Protein Building Blocks and the Expansion of the Genetic Code

  • Birgit Wiltschi


The proteins of all known organisms are built of a set of 20 canonical amino acids prescribed by the genetic code. Many more amino acids occur in nature but they are excluded from ribosomal translation. Nevertheless, nature exploits their vast chemical diversity for the production of highly bioactive peptides by non-ribosomal biosynthesis routes. The extraordinarily rich structural and functional repertoire of the noncanonical amino acids holds great promise for the future of protein engineering, yet we have only just begun to tap the cornucopia of noncanonical building blocks for the biosynthesis of synthetic proteins.

This chapter provides a broad overview of canonical as well as noncanonical amino acids as building blocks for proteins and peptides. It recapitulates the genetic code and its natural deviations. The structures of selected naturally occurring noncanonical amino acids are listed referencing their source and biosynthesis pathways where known. The principles of current approaches to engineer and expand the genetic code are described. Numerous examples illustrate their application in protein engineering, and they are complemented by a compilation of the noncanonical building blocks involved.


Genetic Code Chloramphenicol Acetyl Transferase SECIS Element Standard Genetic Code Sense Codon 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Aminoacyl-tRNA synthetase


Bioorthogonal conjugation


Bioorthogonal noncanonical amino acid tagging


Canonical amino acid


Conjugative assembly genome engineering


Cyan fluorescent protein


Copper(I)-catalyzed azide–alkyne cycloaddition


Fluorescent noncanonical amino acid tagging


Green fluorescent protein


Inverse electron-demand Diels–Alder reaction


Multiplex automated genome engineering


Orthogonal PylRS/tRNACUA Pyl pair from Methanosarcina mazei


Noncanonical amino acid


ncAA-specific aminoacyl-tRNA synthetase


Non-ribosomal peptide


Non-ribosomal peptide synthesis


Orthogonal pair


Polyfluorinated amino acid


Posttranslational modification


Sense codon recoding


Stop codon suppression


Strain-promoted Huisgen 1,3-dipolar cycloadditions between azides and cyclooctynes


Supplementation-based incorporation



This work has been supported by the Federal Ministry of Science, Research and Economy (BMWFW); the Federal Ministry of Traffic, Innovation and Technology (bmvit); the Styrian Business Promotion Agency SFG; the Standortagentur Tirol; the government of Lower Austria; and ZIT—Technology Agency of the City of Vienna through the COMET Funding Program managed by the Austrian Research Promotion Agency FFG.

I am grateful for support by CHEM21 in the frame of the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115360, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in-kind contribution.


