Abstract
Mutations in an enzyme can result in a neomorphic catalytic activity in cancers. We applied cancer-associated mutations from isocitrate dehydrogenases to homologous residues in the active sites of homoisocitrate dehydrogenases to derive enzymes that catalyze the conversion of 2-oxoadipate to (R)-2-hydroxyadipate, a critical step for adipic acid production. Thus, we provide a prototypic example of how insights from cancer genome sequencing and functional studies can aid in enzyme redesign.
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Acknowledgements
This work is supported by US National Institutes of Health grant R01 CA1403160 (H.Y.). We thank P.F. Cook at the University of Oklahoma for an HIDH expression plasmid, E. Spana at Duke University for S. cerevisiae genomic DNA, P. Fan for technical assistance and I. Fridovich and I. Batinic-Haberle for feedback on the manuscript.
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Z.J.R. and B.D.C. performed experiments and wrote the manuscript; I.S. performed LC/MS/MS analysis; D.D.B. and J.H.S. provided reagents; H.Y. contributed reagents, funding, and critical feedback on the manuscript.
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Reitman, Z., Choi, B., Spasojevic, I. et al. Enzyme redesign guided by cancer-derived IDH1 mutations. Nat Chem Biol 8, 887–889 (2012). https://doi.org/10.1038/nchembio.1065
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DOI: https://doi.org/10.1038/nchembio.1065
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