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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adipates / chemistry
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Adipates / metabolism
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Alcohol Oxidoreductases / genetics*
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Alcohol Oxidoreductases / metabolism*
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Biocatalysis
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Catalytic Domain
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Humans
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Isocitrate Dehydrogenase / genetics*
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Models, Molecular
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Mutation*
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Neoplasms / enzymology
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Neoplasms / genetics*
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Protein Engineering*
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Saccharomyces cerevisiae / enzymology*
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Saccharomyces cerevisiae / genetics
Substances
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Adipates
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2-hydroxyadipic acid
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adipic acid
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alpha-ketoadipic acid
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Alcohol Oxidoreductases
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Isocitrate Dehydrogenase
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IDH1 protein, human
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homoisocitrate dehydrogenase