  1. Acevedo-Rocha CG, Hoesl MG, Nehring S et al (2013) Non-canonical amino acids as a useful synthetic biological tool for lipase-catalysed reactions in hostile environments. Catal Sci Technol 3(5):1198–1201CrossRefGoogle Scholar
  2. Ai H-W, Shen W, Brustad E, Schultz PG (2010) Genetically encoded alkenes in yeast. Angew Chem Int Ed Engl 49(5):935–937PubMedCrossRefGoogle Scholar
  3. Albayrak C, Swartz JR (2014) Direct polymerization of proteins. ACS Synth Biol 3(6):353–362PubMedCrossRefGoogle Scholar
  4. Aldag C, Gromov IA, García-Rubio I et al (2009) Probing the role of the proximal heme ligand in cytochrome P450cam by recombinant incorporation of selenocysteine. Proc Natl Acad Sci USA 106(14):5481–5486PubMedCentralPubMedCrossRefGoogle Scholar
  5. Aldag C, Bröcker MJ, Hohn MJ et al (2013) Rewiring translation for elongation factor Tu-dependent selenocysteine incorporation. Angew Chem Int Ed Engl 52(5):1441–1445PubMedCentralPubMedCrossRefGoogle Scholar
  6. Alfonta L, Zhang Z, Uryu S, Loo JA, Schultz PG (2003) Site-specific incorporation of a redox-active amino acid into proteins. J Am Chem Soc 125(48):14662–14663PubMedCrossRefGoogle Scholar
  7. Alix JH (1982) Molecular aspects of the in vivo and in vitro effects of ethionine, an analog of methionine. Microbiol Rev 46(3):281–295PubMedCentralPubMedGoogle Scholar
  8. Ambrogelly A, Palioura S, Söll D (2007) Natural expansion of the genetic code. Nat Chem Biol 3(1):29–35PubMedCrossRefGoogle Scholar
  9. Anderson JC, Wu N, Santoro SW, Lakshman V, King DS, Schultz PG (2004) An expanded genetic code with a functional quadruplet codon. Proc Natl Acad Sci USA 101(20):7566–7571PubMedCentralPubMedCrossRefGoogle Scholar
  10. Asatoor AM (1969) The occurrence of εN-methyllysine in human urine. Clin Chim Acta 26(1):147–154PubMedCrossRefGoogle Scholar
  11. Bae JH, Alefelder S, Kaiser JT et al (2001) Incorporation of beta-selenolo[3,2-b]pyrrolyl-alanine into proteins for phase determination in protein X-ray crystallography. J Mol Biol 309(4):925–936PubMedCrossRefGoogle Scholar
  12. Bae JH, Rubini M, Jung G et al (2003) Expansion of the genetic code enables design of a novel “gold” class of green fluorescent proteins. J Mol Biol 328(5):1071–1081PubMedCrossRefGoogle Scholar
  13. Bagert JD, Xie YJ, Sweredoski MJ et al (2014) Quantitative, time-resolved proteomic analysis by combining bioorthogonal noncanonical amino acid tagging and pulsed stable isotope labeling by amino acids in cell culture. Mol Cell Proteomics 13(5):1352–1358PubMedCentralPubMedCrossRefGoogle Scholar
  14. Baker PJ, Montclare JK (2011) Enhanced refoldability and thermoactivity of fluorinated phosphotriesterase. ChemBioChem 12(12):1845–1848PubMedCrossRefGoogle Scholar
  15. Barrett GC, Elmore DT (1998) Biological roles of amino acids and peptides. In: Amino acids and peptides. Cambridge University Press, Cambridge, pp 174–199Google Scholar
  16. Beatty KE, Tirrell DA (2008) Two-color labeling of temporally defined protein populations in mammalian cells. Bioorg Med Chem Lett 18(22):5995–5999PubMedCentralPubMedCrossRefGoogle Scholar
  17. Beatty KE, Xie F, Wang Q, Tirrell DA (2005) Selective dye-labeling of newly synthesized proteins in bacterial cells. J Am Chem Soc 127(41):14150–14151PubMedCrossRefGoogle Scholar
  18. Beatty KE, Liu JC, Xie F et al (2006) Fluorescence visualization of newly synthesized proteins in mammalian cells. Angew Chem Int Ed Engl 45(44):7364–7367PubMedCrossRefGoogle Scholar
  19. Beatty KE, Fisk JD, Smart BP et al (2010) Live-cell imaging of cellular proteins by a strain-promoted azide-alkyne cycloaddition. ChemBioChem 11(15):2092–2095PubMedCentralPubMedCrossRefGoogle Scholar
  20. Behrens CR, Hooker JM, Obermeyer AC, Romanini DW, Katz EM, Francis MB (2011) Rapid chemoselective bioconjugation through oxidative coupling of anilines and aminophenols. J Am Chem Soc 133(41):16398–16401PubMedCentralPubMedCrossRefGoogle Scholar
  21. Beiboer SHW, Berg BVD, Dekker N, Cox RC, Verheij HM (1996) Incorporation of an unnatural amino acid in the active site of porcine pancreatic phospholipase A2. Substitution of histidine by 1,2,4-triazole-3-alanine yields an enzyme with high activity at acidic pH. Protein Eng 9(4):345–352PubMedCrossRefGoogle Scholar
  22. Bessho Y, Hodgson DRW, Suga H (2002) A tRNA aminoacylation system for non-natural amino acids based on a programmable ribozyme. Nat Biotechnol 20(7):723–728PubMedCrossRefGoogle Scholar
  23. Bianco A, Townsley FM, Greiss S, Lang K, Chin JW (2012) Expanding the genetic code of Drosophila melanogaster. Nat Chem Biol 8(9):748–750PubMedCrossRefGoogle Scholar
  24. Bischoff R, Schlüter H (2012) Amino acids: chemistry, functionality and selected non-enzymatic post-translational modifications. J Proteom 75(8):2275–2296CrossRefGoogle Scholar
  25. Blight SK, Larue RC, Mahapatra A et al (2004) Direct charging of tRNACUA with pyrrolysine in vitro and in vivo. Nature 431(7006):333–335PubMedCrossRefGoogle Scholar
  26. Böck A, Forchhammer K, Heider J, Baron C (1991) Selenoprotein synthesis: an expansion of the genetic code. Trends Biochem Sci 16:463–467PubMedCrossRefGoogle Scholar
  27. Bogosian G, Violand BN, Dorward-King EJ, Workman WE, Jung PE, Kane JF (1989) Biosynthesis and incorporation into protein of norleucine by Escherichia coli. J Biol Chem 264(1):531–539PubMedGoogle Scholar
  28. Brenner S, Stretton AOW, Kaplan S (1965) Genetic code: the ‘nonsense’ triplets for chain termination and their suppression. Nature 206(4988):994–998PubMedCrossRefGoogle Scholar
  29. Brustad E, Bushey ML, Lee JW, Groff D, Liu W, Schultz PG (2008) A genetically encoded boronate-containing amino acid. Angew Chem Int Ed Engl 47(43):8220–8223PubMedCentralPubMedCrossRefGoogle Scholar
  30. Budisa N (2004) Prolegomena to future experimental efforts on genetic code engineering by expanding its amino acid repertoire. Angew Chem Int Ed Engl 43(47):6426–6463PubMedCrossRefGoogle Scholar
  31. Budisa N, Pal PP (2004) Designing novel spectral classes of proteins with a tryptophan-expanded genetic code. Biol Chem 385(10):893–904PubMedCrossRefGoogle Scholar
  32. Budisa N, Pal PP, Alefelder S et al (2004) Probing the role of tryptophans in Aequorea victoria green fluorescent proteins with an expanded genetic code. Biol Chem 385(2):191–202PubMedCrossRefGoogle Scholar
