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Expanding the Genetic Code Lei Wang and Peter G Reviews P. G. Schultz and L. Wang Protein Science Expanding the Genetic Code Lei Wang and Peter G. Schultz* Keywords: amino acids · genetic code · protein chemistry Angewandte Chemie 34 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/anie.200460627 Angew. Chem. Int. Ed. 2005, 44,34–66 Angewandte Protein Science Chemie Although chemists can synthesize virtually any small organic molecule, our From the Contents ability to rationally manipulate the structures of proteins is quite limited, despite their involvement in virtually every life process. For most proteins, 1. Introduction 35 modifications are largely restricted to substitutions among the common 20 2. Chemical Approaches 35 amino acids. Herein we describe recent advances that make it possible to add new building blocks to the genetic codes of both prokaryotic and 3. In Vitro Biosynthetic eukaryotic organisms. Over 30 novel amino acids have been genetically Approaches to Protein encoded in response to unique triplet and quadruplet codons including Mutagenesis 39 fluorescent, photoreactive, and redox-active amino acids, glycosylated 4. In Vivo Protein amino acids, and amino acids with keto, azido, acetylenic, and heavy-atom- Mutagenesis 43 containing side chains. By removing the limitations imposed by the existing 20 amino acid code, it should be possible to generate proteins and perhaps 5. An Expanded Code 46 entire organisms with new or enhanced properties. 6. Outlook 61 1. Introduction The genetic codes of all known organisms specify the same functional roles to amino acid residues in proteins. Selectivity 20 amino acid building blocks. These building blocks contain a depends on the number and reactivity (dependent on both limited number of functional groups including carboxylic steric and electronic factors) of a particular amino acid side acids and amides, a thiol and thiol ether, alcohols, basic chain. Typical modifications include the oxidation or alkyla- amines, and alkyl and aryl groups. Although various argu- tion of cysteine residues, acylation of either the N-terminal a- ments have been put forth to explain the nature and number amino group or the e-amino group of lysine, and the of amino acids in the code,[1–3] it is clear that proteins require condensation of amines with the carboxylate groups of additional chemical groups to carry out their natural func- aspartate or glutamate. In some cases it is possible to exploit tions. These groups are provided through posttranslational the unique reactivity of active-site residues for selective modifications including phosphorylation, methylation, acety- chemical modification. For example, treatment of the pro- lation, and hydroxylation; cofactors; and in rare cases, tease subtilisin with phenylmethanesulfonyl fluoride, fol- organisms have evolved novel translational machinery to lowed by reaction with thioacetate and hydrolysis, selectively incorporate either selenocysteine or pyrrolysine.[4,5] The need converts the serine residue at the active site into a cysteine for additional factors in so many protein-mediated processes residue (Figure 1a). [9,10] This mutant thiosubtilisin has dimin- suggests that while a code consisting of 20 amino acids is ished proteolytic activity, but still functions as an esterase. sufficient for life, it may not be ideal. Consequently, the Similar approaches have been used to generate a redox-active development of a method that makes possible the systematic selenosubtilisin[11,12] and selenotrypsin[13] (Figure 1b). expansion of the genetic codes of living organisms might Chemical modification has also been used to introduce enable the evolution of proteins, or even entire organisms, reactive molecules, biophysical probes, tags, and other non- with new or enhanced properties. Moreover, such method- peptidic groups selectively into proteins. Cysteine is the most ology would dramatically increase our ability to manipulate commonly used residue for this purpose because of its protein structure and function both in vitro and in vivo. This relatively low abundance in proteins and the increased in turn would allow a more classical chemical approach to the nucleophilicity of the thio group relative to the side chains study of proteins, in which carefully defined changes in the of other amino acids. Moreover, site-directed mutagenesis steric or electronic properties of an amino acid are correlated makes it possible to selectively introduce a cysteine residue at with changes in the properties of proteins.