A zinc salt was employed as Lewis acid for lipidation of cysteine through the catalytic activation of both nucleophiles and electrophiles (Scheme 12A, 12B). 168 S-lipidation is a naturally occurring post-translational modification that is relevant to various cell signaling events including synaptic transmission and GPCR protein signaling. In the report by Fairlie and co-workers achieving a chemical way for S-lipidation, zinc ions played catalytic roles in the SN2 reaction between thiol groups on cysteine residues and alkyl halides that contain fatty acid moieties. The zinc catalyst was suggested to have dual functions: increase of nucleophilicity of the thiol group and increase of electrophilicity of the alkyl halide. In other words, the catalyst would not only interact with the halide leaving group to enhance the electrophilicity of the alkyl halide, the nucleophile of cysteine residue can also be activated by the catalyst interaction lowering pKa of SH to thiolate ion. This design was perhaps inspired by a similar phenomenon found in natural zinc-containing enzymes (e.g. zinc-dependent transferases and zinc finger proteins ). As the catalysis proceeds with other divalent ions such as Ni and Cd 2+ , the affinity of the metal ions to the thiol group might be playing key roles in the system. Hexafluoroisopropanol (HFIP) can facilitate electrophilic aromatic substitution of tryptophan through activation of thiophene-ethanol labeling reagent by a metal, Lewis acidic catalyst (Scheme 12A, 12B). 172 HFIP, like other fluoroalcohols such as trifluoroethanol (TFE), is known to induce α-helical structures of polypeptide, and protein substrates may not always tolerate such conditions. The recent work by Ohata and co-workers demonstrated that increased protein compatibility of HFIP by ionic liquid additives. For instance, an anti-HER2 antibody, trastuzumab was shown to lose its selective antigenbinding activity after treatment in HFIP, but the activity and selectivity was retained when the antibody was treated with HFIP containing ionic liquids. Because HFIP and other fluoroalcohols are increasingly used for biomolecule modification recently, 111 the potential compatibility of the solvents with proteins motivates their application for catalytic protein bioconjugation. The HFIP-based bioconjugation work by Ohata and co-workers took advantage of Lewis-acid-catalyzed dehydrative alkylation reaction (Friedel-Crafts type process) 178 of tryptophan residues. Catalytic actions of the Lewis acid such as scandium ions were studied using density functional theory (DFT) calculations, suggesting that the acidity of HFIP is increased through the coordination of HFIP to scandium. The increased acidity of HFIP by the coordination was shown to cause protonation and liberation of the OH group of the labeling reagent (thiophene-ethanol) as shown in Scheme 12B. In other words, the preliminary computational study indicated HFIP as a proton donor for the dehydration process, and consistent with the observation, the same group also demonstrated use of Brønsted acid to catalyze the process as well. Although aqueous media have been often considered a requirement for useful protein bioconjugation methods, 180 this example in addition to a carboxylic acid-based serine modification method described below (the acid-catalyzed hydrolysis and alcoholysis section) may suggest practical usefulness of nonaqueous approaches.