  33. Budisa N, Wenger W, Wiltschi B (2010) Residue-specific global fluorination of Candida antarctica lipase B in Pichia pastoris. Mol Biosyst 6(9):1630–1639PubMedCrossRefGoogle Scholar
  34. Burk RF, Hill KE (2005) Selenoprotein P: an extracellular protein with unique physical characteristics and a role in selenium homeostasis. Annu Rev Nutr 25(1):215–235PubMedCrossRefGoogle Scholar
  35. Caboche S, Leclère V, Pupin M, Kucherov G, Jacques P (2010) Diversity of monomers in nonribosomal peptides: towards the prediction of origin and biological activity. J Bacteriol 192(19):5143–5150PubMedCentralPubMedCrossRefGoogle Scholar
  36. Carrico IS, Maskarinec SA, Heilshorn SC et al (2007) Lithographic patterning of photoreactive cell-adhesive proteins. J Am Chem Soc 129(16):4874–4875PubMedCentralPubMedCrossRefGoogle Scholar
  37. Chatterjee A, Xiao H, Schultz PG (2012) Evolution of multiple, mutually orthogonal prolyl-tRNA synthetase/tRNA pairs for unnatural amino acid mutagenesis in Escherichia coli. Proc Natl Acad Sci USA 109(37):14841–14846PubMedCentralPubMedCrossRefGoogle Scholar
  38. Chilton WS, Tsou G (1972) A chloro amino acid from Amanita solitaria. Phytochemistry 11(9):2853–2857CrossRefGoogle Scholar
  39. Chin JW, Martin AB, King DS, Wang L, Schultz PG (2002a) Addition of a photocrosslinking amino acid to the genetic code of Escherichia coli. Proc Natl Acad Sci USA 99(17):11020–11024PubMedCentralPubMedCrossRefGoogle Scholar
  40. Chin JW, Santoro SW, Martin AB, King DS, Wang L, Schultz PG (2002b) Addition of p-azido-L-phenylalanine to the genetic code of Escherichia coli. J Am Chem Soc 124(31):9026–9027PubMedCrossRefGoogle Scholar
  41. Chin JW, Cropp TA, Anderson JC, Mukherji M, Zhang Z, Schultz PG (2003a) An expanded eukaryotic genetic code. Science 301(5635):964–967PubMedCrossRefGoogle Scholar
  42. Chin JW, Cropp TA, Chu S, Meggers E, Schultz PG (2003b) Progress toward an expanded eukaryotic genetic code. Chem Biol 10(6):511–519PubMedCrossRefGoogle Scholar
  43. Cho H, Daniel T, Buechler YJ et al (2011) Optimized clinical performance of growth hormone with an expanded genetic code. Proc Natl Acad Sci USA 108(22):9060–9065PubMedCentralPubMedCrossRefGoogle Scholar
  44. Cirino PC, Tang Y, Takahashi K, Tirrell DA, Arnold FH (2003) Global incorporation of norleucine in place of methionine in cytochrome P450 BM-3 heme domain increases peroxygenase activity. Biotechnol Bioeng 83(6):729–734PubMedCrossRefGoogle Scholar
  45. Cobucci-Ponzano B, Rossi M, Moracci M (2012) Translational recoding in archaea. Extremophiles 16(6):793–803PubMedCrossRefGoogle Scholar
  46. Cohen GN, Cowie DB (1957) Total replacement of methionine by selenomethionine in the proteins of Escherichia coli. C R Hebd Seances Acad Sci 244(5):680–683PubMedGoogle Scholar
  47. Commans S, Böck A (1999) Selenocysteine inserting tRNAs: an overview. FEMS Microbiol Rev 23(3):335–351PubMedCrossRefGoogle Scholar
  48. Cowie DB, Cohen GN (1957) Biosynthesis by Escherichia coli of active altered proteins containing selenium instead of sulfur. Biochim Biophys Acta 26(2):252–261PubMedCrossRefGoogle Scholar
  49. Crespo MD, Rubini M (2011) Rational design of protein stability: effect of (2S,4R)-4-fluoroproline on the stability and folding pathway of ubiquitin. PLoS One 6(5):e19425PubMedCentralPubMedCrossRefGoogle Scholar
  50. Crick FHC (1968) The origin of the genetic code. J Mol Biol 38(3):367–379PubMedCrossRefGoogle Scholar
  51. Datta D, Wang P, Carrico IS, Mayo SL, Tirrell DA (2002) A designed phenylalanyl-tRNA synthetase variant allows efficient in vivo incorporation of aryl ketone functionality into proteins. J Am Chem Soc 124(20):5652–5653PubMedCrossRefGoogle Scholar
  52. Deepankumar K, Shon M, Nadarajan SP et al (2014) Enhancing thermostability and organic solvent tolerance of ω-transaminase through global incorporation of fluorotyrosine. Adv Synth Catal 356(5):993–998CrossRefGoogle Scholar
  53. Deepankumar K, Nadarajan SP, Mathew S et al (2015) Engineering transaminase for stability enhancement and site-specific immobilization through multiple noncanonical amino acids incorporation. ChemCatChem 7(3):417–421CrossRefGoogle Scholar
  54. Deiters A, Schultz PG (2005) In vivo incorporation of an alkyne into proteins in Escherichia coli. Bioorg Med Chem Lett 15(5):1521–1524PubMedCrossRefGoogle Scholar
  55. Deiters A, Cropp TA, Mukherji M, Chin JW, Anderson JC, Schultz PG (2003) Adding amino acids with novel reactivity to the genetic code of Saccharomyces cerevisiae. J Am Chem Soc 125(39):11782–11783PubMedCrossRefGoogle Scholar
  56. Deiters A, Groff D, Ryu Y, Xie J, Schultz PG (2006) A genetically encoded photocaged tyrosine. Angew Chem Int Ed Engl 45(17):2728–2731PubMedCrossRefGoogle Scholar
  57. Di Giulio M (2005) The origin of the genetic code: theories and their relationships, a review. Biosystems 80(2):175–184PubMedCrossRefGoogle Scholar
  58. Dieterich DC, Link AJ, Graumann J, Tirrell DA, Schuman EM (2006) Selective identification of newly synthesized proteins in mammalian cells using bioorthogonal noncanonical amino acid tagging (BONCAT). Proc Natl Acad Sci USA 103(25):9482–9487PubMedCentralPubMedCrossRefGoogle Scholar
  59. Dieterich DC, Hodas JJL, Gouzer G et al (2010) In situ visualization and dynamics of newly synthesized proteins in rat hippocampal neurons. Nat Neurosci 13(7):897–905PubMedCentralPubMedCrossRefGoogle Scholar
  60. Dirksen A, Dawson PE (2008) Rapid oxime and hydrazone ligations with aromatic aldehydes for biomolecular labeling. Bioconjug Chem 19(12):2543–2548PubMedCentralPubMedCrossRefGoogle Scholar
  61. Dougherty DA, Van Arnam EB (2014) In vivo incorporation of non-canonical amino acids by using the chemical aminoacylation strategy: a broadly applicable mechanistic tool. ChemBioChem 15(12):1710–1720PubMedCentralPubMedCrossRefGoogle Scholar
  62. Dymond JS, Richardson SM, Coombes CE et al (2011) Synthetic chromosome arms function in yeast and generate phenotypic diversity by design. Nature 477(7365):471–476PubMedCentralPubMedCrossRefGoogle Scholar
  63. Edwardraja S, Sriram S, Govindan R, Budisa N, Lee S-G (2011) Enhancing the thermal stability of a single-chain Fv fragment by in vivo global fluorination of the proline residues. Mol Biosyst 7(1):258–265PubMedCrossRefGoogle Scholar
