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Structure-guided function discovery of an NRPS-like glycine betaine reductase for choline biosynthesis in fungi

Huang, Arthur M. ; Tang, Yi

Proceedings of the National Academy of Sciences - PNAS, 2019-05, Vol.116 (21), p.10348-10353 [Periódico revisado por pares]

United States: National Academy of Sciences

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Título:
Structure-guided function discovery of an NRPS-like glycine betaine reductase for choline biosynthesis in fungi
Autor: Huang, Arthur M. ; Tang, Yi
Assuntos: Amino Acid Oxidoreductases - metabolism ; Betaine - metabolism ; Biodegradation ; Biological Sciences ; Biosynthesis ; Choline ; Choline - metabolism ; Enzymes ; Functionals ; Fungal Proteins - genetics ; Fungal Proteins - metabolism ; Fungi ; Fungi - metabolism ; Genome - genetics ; Genomes ; Glycine ; Glycine - metabolism ; Glycine betaine ; Homeostasis ; Homology ; Metabolism ; Multienzyme Complexes - metabolism ; Peptide Synthases - metabolism ; Physical Sciences ; Reductase ; Structural analysis ; Structure-function relationships ; Substrate inhibition ; Substrate Specificity ; Substrates
É parte de: Proceedings of the National Academy of Sciences - PNAS, 2019-05, Vol.116 (21), p.10348-10353
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Author contributions: Y.H. and Y.T. designed research; Y.H. and A.M.H. performed research; Y.H. analyzed data; and Y.H. and Y.T. wrote the paper.
Edited by Wilfred A. van der Donk, Howard Hughes Medical Institute and University of Illinois, Urbana–Champaign, Urbana, IL, and accepted by Editorial Board Member Stephen J. Benkovic April 10, 2019 (received for review February 27, 2019)
Descrição: Nonribosomal peptide synthetases (NRPSs) and NRPS-like enzymes have diverse functions in primary and secondary metabolisms. By using a structure-guided approach, we uncovered the function of a NRPS-like enzyme with unusual domain architecture, catalyzing two sequential two-electron reductions of glycine betaine to choline. Structural analysis based on the 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 kingdom fungi. 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 insight in understanding fungal choline metabolism. The use of an NRPS-like enzyme for reductive choline formation is energetically efficient compared with known pathways. Our discovery also underscores the capabilities of the structure-guided approach in assigning functions of uncharacterized multidomain proteins, which can potentially aid functional discovery of new enzymes by genome mining.
Editor: United States: National Academy of Sciences
Idioma: Inglês

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Structure-guided function discovery of an NRPS-like glycine betaine reductase for choline biosynthesis in fungi

Huang, Arthur M. ; Tang, Yi

United States: National Academy of Sciences

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