Metallocarbene-and metallonitrene-based catalysis has been widely explored for chemical modification of natural proteins (Scheme 7A, 7B, 7C). The carbene and nitrene chemistry functions with the nucleophilic reactivity of amino acid side chains such as indole (Trp) and amine (Lys) through generation of electrophilic metal species from stable precursor molecules (e.g., diazo and sulfonamide compounds). Copper, rhodium, 118 and ruthenium 119 complexes have been shown to be useful for targeting various amino acid residues through metallocarbene intermediates (Scheme 7B). The majority of the metallocarbenebased strategies relied on discrete complexes such as a paddlewheel rhodium complex and ruthenium porphyrin complex, perhaps increasing the life time of the catalysts in aqueous solution in the presence of the nucleophilic biomolecules. Those metal complexes exhibits electrophilic nature, and the reactivity of the carbene complex can be enhanced through coordination of a buffer component to the metal center (Scheme 7D). Such a ligand binding can also cause the alteration of chemoselectivity of dirhodium carbene reactivity toward tryptophan to cysteine by use of a reagent bearing thioether group (i.e., biotin group). The rhodium carbenoid system can be coupled with a proximity-driven strategy to target many amino acid residues other than tryptophan (see the Supramolecular catalysis section). 122 More recently, copper nitrene complex was shown to act as a methionineselective protein modification method, where copper bromide salt and sulfonamide are the precursors of the nitrene complex. The unique chemoselectivity of the nitrene chemistry was ascribed to the thioether reactivity to the electrophilic metal center bound with acetonitrile ligands. As such, there has been a variety of carbeneand nitrene-based metal catalysis for protein modification since the initial report of the tryptophan-selective carbenoid method as one of the early examples of the modern protein bioconjugation study. In addition to the carbene and nitrene catalysis, a copper-catalyzed azide transfer reaction using sulfonyl azide to alkyl amine groups of proteins should be mentioned here, as the transfer mechanism has similarity to the diazo reagent preparation. 124 Scheme 7. Carbene and nitrene catalysis by copper, rhodium, and ruthenium complexes. (A) General reaction scheme. (B) Chemical structures of catalysts. (C) General depiction of mechanism of actions of catalysts. (D) Coordination of an additional ligand to a metal center as strategies to increase catalytic activity or alter chemoselectivity