  64. Eichelbaum K, Winter M, Diaz MB, Herzig S, Krijgsveld J (2012) Selective enrichment of newly synthesized proteins for quantitative secretome analysis. Nat Biotechnol 30(10):984–990PubMedCrossRefGoogle Scholar
  65. Finking R, Marahiel MA (2004) Biosynthesis of nonribosomal peptides. Annu Rev Microbiol 58(1):453–488PubMedCrossRefGoogle Scholar
  66. Fisher JF, Mallette MF (1961) The natural occurrence of ethionine in bacteria. J Gen Physiol 45(1):1–13PubMedCentralPubMedCrossRefGoogle Scholar
  67. Fotheringham IG, Grinter N, Pantaleone DP, Senkpeil RF, Taylor PP (1999) Engineering of a novel biochemical pathway for the biosynthesis of L-2-aminobutyric acid in Escherichia coli K12. Bioorg Med Chem 7(10):2209–2213PubMedCrossRefGoogle Scholar
  68. Fowden L (1972) Amino acid complement of plants. Phytochemistry 11(7):2271–2276CrossRefGoogle Scholar
  69. Fowden L, Lewis D, Tristram H (1967) Toxic amino acids: their action as antimetabolites. In: Nord FF (ed) Advances in enzymology and related areas of molecular biology. Wiley, New York, pp 89–163Google Scholar
  70. Furter R (1998) Expansion of the genetic code: site-directed p-fluoro-phenylalanine incorporation in Escherichia coli. Protein Sci 7(2):419–426PubMedCentralPubMedCrossRefGoogle Scholar
  71. Gaston MA, Jiang R, Krzycki JA (2011) Functional context, biosynthesis, and genetic encoding of pyrrolysine. Curr Opin Microbiol 14(3):342–349PubMedCentralPubMedCrossRefGoogle Scholar
  72. Giege R, Sissler M, Florentz C (1998) Universal rules and idiosyncratic features in tRNA identity. Nucleic Acids Res 26(22):5017–5035PubMedCentralPubMedCrossRefGoogle Scholar
  73. Goerke AR, Swartz JR (2009) High-level cell-free synthesis yields of proteins containing site-specific non-natural amino acids. Biotechnol Bioeng 102(2):400–416PubMedCrossRefGoogle Scholar
  74. Grammel M, Zhang MM, Hang HC (2010) Orthogonal alkynyl amino acid reporter for selective labeling of bacterial proteomes during infection. Angew Chem Int Ed Engl 49(34):5970–5974PubMedCentralPubMedCrossRefGoogle Scholar
  75. Greiss S, Chin JW (2011) Expanding the genetic code of an animal. J Am Chem Soc 133(36):14196–14199PubMedCentralPubMedCrossRefGoogle Scholar
  76. Hatanaka S-I (1969) A new amino acid isolated from Morchella esculenta and related species. Phytochemistry 8(7):1305–1308CrossRefGoogle Scholar
  77. Hendrickson WA, Horton JR, LeMaster DM (1990) Selenomethionyl proteins produced for analysis by multiwavelength anomalous diffraction (MAD): a vehicle for direct determination of three-dimensional structure. EMBO J 9(5):1665–1672PubMedCentralPubMedGoogle Scholar
  78. Hinz FI, Dieterich DC, Tirrell DA, Schuman EM (2012) Non-canonical amino acid labeling in vivo to visualize and affinity purify newly synthesized proteins in larval zebrafish. ACS Chem Neurosci 3(1):40–49PubMedCentralPubMedCrossRefGoogle Scholar
  79. Hinz FI, Dieterich DC, Schuman EM (2013) Teaching old NCATs new tricks: using non-canonical amino acid tagging to study neuronal plasticity. Curr Opin Chem Biol 17(5):738–746PubMedCrossRefGoogle Scholar
  80. Hodas JJL, Nehring A, Höche N et al (2012) Dopaminergic modulation of the hippocampal neuropil proteome identified by bio-orthogonal non-canonical amino-acid tagging (BONCAT). Proteomics 12(15-16):2464–2476PubMedCentralPubMedCrossRefGoogle Scholar
  81. Hoesl MG, Budisa N (2011a) In vivo incorporation of multiple noncanonical amino acids into proteins. Angew Chem Int Ed Engl 50(13):2896–2902PubMedCrossRefGoogle Scholar
  82. Hoesl MG, Budisa N (2011b) Expanding and engineering the genetic code in a single expression experiment. ChemBioChem 12(4):552–555PubMedCrossRefGoogle Scholar
  83. Hoesl MG, Acevedo-Rocha CG, Nehring S et al (2011) Lipase congeners designed by genetic code engineering. ChemCatChem 3(1):213–221CrossRefGoogle Scholar
  84. Holzberger B, Marx A (2010) Replacing 32 proline residues by a noncanonical amino acid results in a highly active DNA polymerase. J Am Chem Soc 132(44):15708–15713PubMedCrossRefGoogle Scholar
  85. Hong SH, Kwon Y-C, Jewett MC (2014) Non-standard amino acid incorporation into proteins using Escherichia coli cell-free protein synthesis. Front Chem 2 (eCollection 2014)Google Scholar
  86. Howden AJM, Geoghegan V, Katsch K et al (2013) QuaNCAT: quantitating proteome dynamics in primary cells. Nat Methods 10(4):343–346PubMedCentralPubMedCrossRefGoogle Scholar
  87. Hunt S (1985) The non-protein amino acids. In: Barrett G (ed) Chemistry and biochemistry of the amino acids. Chapman and Hall, London, pp 55–137CrossRefGoogle Scholar
  88. Ibba M, Söll D (2000) Aminoacyl-tRNA synthesis. Annu Rev Biochem 69(1):617–650PubMedCrossRefGoogle Scholar
  89. Isaacs FJ, Carr PA, Wang HH et al (2011) Precise manipulation of chromosomes in vivo enables genome-wide codon replacement. Science 333(6040):348–353PubMedCrossRefGoogle Scholar
  90. Jackson JC, Duffy SP, Hess KR, Mehl RA (2006) Improving nature’s enzyme active site with genetically encoded unnatural amino acids. J Am Chem Soc 128(34):11124–11127PubMedCrossRefGoogle Scholar
  91. Jewett JC, Bertozzi CR (2010) Cu-free click cycloaddition reactions in chemical biology. Chem Soc Rev 39(4):1272–1279PubMedCentralPubMedCrossRefGoogle Scholar
  92. Johnson DBF, Xu J, Shen Z et al (2011) RF1 knockout allows ribosomal incorporation of unnatural amino acids at multiple sites. Nat Chem Biol 7(11):779–786PubMedCentralPubMedCrossRefGoogle Scholar
  93. Johnson DBF, Wang C, Xu J et al (2012) Release factor one is nonessential in Escherichia coli. ACS Chem Biol 7(8):1337–1344PubMedCentralPubMedCrossRefGoogle Scholar
  94. Jones D, Cellitti S, Hao X et al (2010) Site-specific labeling of proteins with NMR-active unnatural amino acids. J Biomol NMR 46(1):89–100PubMedCrossRefGoogle Scholar
  95. Jung MJ (1985) Enzyme inhibition by amino acids and their derivatives. In: Barrett GC (ed) Chemistry and biochemistry of the amino acids. Chapman and Hall, London, pp 227–245CrossRefGoogle Scholar
  96. Kast P, Hennecke H (1991) Amino acid substrate specificity of Escherichia coli phenylalanyl-tRNA synthetase altered by distinct mutations. J Mol Biol 222(1):99–124PubMedCrossRefGoogle Scholar
