A Similarity-Based Method for Predicting Enzymatic Functions in Yeast Uncovers a New AMP Hydrolase. Issue 7 (15th April 2022)

• Record Type: Journal Article
• Authors: Cohen, Nir; Kahana, Amit; Schuldiner, Maya
• Is Part Of: Journal of molecular biology. Volume 434:Issue 7(2022)
• Publication Date: 2022-04-15
• Subjects: Saccharomyces cerevisiae -- Yhr202w -- Smn1 -- AnalogYeast -- metabolomics; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2022.167478
• Languages: English
• ISSNs: 0022-2836

Abstract

Graphical abstract: Highlights: A quarter of the Saccharomyces cerevisiae genome is not functionally annotated. We created a database of sensitive sequence similarity predictions for yeast proteins. We use our database to identify candidate enzymes for non-annotated reactions. We demonstrate a new function for the previously uncharacterized enzyme Yhr202w. Our methodology allows uncovering new functions of uncharacterized proteins. Abstract: Despite decades of research and the availability of the full genomic sequence of the baker's yeast Saccharomyces cerevisiae, still a large fraction of its genome is not functionally annotated. This hinders our ability to fully understand cellular activity and suggests that many additional processes await discovery. The recent years have shown an explosion of high-quality genomic and structural data from multiple organisms, ranging from bacteria to mammals. New computational methods now allow us to integrate these data and extract meaningful insights into the functional identity of uncharacterized proteins in yeast. Here, we created a database of sensitive sequence similarity predictions for all yeast proteins. We use this information to identify candidate enzymes for known biochemical reactions whose enzymes are unidentified, and show how this provides a powerful basis for experimental validation. Using one pathway as a test case we pair a new function for the previously uncharacterized enzyme Yhr202w, as an extra-cellular AMP hydrolase in the NAD degradation pathway. Yhr202w, which we now term Smn1 for Scavenger MonoNucleotidase 1, is a highly conserved protein that is similar to the human protein E5NT/CD73, which is associated with multiple cancers. Hence, our new methodology provides a paradigm, that can be adopted to other organisms, for uncovering new enzymatic functions of uncharacterized proteins.