A map of the rubisco biochemical landscape

Noam Prywes, Naiya R. Phillips, Luke M. Oltrogge, Sebastian Lindner, Leah J. Taylor-Kearney, Yi-Chin Candace Tsai, Benoit Pins, Aidan E. Cowan, Hana A. Chang, Renée Z. Wang, Laina N. Hall, Daniel Bellieny-Rabelo, Hunter M. Nisonoff, Rachel F. Weissman, Avi I. Flamholz, David Ding, Abhishek Y. Bhatt, Oliver Mueller-Cajar, Patrick M. Shih, Ron Milo and David F. Savage ()
Additional contact information
Noam Prywes: University of California Berkeley
Naiya R. Phillips: University of California Berkeley
Luke M. Oltrogge: University of California Berkeley
Sebastian Lindner: University of Heidelberg
Leah J. Taylor-Kearney: University of California Berkeley
Yi-Chin Candace Tsai: Nanyang Technological University
Benoit Pins: University of Naples Federico II
Aidan E. Cowan: University of California Berkeley
Hana A. Chang: University of California Berkeley
Renée Z. Wang: University of California Berkeley
Laina N. Hall: University of California Berkeley
Daniel Bellieny-Rabelo: University of California Berkeley
Hunter M. Nisonoff: University of California Berkeley
Rachel F. Weissman: University of California Berkeley
Avi I. Flamholz: California Institute of Technology
David Ding: University of California Berkeley
Abhishek Y. Bhatt: University of California Berkeley
Oliver Mueller-Cajar: Nanyang Technological University
Patrick M. Shih: University of California Berkeley
Ron Milo: Weizmann Institute of Science
David F. Savage: University of California Berkeley

Nature, 2025, vol. 638, issue 8051, 823-828

Abstract: Abstract Rubisco is the primary CO2-fixing enzyme of the biosphere1, yet it has slow kinetics2. The roles of evolution and chemical mechanism in constraining its biochemical function remain debated3,4. Engineering efforts aimed at adjusting the biochemical parameters of rubisco have largely failed5, although recent results indicate that the functional potential of rubisco has a wider scope than previously known6. Here we developed a massively parallel assay, using an engineered Escherichia coli7 in which enzyme activity is coupled to growth, to systematically map the sequence–function landscape of rubisco. Composite assay of more than 99% of single-amino acid mutants versus CO2 concentration enabled inference of enzyme velocity and apparent CO2 affinity parameters for thousands of substitutions. This approach identified many highly conserved positions that tolerate mutation and rare mutations that improve CO2 affinity. These data indicate that non-trivial biochemical changes are readily accessible and that the functional distance between rubiscos from diverse organisms can be traversed, laying the groundwork for further enzyme engineering efforts.

Date: 2025
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DOI: 10.1038/s41586-024-08455-0

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