  97. Kaya E, Gutsmiedl K, Vrabel M, Müller M, Thumbs P, Carell T (2009) Synthesis of threefold glycosylated proteins using click chemistry and genetically encoded unnatural amino acids. ChemBioChem 10(18):2858–2861PubMedCrossRefGoogle Scholar
  98. Kaya E, Vrabel M, Deiml C, Prill S, Fluxa VS, Carell T (2012) A genetically encoded norbornene amino acid for the mild and selective modification of proteins in a copper-free click reaction. Angew Chem Int Ed Engl 51(18):4466–4469PubMedCrossRefGoogle Scholar
  99. Kean EA, Lewis CE (1981) Biosynthesis of L-β-(methylenecyclopropyl)-alanine (hypoglycin) in Blighia sapida. Phytochemistry 20(9):2161–2164CrossRefGoogle Scholar
  100. Kiick KL, van Hest JCM, Tirrell DA (2000) Expanding the scope of protein biosynthesis by altering the methionyl-tRNA synthetase activity of a bacterial expression host. Angew Chem Int Ed Engl 39(12):2148–2152PubMedCrossRefGoogle Scholar
  101. Kiick KL, Weberskirch R, Tirrell DA (2001) Identification of an expanded set of translationally active methionine analogues in Escherichia coli. FEBS Lett 502(1-2):25–30PubMedCrossRefGoogle Scholar
  102. Kiick KL, Saxon E, Tirrell DA, Bertozzi CR (2002) Incorporation of azides into recombinant proteins for chemoselective modification by the Staudinger ligation. Proc Natl Acad Sci USA 99(1):19–24PubMedCentralPubMedCrossRefGoogle Scholar
  103. Kim S, Paik WK (1965) Studies on the origin of epsilon-N-methyl-L-lysine in protein. J Biol Chem 240(12):4629–4634PubMedGoogle Scholar
  104. Kim W, George A, Evans M, Conticello VP (2004) Cotranslational incorporation of a structurally diverse series of proline analogues in an Escherichia coli expression system. ChemBioChem 5(7):928–936PubMedCrossRefGoogle Scholar
  105. Kim CH, Axup JY, Schultz PG (2013) Protein conjugation with genetically encoded unnatural amino acids. Curr Opin Chem Biol 17(3):412–419PubMedCentralPubMedCrossRefGoogle Scholar
  106. Kirshenbaum K, Carrico IS, Tirrell DA (2002) Biosynthesis of proteins incorporating a versatile set of phenylalanine analogues. ChemBioChem 3(2-3):235–237PubMedCrossRefGoogle Scholar
  107. Knight RD, Freeland SJ, Landweber LF (2001) Rewiring the keyboard: evolvability of the genetic code. Nat Rev Genet 2(1):49–58PubMedCrossRefGoogle Scholar
  108. Kodama K, Nakayama H, Sakamoto K et al (2010) Site-specific incorporation of 4-iodo-L-phenylalanine through opal suppression. J Biochem 148(2):179–187PubMedCrossRefGoogle Scholar
  109. Kolev JN, Zaengle JM, Ravikumar R, Fasan R (2014) Enhancing the efficiency and regioselectivity of P450 oxidation catalysts by unnatural amino acid mutagenesis. ChemBioChem 15(7):1001–1010PubMedCentralPubMedCrossRefGoogle Scholar
  110. Krishnakumar R, Ling J (2014) Experimental challenges of sense codon reassignment: an innovative approach to genetic code expansion. FEBS Lett 588(3):383–388PubMedCrossRefGoogle Scholar
  111. Krishnakumar R, Prat L, Aerni H-R et al (2013) Transfer RNA misidentification scrambles sense codon recoding. ChemBioChem 14(15):1967–1972PubMedCrossRefGoogle Scholar
  112. Krzycki JA (2005) The direct genetic encoding of pyrrolysine. Curr Opin Microbiol 8(6):706–712PubMedCrossRefGoogle Scholar
  113. Kuhn SM, Rubini M, Fuhrmann M, Theobald I, Skerra A (2010) Engineering of an orthogonal aminoacyl-tRNA synthetase for efficient incorporation of the non-natural amino acid O-methyl-L-tyrosine using fluorescence-based bacterial cell sorting. J Mol Biol 404(1):70–87PubMedCrossRefGoogle Scholar
  114. Kwon I, Lim SI (2015) Tailoring the substrate specificity of yeast phenylalanyl-tRNA synthetase toward a phenylalanine analog using multiple-site-specific incorporation. ACS Synth Biol 4(5):634–643PubMedCrossRefGoogle Scholar
  115. Kwon I, Tirrell DA (2007) Site-specific incorporation of tryptophan analogues into recombinant proteins in bacterial cells. J Am Chem Soc 129(34):10431–10437PubMedCrossRefGoogle Scholar
  116. Kwon I, Kirshenbaum K, Tirrell DA (2003) Breaking the degeneracy of the genetic code. J Am Chem Soc 125(25):7512–7513PubMedCrossRefGoogle Scholar
  117. Labunskyy VM, Hatfield DL, Gladyshev VN (2014) Selenoproteins: molecular pathways and physiological roles. Physiol Rev 94(3):739–777PubMedCentralPubMedCrossRefGoogle Scholar
  118. Lajoie MJ, Rovner AJ, Goodman DB et al (2013) Genomically recoded organisms expand biological functions. Science 342(6156):357–360PubMedCrossRefGoogle Scholar
  119. Landgraf P, Antileo E, Schuman E, Dieterich D (2015) BONCAT: metabolic labeling, click chemistry, and affinity purification of newly synthesized proteomes. Methods Mol Biol 1266:199–215PubMedCrossRefGoogle Scholar
  120. Lang K, Davis L, Wallace S et al (2012a) Genetic encoding of bicyclononynes and trans-cyclooctenes for site-specific protein labeling in vitro and in live mammalian cells via rapid fluorogenic Diels–Alder reactions. J Am Chem Soc 134(25):10317–10320PubMedCentralPubMedCrossRefGoogle Scholar
  121. Lang K, Davis L, Torres-Kolbus J, Chou C, Deiters A, Chin JW (2012b) Genetically encoded norbornene directs site-specific cellular protein labelling via a rapid bioorthogonal reaction. Nat Chem 4(4):298–304PubMedCentralPubMedCrossRefGoogle Scholar
  122. Lenstra R (2014) Evolution of the genetic code through progressive symmetry breaking. J Theor Biol 347:95–108PubMedCrossRefGoogle Scholar
  123. Lepthien S, Hoesl MG, Merkel L, Budisa N (2008) Azatryptophans endow proteins with intrinsic blue fluorescence. Proc Natl Acad Sci USA 105(42):16095–16100PubMedCentralPubMedCrossRefGoogle Scholar
  124. Lepthien S, Merkel L, Budisa N (2010) In vivo double and triple labeling of proteins using synthetic amino acids. Angew Chem Int Ed Engl 49(32):5446–5450PubMedCrossRefGoogle Scholar
  125. Letendre CH, Dickens G, Guroff G (1974) The tryptophan hydroxylase of Chromobacterium violaceum. J Biol Chem 249(22):7186–7191PubMedGoogle Scholar
  126. Ling J, Reynolds N, Ibba M (2009) Aminoacyl-tRNA synthesis and translational quality control. Annu Rev Microbiol 63(1):61–78PubMedCrossRefGoogle Scholar
  127. Link AJ, Tirrell DA (2003) Cell surface labeling of Escherichia coli via copper(I)-catalyzed [3+2] cycloaddition. J Am Chem Soc 125(37):11164–11165PubMedCrossRefGoogle Scholar
