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Experimental Strategies for Functional Annotation and Metabolism Discovery: Targeted Screening of Solute Binding Proteins and Unbiased Panning of Metabolomes
TLDR
High-throughput protein production and differential scanning fluorimetry platforms enabled the screening of 158 SBPs against a 189 component library specifically tailored for this class of proteins, and illustrates the promise of crystallographic- and mass spectrometric-based approaches for the unbiased use of entire metabolomes as screening libraries. Expand
Investigating the Physiological Roles of Low-Efficiency d-Mannonate and d-Gluconate Dehydratases in the Enolase Superfamily: Pathways for the Catabolism of l-Gulonate and l-Idonate
TLDR
The physiological functions of three low-efficiency members of the ManD subgroup are investigated and a novel physiologically relevant pathway for l-gulonate catabolism in Chromohalobacter salexigens DSM3043 is identified, allowing the suggestion that these pathways may be either evolutionary relics or the starting points for new metabolic potential. Expand
Panoramic view of a superfamily of phosphatases through substrate profiling
TLDR
The functional space of the ubiquitous haloalkanoate dehalogenase superfamily (HADSF) was revealed by screening a customized substrate library against >200 enzymes from representative prokaryotic species, enabling inferred annotation of ∼35% of the HADSF. Expand
Structure-guided discovery of the metabolite carboxy-SAM that modulates tRNA function
TLDR
A new metabolite, carboxy-S-adenosyl-l-methionine (Cx-SAM), its biosynthetic pathway and its role in transfer RNA modification are described and the value of structural genomics approaches in identifying ligands within the context of their physiologically relevant macromolecular binding partners, and in revealing their functions are highlighted. Expand
Assignment of function to a domain of unknown function: DUF1537 is a new kinase family in catabolic pathways for acid sugars
TLDR
This study combined high-throughput ligand screening results for transport system solute binding proteins with the synergetic analysis of sequence similarity networks and genome neighborhood networks to establish that the members of the DUF1537 family are novel ATP-dependent four-carbon sugar kinases. Expand
A General Strategy for the Discovery of Metabolic Pathways: d-Threitol, l-Threitol, and Erythritol Utilization in Mycobacterium smegmatis.
We describe a general integrated bioinformatic and experimental strategy to discover the in vitro enzymatic activities and in vivo functions (metabolic pathways) of uncharacterized enzymes discoveredExpand
Covalent Docking Predicts Substrates for Haloalkanoate Dehalogenase Superfamily Phosphatases
TLDR
Investigation of the ability of covalent docking to identify substrates that pass through such a covalents intermediate, focusing particularly on the haloalkanoate dehalogenase superfamily, suggested the identity of the enzyme that catalyzes the orphan phosphatase reaction in the riboflavin biosynthetic pathway of Bacteroides. Expand
Identification of the in Vivo Function of the High-Efficiency d-Mannonate Dehydratase in Caulobacter crescentus NA1000 from the Enolase Superfamily
TLDR
In vivo functional characterization of a high-efficiency ManD from Caulobacter crescentus NA1000 (UniProt entry B8GZZ7) is reported by in vivo discovery of its essential role in d-glucuronate metabolism, and this in vivo functional annotation may be extended to ∼50 additional proteins. Expand
Prediction of enzymatic pathways by integrative pathway mapping
TLDR
A computational method is described that predicts the functions of orphan enzymes by organizing them into a linear metabolic pathway by finding those pathways that satisfy structural and network restraints implied by varied input information, including that from virtual screening, chemoinformatics, genomic context analysis, and ligand -binding experiments. Expand
Structure-guided discovery of carboxy-SAM as a novel metabolite modulating tRNA function
Identifying novel metabolites and characterizing their biological functions are major challenges of the post-genomic era. X-ray crystallography can reveal unanticipated ligands which persist throughExpand
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