Yeast to Study Human Purine Metabolism Diseases

Abstract

Purine nucleotides are involved in a multitude of cellular processes, and the dysfunction of purine metabolism has drastic physiological and pathological consequences. Accordingly, several genetic disorders associated with defective purine metabolism have been reported. The etiology of these diseases is poorly understood and simple model organisms, such as yeast, have proved valuable to provide a more comprehensive view of the metabolic consequences caused by the identified mutations. In this review, we present results obtained with the yeast Saccharomyces cerevisiae to exemplify how a eukaryotic unicellular organism can offer highly relevant information for identifying the molecular basis of complex human diseases. Overall, purine metabolism illustrates a remarkable conservation of genes, functions and phenotypes between humans and yeast.

Keywords: ADSL; AMP-deaminase; ATIC; Lesch–Nyhan; PRPS; hyperuricemia; nucleotide synthesis; purine metabolism; purine-associated deficiencies.

Figure 1

Schematic representation of the human and Saccharomyces cerevisiae purine biosynthesis pathways. Features of human and yeast enzymes are listed in Table A1, Table A2 and are shown in black and pink, respectively. For human enzymes, the numerous isoforms detected for some enzymes are not presented. Ortholog identity scores were determined as described in supplementary Table A3. Grey boxes correspond to enzymes with no or unidentified orthologs between yeast and human. “ATP production” in both yeast and human cells corresponds to the different ATP production pathways such as glycolysis and the respiratory chain/ATP synthase complexes. “Nucl.” stands for the numerous human nucleotidases, such as for example the NT5 family. Abbreviations: IMP: Inosine monophosphate; PRPP: Phosphorybosyl pyrophosphate; SAMP: Succinyl-AMP; SZMP: Succinyl Amino Imidazole Carboxamide Ribonucleotide monophosphate; XMP: Xanthosine monophosphate; ZMP: Amino Imidazole CarboxAmide Ribonucleotide monophosphate.

Figure 2

Functional complementation of the yeast phosphoribosyl aminoimidazole succinocarboxamide synthetase by the Xenopus laevis ortholog paics1.L. (a). Simplified scheme of the yeast purine pathway. (b). Yeast wild-type and knock-out mutant (ade1Δ) strains were either transformed with a plasmid allowing expression of the yeast (ADE1 Sc) or the Xenopus laevis (paics 1.L) amino imidazole succinocarboxamide synthetase encoded gene, or with the empty vector (None). Serial dilutions (1/10) of transformants were dropped on SDCASAW medium to score the ability of the yeast and xenopus genes to complement the ade1 mutant auxotrophy observed in the absence of external purine source. A medium supplemented with adenine was used as a viability control of transformants and images were obtained after 34 h of growth at 37 °C.