General approach to reversing ketol-acid reductoisomerase cofactor dependence from NADPH to NADH

Brinkmann-Chen, Sabine; Flock, Tilman; Cahn, Jackson K. B.; Snow, Christopher D.; Brustad, Eric M.; McIntosh, John A.; Meinhold, Peter; Zhang, Liang; Arnold, Frances H.

doi:10.1073/pnas.1306073110

Title: General approach to reversing ketol-acid reductoisomerase cofactor dependence from NADPH to NADH

Journal Article · Mon Jun 17 00:00:00 EDT 2013 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1306073110· OSTI ID:1128893

Brinkmann-Chen, Sabine ^[1]; Flock, Tilman ^[2]; Cahn, Jackson K. B. ^[1]; Snow, Christopher D. ^[3]; Brustad, Eric M. ^[4]; McIntosh, John A. ^[1]; Meinhold, Peter ^[5]; Zhang, Liang ^[1]; Arnold, Frances H. ^[1]

California Inst. of Technology (CalTech), Pasadena, CA (United States)
California Inst. of Technology (CalTech), Pasadena, CA (United States); MRC Lab. of Molecular Biology, Cambridge (United Kingdom)
California Inst. of Technology (CalTech), Pasadena, CA (United States); Colorado State Univ., Fort Collins, CO (United States)
California Inst. of Technology (CalTech), Pasadena, CA (United States); Univ. of North Carolina, Chapel Hill, NC (United States)
Gevo, Inc., Englewood, CO (United States)

To date, efforts to switch the cofactor specificity of oxidoreductases from nicotinamide adenine dinucleotide phosphate (NADPH) to nicotinamide adenine dinucleotide (NADH) have been made on a case-by-case basis with varying degrees of success. Here we present a straightforward recipe for altering the cofactor specificity of a class of NADPH-dependent oxidoreductases, the ketol-acid reductoisomerases (KARIs). Combining previous results for an engineered NADH-dependent variant of Escherichia coli KARI with available KARI crystal structures and a comprehensive KARI-sequence alignment, we identified key cofactor specificity determinants and used this information to construct five KARIs with reversed cofactor preference. Additional directed evolution generated two enzymes having NADH-dependent catalytic efficiencies that are greater than the wild-type enzymes with NADPH. As a result, high-resolution structures of a wild-type/variant pair reveal the molecular basis of the cofactor switch.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1128893

Report Number(s):: SLAC-REPRINT-2014-040

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, Issue 27; ISSN 0027-8424

Publisher:: National Academy of Sciences, Washington, DC (United States)Copyright Statement

Country of Publication:: United States

Language:: English

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branched-chain amino acid pathway
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Title: General approach to reversing ketol-acid reductoisomerase cofactor dependence from NADPH to NADH

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