Our laboratory, and now many others, have added well over 100 noncanonical amino acids (ncAAs) to the genetic codes of single and multi-cellular organisms [1, 2]. These amino acids include spectroscopic probes, metal ion chelators, post-translationally modified amino acids and stable analogues thereof, amino acids with bio-orthogonal chemical reactivity, photocrosslinkers, and a host of other novel functions. Moreover, we have distributed this technology to hundreds of laboratories throughout the world to probe protein structure and function both inside and outside the cell, to engineer proteins with enhanced catalytic, physical and biological properties, and to create novel biotherapeutics. Here we propose to further expand our ability to manipulate the genetic code and apply this approach to important problems in biomedical research including exploring the function of short open reading frame encoded peptides, evolving proteins with enhanced properties, and genetically encoding ncAAs in hematopoietic stem cells and lineages derived therefrom in mice.
The ability to genetically encode unnatural amino acids beyond the common twenty significantly enhances our ability to manipulate protein structure. The result of this project will be new tools to study protein function in vitro and in vivo and new strategies to generate novel proteins with novel chemical or biological properties.
|Young, Douglas D; Schultz, Peter G (2018) Playing with the Molecules of Life. ACS Chem Biol 13:854-870|
|Xuan, Weimin; Collins, Daniel; Koh, Minseob et al. (2018) Site-Specific Incorporation of a Thioester Containing Amino Acid into Proteins. ACS Chem Biol 13:578-581|
|Xuan, Weimin; Schultz, Peter G (2017) A Strategy for Creating Organisms Dependent on Noncanonical Amino Acids. Angew Chem Int Ed Engl 56:9170-9173|
|Zambaldo, Claudio; Luo, Xiaozhou; Mehta, Angad P et al. (2017) Recombinant Macrocyclic Lanthipeptides Incorporating Non-Canonical Amino Acids. J Am Chem Soc 139:11646-11649|
|Xuan, Weimin; Yao, Anzhi; Schultz, Peter G (2017) Genetically Encoded Fluorescent Probe for Detecting Sirtuins in Living Cells. J Am Chem Soc 139:12350-12353|
|Luo, Xiaozhou; Fu, Guangsen; Wang, Rongsheng E et al. (2017) Genetically encoding phosphotyrosine and its nonhydrolyzable analog in bacteria. Nat Chem Biol 13:845-849|
|Xuan, Weimin; Shao, Sida; Schultz, Peter G (2017) Protein Crosslinking by Genetically Encoded Noncanonical Amino Acids with Reactive Aryl Carbamate Side Chains. Angew Chem Int Ed Engl 56:5096-5100|
|Mehta, Angad P; Li, Han; Reed, Sean A et al. (2016) Replacement of Thymidine by a Modified Base in the Escherichia coli Genome. J Am Chem Soc 138:7272-5|
|Luo, Xiaozhou; Zambaldo, Claudio; Liu, Tao et al. (2016) Recombinant thiopeptides containing noncanonical amino acids. Proc Natl Acad Sci U S A 113:3615-20|
|Liu, Yan; Wang, Ying; Zhang, Yong et al. (2016) Rational Design of Dual Agonist-Antibody Fusions as Long-acting Therapeutic Hormones. ACS Chem Biol 11:2991-2995|
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