  128. Link AJ, Vink MKS, Tirrell DA (2004) Presentation and detection of azide functionality in bacterial cell surface proteins. J Am Chem Soc 126(34):10598–10602PubMedCrossRefGoogle Scholar
  129. Liu CC, Schultz PG (2010) Adding new chemistries to the genetic code. Annu Rev Biochem 79(1):413–444PubMedCrossRefGoogle Scholar
  130. Liu W, Brock A, Chen S, Chen S, Schultz PG (2007) Genetic incorporation of unnatural amino acids into proteins in mammalian cells. Nat Methods 4(3):239–244PubMedCrossRefGoogle Scholar
  131. Liu CC, Mack AV, Tsao M-L et al (2008) Protein evolution with an expanded genetic code. Proc Natl Acad Sci USA 105(46):17688–17693PubMedCentralPubMedCrossRefGoogle Scholar
  132. Luesch H, Hoffmann D, Hevel JM, Becker JE, Golakoti T, Moore RE (2002) Biosynthesis of 4-methylproline in cyanobacteria: cloning of nosE and nosF genes and biochemical characterization of the encoded dehydrogenase and reductase activities. J Org Chem 68(1):83–91CrossRefGoogle Scholar
  133. Ma Y, Biava H, Contestabile R, Budisa N, Di Salvo M (2014) Coupling bioorthogonal chemistries with artificial metabolism: intracellular biosynthesis of azidohomoalanine and its incorporation into recombinant proteins. Molecules 19(1):1004–1022PubMedCrossRefGoogle Scholar
  134. Mehl RA, Anderson JC, Santoro SW et al (2003) Generation of a bacterium with a 21 amino acid genetic code. J Am Chem Soc 125(4):935–939PubMedCrossRefGoogle Scholar
  135. Mehta KR, Yang CY, Montclare JK (2011) Modulating substrate specificity of histone acetyltransferase with unnatural amino acids. Mol Biosyst 7(11):3050–3055PubMedCrossRefGoogle Scholar
  136. Meldal M, Tornøe CW (2008) Cu-catalyzed azide-alkyne cycloaddition. Chem Rev 108(8):2952–3015PubMedCrossRefGoogle Scholar
  137. Merkel L, Schauer M, Antranikian G, Budisa N (2010) Parallel incorporation of different fluorinated amino acids: on the way to “teflon” proteins. ChemBioChem 11(11):1505–1507PubMedCrossRefGoogle Scholar
  138. Milner-White EJ, Bell LH, Maccallum PH (1992) Pyrrolidine ring puckering in cis and trans-proline residues in proteins and polypeptides: different puckers are favoured in certain situations. J Mol Biol 228(3):725–734PubMedCrossRefGoogle Scholar
  139. Minks C, Huber R, Moroder L, Budisa N (2000) Noninvasive tracing of recombinant proteins with “fluorophenylalanine-fingers”. Anal Biochem 284(1):29–34PubMedCrossRefGoogle Scholar
  140. Minnihan EC, Young DD, Schultz PG, Stubbe J (2011) Incorporation of fluorotyrosines into ribonucleotide reductase using an evolved, polyspecific aminoacyl-tRNA synthetase. J Am Chem Soc 133(40):15942–15945PubMedCentralPubMedCrossRefGoogle Scholar
  141. Moghal A, Mohler K, Ibba M (2014) Mistranslation of the genetic code. FEBS Lett 588(23):4305–4310PubMedCrossRefPubMedCentralGoogle Scholar
  142. Montclare JK, Tirrell DA (2006) Evolving proteins of novel composition. Angew Chem Int Ed Engl 45(27):4518–4521PubMedCrossRefGoogle Scholar
  143. Moore PB, Steitz TA (2011) The roles of RNA in the synthesis of protein. Cold Spring Harb Perspect Biol 3(11):a003780PubMedCentralPubMedCrossRefGoogle Scholar
  144. Mukai T, Kobayashi T, Hino N, Yanagisawa T, Sakamoto K, Yokoyama S (2008) Adding L-lysine derivatives to the genetic code of mammalian cells with engineered pyrrolysyl-tRNA synthetases. Biochem Biophys Res Commun 371(4):818–822PubMedCrossRefGoogle Scholar
  145. Mukai T, Hayashi A, Iraha F et al (2010) Codon reassignment in the Escherichia coli genetic code. Nucleic Acids Res 38(22):8188–8195PubMedCentralPubMedCrossRefGoogle Scholar
  146. Nagatsu T, Levitt M, Udenfriend S (1964) Tyrosine hydroxylase: the initial step in norepinephrine biosynthesis. J Biol Chem 239(9):2910–2917PubMedGoogle Scholar
  147. Nakamura Y, Gojobori T, Ikemura T (2000) Codon usage tabulated from international DNA sequence databases: status for the year 2000. Nucleic Acids Res 28(1):292PubMedCentralPubMedCrossRefGoogle Scholar
  148. Nessen MA, Kramer G, Back J et al (2009) Selective enrichment of azide-containing peptides from complex mixtures. J Proteome Res 8(7):3702–3711PubMedCentralPubMedCrossRefGoogle Scholar
  149. Neumann H, Hancock SM, Buning R et al (2009) A method for genetically installing site-specific acetylation in recombinant histones defines the effects of H3 K56 acetylation. Mol Cell 36(1):153–163PubMedCentralPubMedCrossRefGoogle Scholar
  150. Neumann H, Wang K, Davis L, Garcia-Alai M, Chin JW (2010) Encoding multiple unnatural amino acids via evolution of a quadruplet-decoding ribosome. Nature 464(7287):441–444PubMedCrossRefGoogle Scholar
  151. Neumann CS, Jiang W, Heemstra JR, Gontang EA, Kolter R, Walsh CT (2012) Biosynthesis of piperazic acid via N5-hydroxy-ornithine in Kutzneria spp. 744. ChemBioChem 13(7):972–976PubMedCentralPubMedCrossRefGoogle Scholar
  152. Ngo JT, Tirrell DA (2011) Noncanonical amino acids in the interrogation of cellular protein synthesis. Acc Chem Res 44(9):677–685PubMedCentralPubMedCrossRefGoogle Scholar
  153. Ngo JT, Champion JA, Mahdavi A et al (2009) Cell-selective metabolic labeling of proteins. Nat Chem Biol 5(10):715–717PubMedCentralPubMedCrossRefGoogle Scholar
  154. Ngo JT, Schuman EM, Tirrell DA (2013) Mutant methionyl-tRNA synthetase from bacteria enables site-selective N-terminal labeling of proteins expressed in mammalian cells. Proc Natl Acad Sci USA 110(13):4992–4997PubMedCentralPubMedCrossRefGoogle Scholar
  155. Nguyen DP, Elliott T, Holt M, Muir TW, Chin JW (2011) Genetically encoded 1,2-aminothiols facilitate rapid and site-specific protein labeling via a bio-orthogonal cyanobenzothiazole condensation. J Am Chem Soc 133(30):11418–11421PubMedCrossRefGoogle Scholar
  156. Noren C, Anthony-Cahill S, Griffith M, Schultz P (1989) A general method for site-specific incorporation of unnatural amino acids into proteins. Science 244(4901):182–188PubMedCrossRefGoogle Scholar
  157. Novoa EM, Ribas De Pouplana L (2012) Speeding with control: codon usage, tRNAs, and ribosomes. Trends Genet 28(11):574–581PubMedCrossRefGoogle Scholar
  158. O’Donoghue P, Prat L, Heinemann IU et al (2012) Near-cognate suppression of amber, opal and quadruplet codons competes with aminoacyl-tRNAPyl for genetic code expansion. FEBS Lett 586(21):3931–3937PubMedCentralPubMedCrossRefGoogle Scholar
