Advancing Genetically Encoded Lysine (GEK) Chemistry: From Precision Modulation to Therapeutic Innovation
Year: 2025
Type: article
Abstract: Genetically encoded lysine (GEK) chemistry has transformed protein engineering by enabling precise and site-specific modifications, which expand lysine's functional landscape beyond its native post-translational modifications (PTMs). Our work has systematically advanced GEK chemistry by developing engineered pyrrolysyl-tRNA synthetase (PylRS) variants that efficiently incorporate diverse lysine (Lys) derivatives with tailored chemical reactivity. By integrating bioorthogonal handles, acyl and electrophilic warheads, photo-cross-linking groups, and PTM mimics, we have established a set of powerful toolkits for protein labeling, functional studies, and Lys-directed drug design. These advances provide precise control over protein structure and function, facilitating the study of epigenetic modifications, enzyme-substrate interactions, and Lys-guided inhibitor development. As GEK chemistry continues to evolve, its integration with structural/synthetic biology and therapeutic innovation will further expand its impact, unlocking new frontiers in chemical biology and precision therapeutics.
Source: Accounts of Chemical Research
Institution: Texas A&M University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Awards: G1195052402, G1670116962, The Development of Reversible Chemogenetic Switches for Chimeric Antigen Receptor T Cell Therapy, G4848062990, G6553094674, Cancer Therapeutics Training Program (CTTP), The acquisition of an instrument suite to set up a high-throughput screening core at Texas A&M University, Ultrasensitive detection of Mycobacterium tuberculosis infection
OpenAlex ID: W4414537860