119 / 2023-10-10 17:47:20

Synthesis of Phosphorus-Containing Protein and Peptide

protein synthesis, phosphorylation, phosphonate, phosphine

Phosphorus Chemistry and Life & Health science > 1) Phosphorus chemistry in chemical biology

Natural and artificial modifications largely expand the chemical space of protein and peptide, endowing them with abundant properties and biofunctions. Among diverse protein modifications, we maintain particular interests in phosphorus-containing moieties, include natural phosphate, its enzyme-inert phosphonate memetic and noncanonical phosphine at low oxidation state. Since structure-defined homogeneous modified proteins and peptides is demanding for both mechanistic investigation and biomedical application, we have made great efforts to figure out the synthetic challenging.

1. We have developed chemo- and bio- synthetic strategies for accessing proteins and peptides site-specifically modified with phosphate or phosphonate^1,2,3, which were applied to uncover the cross-talk of phosphorylation and lipidation on regulating key signaling proteins K-Ras and Rnd3, as well as modulate bioinorganic interface of tooth enamel⁴.

Phosphorus at low oxidation state has been acting as the privileged ligand of many renowned transitional metal catalysts in organic synthesis. But, it has been never found in natural organisms probably because of its sensitivity to aerobic environment. In fact, natural metalloproteins usually rely on nitrogen, sulfur and oxygen ligands instead of phosphorus from protein chain or cofactor. To bridge the large gap between the nonbiological phosphine ligands and protein chemistry, we recently realized the first genetic incorporation of phosphine ligand into proteins by using a designed borane protected non-canonical amino acid. Furthermore, we disclosed a one-pot deprotection and metal coordination strategy to allow for a facile synthesis of palladium-bound protein phosphine under aerobic conditions.⁵ This platform can enable the rational design of novel artificial metalloenzymes or functional metalloproteins.