  159. O’Donoghue P, Ling J, Wang Y-S, Soll D (2013) Upgrading protein synthesis for synthetic biology. Nat Chem Biol 9(10):594–598PubMedCentralPubMedCrossRefGoogle Scholar
  160. Odar C, Winkler M, Wiltschi B (2015) Fluoro amino acids: a rarity in nature, yet a prospect for protein engineering. Biotechnol J 10(3):427–446PubMedCrossRefGoogle Scholar
  161. Odoi KA, Huang Y, Rezenom YH, Liu WR (2013) Nonsense and sense suppression abilities of original and derivative Methanosarcina mazei pyrrolysyl-tRNA synthetase-tRNA(Pyl) pairs in the Escherichia coli BL21(DE3) cell strain. PLoS One 8(3):e57035PubMedCentralPubMedCrossRefGoogle Scholar
  162. Oldach F, Al Toma R, Kuthning A et al (2012) Congeneric lantibiotics from ribosomal in vivo peptide synthesis with noncanonical amino acids. Angew Chem Int Ed Engl 51(2):415–418PubMedCrossRefGoogle Scholar
  163. Ouellette SP, Dorsey FC, Moshiach S, Cleveland JL, Carabeo RA (2011) Chlamydia species-dependent differences in the growth requirement for lysosomes. PLoS One 6(3):e16783PubMedCentralPubMedCrossRefGoogle Scholar
  164. Park H-S, Hohn MJ, Umehara T et al (2011) Expanding the genetic code of Escherichia coli with phosphoserine. Science 333(6046):1151–1154PubMedCrossRefGoogle Scholar
  165. Parsons JF, Xiao G, Gilliland GL, Armstrong RN (1998) Enzymes harboring unnatural amino acids: mechanistic and structural analysis of the enhanced catalytic activity of a glutathione transferase containing 5-fluorotryptophan. Biochemistry 37(18):6286–6294PubMedCrossRefGoogle Scholar
  166. Peeler JC, Woodman BF, Averick S et al (2010) Genetically encoded initiator for polymer growth from proteins. J Am Chem Soc 132(39):13575–13577PubMedCrossRefGoogle Scholar
  167. Petrović DM, Leenhouts K, van Roosmalen ML, Broos J (2013) An expression system for the efficient incorporation of an expanded set of tryptophan analogues. Amino Acids 44(5):1329–1336PubMedCrossRefGoogle Scholar
  168. Plass T, Milles S, Koehler C, Schultz C, Lemke EA (2011) Genetically encoded copper-free click chemistry. Angew Chem Int Ed Engl 50(17):3878–3881PubMedCentralPubMedCrossRefGoogle Scholar
  169. Prasuhn DE, Singh P, Strable E, Brown S, Manchester M, Finn MG (2008) Plasma clearance of bacteriophage Qbeta particles as a function of surface charge. J Am Chem Soc 130(4):1328–1334PubMedCentralPubMedCrossRefGoogle Scholar
  170. Prat L, Heinemann IU, Aerni HR, Rinehart J, O’donoghue P, Söll D (2012) Carbon source-dependent expansion of the genetic code in bacteria. Proc Natl Acad Sci USA 109(51):21070–21075PubMedCentralPubMedCrossRefGoogle Scholar
  171. Rackham O, Chin JW (2005) A network of orthogonal ribosome x mRNA pairs. Nat Chem Biol 1(3):159–166PubMedCrossRefGoogle Scholar
  172. Reetz MT (2002) Lipases as practical biocatalysts. Curr Opin Chem Biol 6(2):145–150PubMedCrossRefGoogle Scholar
  173. Reeves MA, Hoffmann PR (2009) The human selenoproteome: recent insights into functions and regulation. Cell Mol Life Sci 66(15):2457–2478PubMedCentralPubMedCrossRefGoogle Scholar
  174. Ressler C, Malodeczky H (1962) Isolation and identification from common vetch of the neurotoxin beta-cyano-L-alanine, a possible factor in neurolathyrism. J Biol Chem 237(3):733–735PubMedGoogle Scholar
  175. Rodgers KJ, Shiozawa N (2008) Misincorporation of amino acid analogues into proteins by biosynthesis. Int J Biochem Cell Biol 40(8):1452–1466PubMedCrossRefGoogle Scholar
  176. Rosenthal GA (1982) L-Canavanine metabolism in Jack Bean, Canavalia ensiformis (L.) DC. (Leguminosae). Plant Physiol 69(5):1066–1069PubMedCentralPubMedCrossRefGoogle Scholar
  177. Rosenthal G, Dahlman D, Janzen D (1976) A novel means for dealing with L-canavanine, a toxic metabolite. Science 192(4236):256–258PubMedCrossRefGoogle Scholar
  178. Sakamoto K, Murayama K, Oki K et al (2009) Genetic encoding of 3-iodo-L-tyrosine in Escherichia coli for single-wavelength anomalous dispersion phasing in protein crystallography. Structure 17(3):335–344PubMedCrossRefGoogle Scholar
  179. Santoro SW, Wang L, Herberich B, King DS, Schultz PG (2002) An efficient system for the evolution of aminoacyl-tRNA synthetase specificity. Nat Biotechnol 20(10):1044–1048PubMedCrossRefGoogle Scholar
  180. Sauerwald A, Zhu W, Major TA et al (2005) RNA-dependent cysteine biosynthesis in archaea. Science 307(5717):1969–1972PubMedCrossRefGoogle Scholar
  181. Scannell JP, Pruess DL, Demny TC, Weiss F, Williams T, Stempel A (1971) Antimetabolites produced by microorganisms. II. L-2-amino-4-pentynoic acid. J Antibiot (Tokyo) 24(4):239–244CrossRefGoogle Scholar
  182. Schlesinger S, Schlesinger MJ (1967) The effect of amino acid analogues on alkaline phosphatase formation in Escherichia coli K-12. I. Substitution of triazolealanine for histidine. J Biol Chem 242(14):3369–3372PubMedGoogle Scholar
  183. Schlesinger S, Schlesinger MJ (1969) The effect of amino acid analogues on alkaline phosphatase formation in Escherichia coli K-12. 3. Substitution of 2-methylhistidine for histidine. J Biol Chem 244(14):3803–3809PubMedGoogle Scholar
  184. Schmidt RL, Simonovic M (2012) Synthesis and decoding of selenocysteine and human health. Croat Med J 53(6):535–550PubMedCentralPubMedCrossRefGoogle Scholar
  185. Scolnick E, Tompkins R, Caskey T, Nirenberg M (1968) Release factors differing in specificity for terminator codons. Proc Natl Acad Sci USA 61(2):768–774PubMedCentralPubMedCrossRefGoogle Scholar
  186. Seitchik JL, Peeler JC, Taylor MT et al (2012) Genetically encoded tetrazine amino acid directs rapid site-specific in vivo bioorthogonal ligation with trans-cyclooctenes. J Am Chem Soc 134(6):2898–2901PubMedCentralPubMedCrossRefGoogle Scholar
  187. Shah R, Neuss N, Gorman M, Boeck LD (1970) Isolation, purification, and characterization of anticapsin. J Antibiot (Tokyo) 23(12):613–619CrossRefGoogle Scholar
  188. Sharma N, Furter R, Kast P, Tirrell DA (2000) Efficient introduction of aryl bromide functionality into proteins in vivo. FEBS Lett 467(1):37–40PubMedCrossRefGoogle Scholar
  189. Staudt H, Hoesl MG, Dreuw A et al (2013) Directed manipulation of a flavoprotein photocycle. Angew Chem Int Ed Engl 52(32):8463–8466PubMedCrossRefGoogle Scholar
