2022
Histamine receptor 2 (HRH2) activation results in gastric acid secretion, and HRH2 blockers are used for the treatment of peptidic ulcers and acid reflux. Current HRH2 blockers carry a five-membered aromatic heterocycle, with two of them additionally carrying a tertiary amine that decomposes to N-nitrosodimethylamine, a human carcinogen. To discover a novel HRH2 blocker scaffold to serve in the development of next-generation HRH2 blockers, we engineer an HRH2-based sensor and use it to identify three HRH2 blockers, chlorquinaldol, chloroxine, and broxyquinoline, all sharing an 8-hydroxyquinoline scaffold, which is not found among known HRH2 antagonists. Taken together, this work demonstrates the utility of GPCR-based sensors for rapid drug discovery applications and identifies a novel HRH2 blocker scaffold.
2021
           In the News: Gizmodo, Space.com, Popular Science
Mars colonization demands technological advances to enable the return of humans to Earth. Shipping the propellant and oxygen for a return journey is not viable. Considering the gravitational and atmospheric differences between Mars and Earth, we propose bioproduction of a Mars-specific rocket propellant, 2,3-butanediol (2,3-BDO), from CO2, sunlight and water on Mars via a biotechnology-enabled in situ resource utilization (bio-ISRU) strategy. Photosynthetic cyanobacteria convert Martian CO2 into sugars that are upgraded by engineered Escherichia coli into 2,3-BDO.
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Cell-free systems have distinct advantages over living organisms in terms of toxicity tolerance and ease of downstream separations processes. However, conventional CFSs lack the ability to synthesize membrane proteins due to a lack of stabilizing interface. Here we review recent advances in membrane augmented CFSs, for the production of membrane proteins, with applications towards high-throughput enzyme screening, complex chemical biosynthesis, enzyme fuel cells, and targeted cell therapeutics using membrane-associated receptor proteins. ​
2020
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Bioproduction of adipic acid offers a renewable alternative to the chemical process. Starting from lignin-derived monomers provides is economic advantageous. However, lignin depolymerization results in a mixed monomer stream. Here we show that an enzyme cascade composed of catechol 1,2-dioxygenase and muconic acid reductase produces adipic acid and adipic acid analogs from catechol and alkyl substituted catechols likely formed during lignin depolymerization. This demonstrates the utility of this enzyme cascade for a variety of lignin-derived feedstocks and the ability to microbially produce adipic acid analogs that can be polymerized to form nylon-like polymers with enhanced properties.
2019
  • Yasi E., Allen A., Sugianto W., Peralta-Yahya P. Identification of three antimicrobials activating serotonin receptor 4 in colon cells ACS Synthetic Biology, 8, 2710-2717, 2019.                                                                                                                                                                                                                      In the news: GaTech
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The serotonin receptor 4 (5-HTR4) is expressed in the gastrointestinal tract and its agonists are used to treat irritable bowel syndrome with constipation (IBS-C). Today, there are no rapid assays for the identification of 5-HTR4 agonists. Here, we developed a 5-HTR4 assay capable of testing one compound per second and used it to screen >1,000 chemicals. We identified three antibiotic ligands that result in increased colon cell motility. This assay can be used to screen larger pharmaceutical libraries to identify novel treatments for IBS-C. This work shows that antimicrobials interact not only with the gut microbiota, but also with the human host.
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Olfactory receptors (ORs) are expressed beyond the olfactory tissue. A key challenge in studying their role is the fact that the majority of ORs are orphaned (i.e. they have no known ligands). We generated sensors for 7 ORs  highly expressed in the colon. We ORs against a 57-member chemical panel and successfully deorphanized 2 of them: OR2T4 and OR10S1. We can now start understanding the role of these receptors in the colon.
2018
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Microbial production of chemicals relies on the introduction of heterologous enzymes (e.g. from plants) into host organisms (e.g. Escherichia coli). Often, little attention is paid to the interaction between the heterologous and host enzymes. Here, we optimized the interphase of the E. coli's acyl carrier protein (ACP) and Acineyobacter baylyi thioesterase to improve medium-chain fatty acid titers more than 3-fold. Simply engineering the interface between heterologous and host enzymes is a viable strategy to increase chemical titers.
2017
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A key limitation in the microbial production of chemicals is the throughput at which strains can be screened for chemical production. Chemical biosensors that convert chemical detection to a fluorescent output can enable high-throughput metabolic engineering applications. Here, we engineered a yeast-based serotonin sensor, used it to detect microbially produced serotonin, and validated it for medium-throughput screening applications.
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A number of pharmaceuticals are obtained via chemical derivatization of plant natural products. Today, plant pathways can be reconstituted in microbes and using engineered enzymes. Modified natural products can be produced to more rapidly and cost-effectively access pharmaceuticals.  Here, we analyzed more than 2,000 FDA approved drugs and proposed pathways and engineered enzymes to produce modified plant alkaloids to accelerate the semi synthesis of 7 pharmaceuticals on the market.
2015
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Anticancer and antimalarial agents are found among plant alkaloids. Isolation of alkaloids from plants is challenging due to their low accumulation and difficult separation from other similar compounds.  To become pharmaceuticals, alkaloids often need to be derivatized to increase bioavailability and reduce toxicity. Here, we engineered the first microbial platform for the production of a modified monoterpene indole alkaloid from simple sugars.
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Chemical biosensors convert chemical detection to a fluorescent or colorimetric output, enabling the screening of microbially produced chemicals up to 5 orders of magnitude faster than mass spectrometry methods.  Here, we developed a platform for the generation of G-protein coupled receptor (GPCR)-based sensors in yeast.
2014 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Postdoctoral and graduate work
de Rond T., Peralta-Yahya P., Cheng X., Northen T.R., Keasling J.D. Versatile synthesis of probes for high-throughput enzyme activity screening, Anal Bioanal Chem, 405, 4969-73, 2013.

