Cross-dressing proteins by olefin metathesis.

metathesis of proteins under aqueous conditions, which makes a powerful reaction in organic and polymer chemistry potentially available for the elaboration of biopolymers. The work by Davis and colleagues raises two follow-up questions regarding the versatility of the metathesis approach and its implementation under physiological conditions. The present study tests metathesis of proteins on a relatively unhindered position. The authors successfully perform cross-metathesis on an allyl substrate placed on a flexible loop of the serine protease subtili-sin (Fig. 1). It will be valuable to determine whether an alkene group placed on a more sterically demanding position, such as in the middle of a helix, can also interact with the metathesis catalyst. Second, the authors used an alcohol-water mixture to solubilize the metathesis catalyst and the protein. These conditions will likely destabilize many folded proteins. Several water-soluble analogs of the metathesis catalysts, including the Hoveyda-Grubbs catalyst, have been described strates for the cross-metathesis reaction in water, although these substrates have undergone the related ring-closing metathesis reaction with greater success 5,6. The studies by Davis et al. describe the conversion of a cysteine residue (Fig. 1, A) into dehydroalanine on protein surfaces (Fig. 1, B) 2. The α,β-unsaturated amide can undergo a conjugate addition reaction with a thiol to provide a functionalized protein (Fig. 1, C). Alternatively, reaction of the dehydroala-nine with allylmercaptan affords an allylsulfide group (Fig. 1, D), which can undergo cross-metathesis with an alkene in the presence of the Hoveyda-Grubbs metathesis catalyst (HG II) 7,8 to obtain the functionalized protein E (Fig. 1) 1. Davis and colleagues find that allylsulfides are superior substrates for the cross-metathesis reaction in water compared with other modified alkenes, including vinyl and homoallylsul-fides, potentially owing to the optimum sulfur coordination to the ruthenium center. The two key developments presented in these studies are generation of the dehydroalanine group as a Michael acceptor on protein surfaces and The covalent modification of biopolymers in living systems typically occurs with extraordinary chemoselectivity and regioselectivity. These reactions allow nature to 'accessorize' biopolymers at precise sites with an array of chemical functionalities that may be absent in the limited repertoire of monomer units available to the biosynthetic machinery. Bioorganic chemists have been remarkably successful in establishing efficient synthetic protocols for standard biopolymer chains. The current challenges are to emulate the precision with which nature performs conjugation reactions and to create artificial macromolecular structures not offered by the natural biosynthetic …