title: Enzyme redesign guided by cancer-derived IDH1 mutations.
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.
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Reitman
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Choi
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojevic
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
mesh_terms: D000272:Adipates / Q000737:chemistry / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000235:genetics* / Q000378:metabolism*; D055162:Biocatalysis; D020134:Catalytic Domain; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics*; D015202:Protein Engineering; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics
chemical_list: D000272:Adipates; C076761:2-hydroxyadipic acid; C029900:adipic acid; C001918:alpha-ketoadipic acid; D000429:Alcohol Oxidoreductases; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C021368:homoisocitrate dehydrogenase