ArticleProtein science : a publication of the Protein Society2009
Computational design of Candida boidinii xylose reductase for altered cofactor specificity.
Article in Protein science : a publication of the Protein Society, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30 citing papers in PubMed, 92 citations in OpenAlex.
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- Comprehensive evaluation of the capacities of microbial cell factories.Nature communications · 2025Article
- Logistic Regression-Guided Identification of Cofactor Specificity-Contributing Residues in Enzyme with Sequence Datasets Partitioned by Catalytic Properties.ACS synthetic biology · 2022Article
- Construction of advanced producers of first- and second-generation ethanol in Saccharomyces cerevisiae and selected species of non-conventional yeasts (Scheffersomyces stipitis, Ogataea polymorpha).Journal of industrial microbiology & biotechnology · 2020Review
- Heterologous expression of Spathaspora passalidarum xylose reductase and xylitol dehydrogenase genes improved xylose fermentation ability of Aureobasidium pullulans.Microbial cell factories · 2018Article
- Enhancing the Co-utilization of Biomass-Derived Mixed Sugars by Yeasts.Frontiers in microbiology · 2018Review
- Protein Engineering for Nicotinamide Coenzyme Specificity in Oxidoreductases: Attempts and Challenges.Frontiers in microbiology · 2018Review
- Computational Redesign of Acyl-ACP Thioesterase with Improved Selectivity toward Medium-Chain-Length Fatty Acids.ACS catalysis · 2017Article
- Production of fuels and chemicals from xylose by engineered Saccharomyces cerevisiae: a review and perspective.Microbial cell factories · 2017Review
- A General Tool for Engineering the NAD/NADP Cofactor Preference of Oxidoreductases.ACS synthetic biology · 2017Article
- Construction of plasmid-free Escherichia coli for the production of arabitol-free xylitol from corncob hemicellulosic hydrolysate.Scientific reports · 2016Article
- Mutations in adenine-binding pockets enhance catalytic properties of NAD(P)H-dependent enzymes.Protein engineering, design & selection : PEDS · 2016Article
- Forcefield_NCAA: ab initio charge parameters to aid in the discovery and design of therapeutic proteins and peptides with unnatural amino acids and their application to complement inhibitors of the compstatin family.ACS synthetic biology · 2014Article
- De novo design and experimental characterization of ultrashort self-associating peptides.PLoS computational biology · 2014Article
- Protein folding and de novo protein design for biotechnological applications.Trends in biotechnology · 2014Review
- BioGPS descriptors for rational engineering of enzyme promiscuity and structure based bioinformatic analysis.PloS one · 2014Article
- Forcefield_PTM:Journal of chemical theory and computation · 2013Article
- An evolution-based approach to De Novo protein design and case study on Mycobacterium tuberculosis.PLoS computational biology · 2013Article
- General approach to reversing ketol-acid reductoisomerase cofactor dependence from NADPH to NADH.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
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6 authors at 1 institution in 1 country.
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Abstract
In this study we introduce a computationally-driven enzyme redesign workflow for altering cofactor specificity from NADPH to NADH. By compiling and comparing data from previous studies involving cofactor switching mutations, we show that their effect cannot be explained as straightforward changes in volume, hydrophobicity, charge, or BLOSUM62 scores of the residues populating the cofactor binding site. Instead, we find that the use of a detailed cofactor binding energy approximation is needed to adequately capture the relative affinity towards different cofactors. The implicit solvation models Generalized Born with molecular volume integration and Generalized Born with simple switching were integrated in the iterative protein redesign and optimization (IPRO) framework to drive the redesign of Candida boidinii xylose reductase (CbXR) to function using the non-native cofactor NADH. We identified 10 variants, out of the 8,000 possible combinations of mutations, that improve the computationally assessed binding affinity for NADH by introducing mutations in the CbXR binding pocket. Experimental testing revealed that seven out of ten possessed significant xylose reductase activity utilizing NADH, with the best experimental design (CbXR-GGD) being 27-fold more active on NADH. The NADPH-dependent activity for eight out of ten predicted designs was either completely abolished or significantly diminished by at least 90%, yielding a greater than 10(4)-fold change in specificity to NADH (CbXR-REG). The remaining two variants (CbXR-RTT and CBXR-EQR) had dual cofactor specificity for both nicotinamide cofactors.
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