Romanini D., Peralta-Yahya P., Mondol V., Cornish V.W. A heritable recombination system for synthetic darwinian evolution in yeast, ACS Synth Biol, 1, 602-9, 2012.

Peralta-Yahya P., Zhang F., del Cardayre S.B., Keasling J.D. Microbial engineering for the production of advanced biofuels, Nature, 488, 320-28, 2012.

McAndrew R,P., Peralta-Yahya P., DeGiovanni A., Pereira J.H., Hadi M.Z., Keasling J.D., Adams P.D. Structure of a three-domain sesquiterpene synthase: a prospective target for advanced biofuels production. Structure, 19, 1875-84, 2011.

Peralta-Yahya P., Ouellet M., Chan R., Mukhopadhyay A., Keasling J.D., Lee T.S. Identification and microbial production of a terpene-based advanced biofuel, Nat Commun 2:483, doi: 10.1038/ncomms1494, 2011.

Bokinsky G., Peralta-Yahya P., George A., Holmes B.M., Steen E.J., Dietrich J., Lee T.S., Tullman-Ercek D., Voigt C.A., Simmons B.A., Keasling J.D Synthesis of three advanced biofuels from ionic liquid-pretreated switchgrass using engineered Escherichia coli, Proc Natl Acad Sci USA. 108, 19949-54, 2011.

Pirakitikulr N., Ostrov N., Peralta-Yahya P., Cornish, V.W. PCRless library mutagenesis via oligonucleotide recombination in yeast. Protein Sci, 19, 2336-46, 2010.

Peralta-Yahya P., Keasling J.D. Advanced biofuel production in microbes, Biotechnol J, 5, 147-62, 2010.

Peralta-Yahya P., Carter B.T., Lin H., Tao H., Cornish V.W. High-throughput selection for cellulase catalysts using chemical complementation, J Am Chem Soc, 130, 17446-52, 2008.

Tao H., Peralta-Yahya P., Decatur J., Cornish V.W. Characterization of a new glycosynthase cloned by using chemical complementation, ChemBioChem, 9, 681-4, 2008.

Peralta-Yahya P., Cornish V.W. Bringing the power of genetics to chemistry, in Chemical Biology, S.L. Schreiber, T. Kapoor, G. WEiss, Eds. Wiley-VCH Verlag, 2007.

Tao H., Peralta-Yahya P., Lin H., Cornish V.W., Optimized design and synthesis of chemical dimerizer substrates for detection of glycosynthase activity via chemical complementation, Bioorg Med Chem, 14, 6940-53, 2006.