[6–8] Herein we any desired site in a protein, in many cases without loss of provide an overview of both chemical and biochemical function. This residue can then be modified, typically by approaches that have been developed in the past to manip- either disulfide bond exchange or alkylation reactions. ulate protein structure, and review in depth recent advances that have made it possible to add new amino acids to the genetic codes of both prokaryotic and eukaryotic organisms. [*] Prof. P. G. Schultz Department of Chemistry and The Skaggs Institute for Chemical Biology 2. Chemical Approaches The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA) Fax : (+1)858-784-9440 2.1. Chemical Modification of Proteins E-mail: [email protected] Dr. L. Wang Reagents that allow the selective chemical modification of Department of Pharmacology, University of California amino acid side chains have proven quite useful in assigning San Diego, 9500 Gilman Drive, La Jolla, CA 92093 (USA) Angew. Chem. Int. Ed. 2005, 44,34–66 DOI: 10.1002/anie.200460627 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 35 Reviews P. G. Schultz and L. Wang Figure 1. Selective conversion of the hydroxy group of serine to a thio (a) or seleno group (b). Cysteine modification has been used to alter the catalytic probe the interaction of this protein with the a subunit of properties of proteins. For example, Kaiser and co-workers RNA polymerase during transcriptional activation.[18] Meares conjugated different flavin analogues to the cysteine residue and co-workers attached ferric EDTA to proteins through the in the active site of papain to generate oxidoreductases that Cys residue to generate oxidative cleavage reagents that can oxidize hydrophobic dihydronicotinamide derivatives (Fig- be used to map protein–protein and protein–nucleic acid ure 2a).[14–16] Conversely, an oligonucleotide binding site was complexes (Figure 2d).[19–23] Likewise, Harbury and co-work- introduced into a Lys116!Cys mutant of the nonspecific ers have created a powerful chemical footprinting technique deoxyribonuclease staphylococcal nuclease to generate a termed misincorporation proton–alkyl exchange,[24] which is semisynthetic enzyme that selectively cleaves DNA adjacent based upon selective cleavage of the protein backbone at to the target sequence (Figure 2b).[17] cysteine residues by 2-nitro-5-thiocyanobenzoic acid (Fig- Cysteine has also been used to introduce a variety of ure 2e).[25] In the related “substituted cysteine accessibility biophysical probes into proteins. For example, a photoacti- method” (SCAM) the surface accessibility of residues is vatable cross-linking agent (Figure 2c) was tethered to an inferred by the ability of the corresponding cysteine mutant to Asp161!Cys mutant of catabolite gene activator protein to react with charged or polymeric reagents.[26, 27] Nitroxide spin Figure 2. Cysteine residues can be modified with a wide range of nonpeptidic groups: a) flavin, b) oligonucleotide, c) an azido-based photo-cross- linking agent, d) [Fe(babe)], e) 2-nitro-5-thiocyanobenzoic acid, f) a nitroxide spin label, g) biarsenical dyes: FlAsH: X= CC6H4COOH, ReAsH: X =N. Peter Schultz received his B.S. and Ph.D. Lei Wang received both his BS in organic (1984) from Caltech. He joined the Berkeley chemistry (1994) and M.S. in physical faculty in 1985 and moved to the Scripps chemistry (1997) from Peking University, Research Institute in 1999 where he is cur- where he conducted research on nanoparti- rently the Scripps Professor of Chemistry and cle properties using scanning probe micro- the Director of the Genomics Institute of the scopy. From 1997 to 2002, he pursued grad- Novartis Research Foundation. His interests uate studies at the University of California, focus on catalytic antibodies; the develop- Berkeley under the guidance of Prof. ment and application of combinatorial Peter G. Schultz, where he developed a gen- methods in biological chemistry, drug discov- eral method for genetically introducing ery, and materials science; and new building unnatural amino acids into proteins in live blocks for the genetic code. He is a founder cells. He is currently a postdoctoral fellow in of numerous companies, and his awards Prof. Roger Y. Tsien’s group at the University include the Alan T. Waterman Award (NSF), the Wolf Prize in Chemistry, of California, San Diego. the Paul Ehrlich Prize, and membership in the National Academy of Scien- ces and Institute of Medicine. 36 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org Angew. Chem. Int. Ed. 2005, 44,34–66 Angewandte Protein Science Chemie labels (Figure 2 f) and environmentally sensitive fluorophores pling reactions (for example, thioester,[47] oxime,[48] thiazoli- have also been conjugated to various proteins through the Cys dine/oxazolidine,[49, 50] thioether,[51] and disulfide[52] bond for- residue to probe side-chain dynamics and backbone fluctua- mation) of unique functional groups incorporated into tions.[28–30] Recently, it was shown
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