Improvement of a synthetic live bacterial therapeutic for phenylketonuria with biosensor-enabled enzyme engineering

Kristin J. Adolfsen, Isolde Callihan, Catherine E. Monahan, Per Jr. Greisen, James Spoonamore, Munira Momin, Lauren E. Fitch, Mary Joan Castillo, Lindong Weng, Lauren Renaud, Carl J. Weile, Jay H. Konieczka, Teodelinda Mirabella, Andres Abin-Fuentes, Adam G. Lawrence and Vincent M. Isabella ()
Additional contact information
Kristin J. Adolfsen: Zymergen Inc. (formerly enEvolv Inc.)
Isolde Callihan: Zymergen Inc. (formerly enEvolv Inc.)
Catherine E. Monahan: Synlogic Inc
Per Jr. Greisen: Zymergen Inc. (formerly enEvolv Inc.)
James Spoonamore: Zymergen Inc. (formerly enEvolv Inc.)
Munira Momin: Synlogic Inc
Lauren E. Fitch: Zymergen Inc. (formerly enEvolv Inc.)
Mary Joan Castillo: Synlogic Inc
Lindong Weng: Zymergen Inc. (formerly enEvolv Inc.)
Lauren Renaud: Synlogic Inc
Carl J. Weile: Zymergen Inc. (formerly enEvolv Inc.)
Jay H. Konieczka: Zymergen Inc. (formerly enEvolv Inc.)
Teodelinda Mirabella: Synlogic Inc
Andres Abin-Fuentes: Synlogic Inc
Adam G. Lawrence: Zymergen Inc. (formerly enEvolv Inc.)
Vincent M. Isabella: Synlogic Inc

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract In phenylketonuria (PKU) patients, a genetic defect in the enzyme phenylalanine hydroxylase (PAH) leads to elevated systemic phenylalanine (Phe), which can result in severe neurological impairment. As a treatment for PKU, Escherichia coli Nissle (EcN) strain SYNB1618 was developed under Synlogic’s Synthetic Biotic™ platform to degrade Phe from within the gastrointestinal (GI) tract. This clinical-stage engineered strain expresses the Phe-metabolizing enzyme phenylalanine ammonia lyase (PAL), catalyzing the deamination of Phe to the non-toxic product trans-cinnamate (TCA). In the present work, we generate a more potent EcN-based PKU strain through optimization of whole cell PAL activity, using biosensor-based high-throughput screening of mutant PAL libraries. A lead enzyme candidate from this screen is used in the construction of SYNB1934, a chromosomally integrated strain containing the additional Phe-metabolizing and biosafety features found in SYNB1618. Head-to-head, SYNB1934 demonstrates an approximate two-fold increase in in vivo PAL activity compared to SYNB1618.

Date: 2021
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DOI: 10.1038/s41467-021-26524-0

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