Structure-guided function discovery of an NRPS-like glycine betaine reductase for choline biosynthesis in fungi
| Autor: | Yi Tang, Arthur J Huang, Yang Hai |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Betaine reductase Glycine choline metabolism 010402 general chemistry 01 natural sciences Choline Substrate Specificity Fungal Proteins 03 medical and health sciences chemistry.chemical_compound Betaine Biosynthesis Nonribosomal peptide Multienzyme Complexes Genetics Homology modeling Peptide Synthases NRPS-like Secondary metabolism 030304 developmental biology 2. Zero hunger chemistry.chemical_classification 0303 health sciences Multidisciplinary Genome 010405 organic chemistry Fungi glycine betaine reductase Biological Sciences 0104 chemical sciences 030104 developmental biology Enzyme chemistry Biochemistry Amino Acid Oxidoreductases biosynthesis |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 116, iss 21 |
| Popis: | Nonribosomal peptide synthetases (NRPS) and NRPS-like enzymes have diverse functions in primary and secondary metabolism. By using a structure-guided approach, we uncovered the function of an NRPS-like enzyme with unusual domain architecture, catalyzing two sequential two-electron reductions of glycine betaine to choline. Structural analysis based on homology model suggests cation-π interactions as the major substrate specificity determinant, which was verified using substrate analogs and inhibitors. Bioinformatic analysis indicates this NRPS-like glycine betaine reductase is highly conserved and widespread in fungi kingdom. Genetic knockout experiments confirmed its role in choline biosynthesis and maintaining glycine betaine homeostasis in fungi. Our findings demonstrate that the oxidative choline-glycine betaine degradation pathway can operate in a fully reversible fashion and provide new insights in understanding fungal choline metabolism. The use of an NRPS-like enzyme for reductive choline formation is energetically efficient compared to known pathways. Our discovery also underscores the capabilities of structure-guided approach in assigning function of uncharacterized multidomain proteins, which can potentially aid functional discovery of new enzymes by genome mining. |
| Databáze: | OpenAIRE |
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