ArticleACS synthetic biology2012
SCHEMA-designed variants of human Arginase I and II reveal sequence elements important to stability and catalysis.
Article in ACS synthetic biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 59 citations in OpenAlex.
- Human arginase I: a potential broad-spectrum anti-cancer agent.3 Biotech · 2023Review
- Human arginase 1, a Jack of all trades?3 Biotech · 2022Review
- Structural insights into human Arginase-1 pH dependence and its inhibition by the small molecule inhibitor CB-1158.Journal of structural biology: X · 2020Article
- In Vivo Selection of a Computationally Designed SCHEMA AAV Library Yields a Novel Variant for Infection of Adult Neural Stem Cells in the SVZ.Molecular therapy : the journal of the American Society of Gene Therapy · 2018Article
- Learning epistatic interactions from sequence-activity data to predict enantioselectivity.Journal of computer-aided molecular design · 2017Article
- Machine learning to design integral membrane channelrhodopsins for efficient eukaryotic expression and plasma membrane localization.PLoS computational biology · 2017Article
- Reduced bioavailable manganese causes striatal urea cycle pathology in Huntington's disease mouse model.Biochimica et biophysica acta. Molecular basis of disease · 2017Article
- Structure-guided SCHEMA recombination generates diverse chimeric channelrhodopsins.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Exploring the Mechanism Responsible for Cellulase Thermostability by Structure-Guided Recombination.PloS one · 2016Article
- Synthetic biology for the directed evolution of protein biocatalysts: navigating sequence space intelligently.Chemical Society reviews · 2015Review
- Arginase as a new concern in blood transfusion.Blood transfusion = Trasfusione del sangue · 2014Article
- SCHEMA computational design of virus capsid chimeras: calibrating how genome packaging, protection, and transduction correlate with calculated structural disruption.ACS synthetic biology · 2013Article
- Chimeragenesis of distantly-related proteins by noncontiguous recombination.Protein science : a publication of the Protein Society · 2013Article
- Random field model reveals structure of the protein recombinational landscape.PLoS computational biology · 2012Article
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
Arginases catalyze the divalent cation-dependent hydrolysis of L-arginine to urea and L-ornithine. There is significant interest in using arginase as a therapeutic antineogenic agent against L-arginine auxotrophic tumors and in enzyme replacement therapy for treating hyperargininemia. Both therapeutic applications require enzymes with sufficient stability under physiological conditions. To explore sequence elements that contribute to arginase stability we used SCHEMA-guided recombination to design a library of chimeric enzymes composed of sequence fragments from the two human isozymes Arginase I and II. We then developed a novel active learning algorithm that selects sequences from this library that are both highly informative and functional. Using high-throughput gene synthesis and our two-step active learning algorithm, we were able to rapidly create a small but highly informative set of seven enzymatically active chimeras that had an average variant distance of 40 mutations from the closest parent arginase. Within this set of sequences, linear regression was used to identify the sequence elements that contribute to the long-term stability of human arginase under physiological conditions. This approach revealed a striking correlation between the isoelectric point and the long-term stability of the enzyme to deactivation under physiological conditions.
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