Proteins of unknown biochemical function - A persistent problem and a roadmap to help overcome it

Molecular Identification of d-Ribulokinase in Budding Yeast and Mammals

“…A major challenge in the post-genomic era is that a large fraction of protein-coding genes remain functionally unknown or poorly characterized in all sequenced genomes (1,2). Even in a well characterized organism such as Saccharomyces cerevisiae, the number of protein-coding genes with no known biological function, based on database searches in UniProt, amounts to ϳ30%, which corresponds to about 2000 proteins.…”

“…The S. cerevisiae genome encodes four SwissProt-reviewed FGGY domain-containing proteins: xylulose kinase (P42826); glycerol kinase (P32190); Mpa43 (P53583); and Ydr109c (Q04585). The motivation behind this study was the existence of a functionally uncharacterized carbohydrate kinase (Ydr109c) in S. cerevisiae with a homologous protein in humans (FGGY), which has been linked to S-ALS 2 and bipolar disorder.…”

Focus Issue on Metabolism: Metabolites, Metabolites Everywhere

“…It furthermore makes a strong case for utilizing bacterial genetics in this task, due to the economy of resources and effort such systems provide. The Update of Moghe and Last (2015) nicely complements the Niehaus et al (2015) article in reviewing the recruitment of enzymes from primary to specialized metabolism. Consideration of this recruitment process on the one hand brings great insight into the evolution of metabolism (Wheeler et al, 2015), while, on the other hand, it provides an opportunity for enzyme discovery in poorly characterized pathways.…”

“…The exact causal mechanism underlying such innovation can be due to a number of factors, including repurposing of promiscuous enzyme activities (Milo and Last, 2012), evolution of substrate specificity or transcriptional regulation, changes in allosteric regulation, or, in extreme cases, reorganization of enzyme complexes. As well as reviewing each of these, Moghe and Last (2015) also propose that similarities in gene sequence, reaction chemistries, and domains of expression can be used in a manner analogous to that described by Niehaus et al (2015) as a first approach toward characterizing unknown pathways of specialized metabolism.…”

“…Finally, they highlight how epigenetic modification of DNA can also lead to dramatic changes in metabolism, a fact that they exemplify by the work of Quadrana et al (2014), who discovered that vitamin E content was regulated by differential methylation of a retrotransposon located in the promoter of the vitamin E defective3 gene. Second, Niehaus et al (2015) illustrate how microbial genomics can be used to inform plant gene functional annotations, providing examples such as thiamin metabolite repair and riboflavin damage-control enzymes as well as Rubisco chaperone function. This article provides an excellent overview of how to tackle the still arduous yet unfortunately much required task of functional gene annotation as we slowly progress toward understanding the function of all metabolically associated genes in plants (Rhee and Mutwil, 2014).…”