于提供多种相互转化选择的代谢网络的结构。尽管代谢网络通常对扰动具有很高的复原力，但是可以通过实验和研究设计出由酶缺陷和特定环境条件引起的代谢失衡。以double amd1 aah1开头严重且有条件地影响酵母生长的突变体，我们仔细表征了与此缺陷相关的代谢改组。我们确定，导致腺苷酸/鸟苷酸核苷酸失衡的GTP降低是造成生长缺陷的原因。的几个基因剂量抑制器鉴定表明TAT1，编码氨基酸转运蛋白，是的鲁棒抑制器AMD1 aah1生长缺陷。我们显示TAT1抑制发生在需要组氨酸生物合成途径的过程中通过补充GTP池而发生。重要的是，我们确定tat1突变体与amd1结合时会表现出综合疾病突变和这种合成表型的两个组成部分可以通过特定的基因剂量抑制剂来抑制。我们的数据共同表明，氨基酸摄入与GTP合成之间存在很强的表型联系，这种联系可以为以后治疗相关的人类缺陷开辟前景，以前据报道在病因上高度保守。