  190. Steiner T, Hess P, Bae JH, Wiltschi B, Moroder L, Budisa N (2008) Synthetic biology of proteins: tuning GFPs folding and stability with fluoroproline. PLoS One 3(2):e1680PubMedCentralPubMedCrossRefGoogle Scholar
  191. Stokes AL, Miyake-Stoner SJ, Peeler JC, Nguyen DP, Hammer RP, Mehl RA (2009) Enhancing the utility of unnatural amino acid synthetases by manipulating broad substrate specificity. Mol Biosyst 5(9):1032–1038PubMedCrossRefGoogle Scholar
  192. Strable E, Prasuhn DE, Udit AK et al (2008) Unnatural amino acid incorporation into virus-like particles. Bioconjug Chem 19(4):866–875PubMedCentralPubMedCrossRefGoogle Scholar
  193. Swartz J (2001) A PURE approach to constructive biology. Nat Biotechnol 19(8):732–733PubMedCrossRefGoogle Scholar
  194. Tamura K, Schimmel P (2002) Ribozyme programming extends the protein code. Nat Biotechnol 20(7):669–670PubMedCrossRefGoogle Scholar
  195. Tang Y, Tirrell DA (2001) Biosynthesis of a highly stable coiled-coil protein containing hexafluoroleucine in an engineered bacterial host. J Am Chem Soc 123(44):11089–11090PubMedCrossRefGoogle Scholar
  196. Tang Y, Ghirlanda G, Petka WA, Nakajima T, Degrado WF, Tirrell DA (2001) Fluorinated coiled-coil proteins prepared in vivo display enhanced thermal and chemical stability. Angew Chem Int Ed Engl 40(8):1494–1496PubMedCrossRefGoogle Scholar
  197. Tang Y, Wang P, Van Deventer JA, Link AJ, Tirrell DA (2009) Introduction of an aliphatic ketone into recombinant proteins in a bacterial strain that overexpresses an editing-impaired leucyl-tRNA synthetase. ChemBioChem 10(13):2188–2190PubMedCentralPubMedCrossRefGoogle Scholar
  198. Teeuwen RLM, van Berkel SS, van Dulmen THH et al (2009) “Clickable” elastins: elastin-like polypeptides functionalized with azide or alkyne groups. Chem Commun (Camb) 27:4022–4024CrossRefGoogle Scholar
  199. Tsao M-L, Tian F, Schultz PG (2005) Selective Staudinger modification of proteins containing p-azidophenylalanine. ChemBioChem 6(12):2147–2149PubMedCrossRefGoogle Scholar
  200. Turanov AA, Lobanov AV, Fomenko DE et al (2009) Genetic code supports targeted insertion of two amino acids by one codon. Science 323(5911):259–261PubMedCentralPubMedCrossRefGoogle Scholar
  201. Ugwumba IN, Ozawa K, Xu Z-Q et al (2010) Improving a natural enzyme activity through incorporation of unnatural amino acids. J Am Chem Soc 133(2):326–333PubMedCrossRefGoogle Scholar
  202. van Hest JC, Kiick KL, Tirrell DA (2000) Efficient incorporation of unsaturated methionine analogues into proteins in vivo. J Am Chem Soc 122(7):1282–1288CrossRefGoogle Scholar
  203. Vandenende CS, Vlasschaert M, Seah SYK (2004) Functional characterization of an aminotransferase required for pyoverdine siderophore biosynthesis in Pseudomonas aeruginosa PAO1. J Bacteriol 186(17):5596–5602PubMedCentralPubMedCrossRefGoogle Scholar
  204. Voloshchuk N, Zhu AY, Snydacker D, Montclare JK (2009) Positional effects of monofluorinated phenylalanines on histone acetyltransferase stability and activity. Bioorg Med Chem Lett 19(18):5449–5451PubMedCrossRefGoogle Scholar
  205. Wagner I, Musso H (1983) New naturally occurring amino acids. Angew Chem Int Ed Engl 22(11):816–828CrossRefGoogle Scholar
  206. Walsh CT (2014) Blurring the lines between ribosomal and nonribosomal peptide scaffolds. ACS Chem Biol 9(8):1653–1661PubMedCrossRefGoogle Scholar
  207. Walsh CT, Garneau-Tsodikova S, Gatto GJJ (2005) Protein posttranslational modifications: the chemistry of proteome diversifications. Angew Chem Int Ed Engl 44(45):7342–7372PubMedCrossRefGoogle Scholar
  208. Walsh CT, O’Brien RV, Khosla C (2013) Nonproteinogenic amino acid building blocks for nonribosomal peptide and hybrid polyketide scaffolds. Angew Chem Int Ed Engl 52(28):7098–7124PubMedCrossRefPubMedCentralGoogle Scholar
  209. Wan W, Huang Y, Wang Z et al (2010) A facile system for genetic incorporation of two different noncanonical amino acids into one protein in Escherichia coli. Angew Chem Int Ed Engl 49(18):3211–3214PubMedCrossRefGoogle Scholar
  210. Wan W, Tharp JM, Liu WR (2014) Pyrrolysyl-tRNA synthetase: an ordinary enzyme but an outstanding genetic code expansion tool. Biochim Biophys Acta 1844(6):1059–1070PubMedCentralPubMedCrossRefGoogle Scholar
  211. Wang L, Schultz PG (2001) A general approach for the generation of orthogonal tRNAs. Chem Biol 8(9):883–890PubMedCrossRefGoogle Scholar
  212. Wang L, Brock A, Herberich B, Schultz PG (2001) Expanding the genetic code of Escherichia coli. Science 292(5516):498–500PubMedCrossRefGoogle Scholar
  213. Wang L, Zhang Z, Brock A, Schultz PG (2003a) Addition of the keto functional group to the genetic code of Escherichia coli. Proc Natl Acad Sci USA 100(1):56–61PubMedCentralPubMedCrossRefGoogle Scholar
  214. Wang L, Xie J, Deniz AA, Schultz PG (2003b) Unnatural amino acid mutagenesis of green fluorescent protein. J Org Chem 68(1):174–176PubMedCrossRefGoogle Scholar
  215. Wang K, Neumann H, Peak-Chew SY, Chin JW (2007a) Evolved orthogonal ribosomes enhance the efficiency of synthetic genetic code expansion. Nat Biotechnol 25(7):770–777PubMedCrossRefGoogle Scholar
  216. Wang J, Schiller SM, Schultz PG (2007b) A biosynthetic route to dehydroalanine-containing proteins. Angew Chem Int Ed Engl 46(36):6849–6851PubMedCrossRefGoogle Scholar
  217. Wang Q, Parrish AR, Wang L (2009) Expanding the genetic code for biological studies. Chem Biol 16(3):323–336PubMedCentralPubMedCrossRefGoogle Scholar
  218. Wang F, Robbins S, Guo J, Shen W, Schultz PG (2010) Genetic incorporation of unnatural amino acids into proteins in Mycobacterium tuberculosis. PLoS One 5(2):e9354PubMedCentralPubMedCrossRefGoogle Scholar
  219. Wang Y-S, Russell WK, Wang Z et al (2011) The de novo engineering of pyrrolysyl-tRNA synthetase for genetic incorporation of L-phenylalanine and its derivatives. Mol Biosyst 7(3):714–717PubMedCrossRefGoogle Scholar
  220. Welter A, Marliert M, Dardenne G (1978) Nouveaux acides amines libres de Afzelia bella: trans-hydroxy-4-L-proline et trans-carboxy-4-L-proline. Phytochemistry 17(1):131–134CrossRefGoogle Scholar
  221. Wilkins BJ, Marionni S, Young DD et al (2010) Site-specific incorporation of fluorotyrosines into proteins in Escherichia coli by photochemical disguise. Biochemistry 49(8):1557–1559PubMedCrossRefGoogle Scholar
  222. Wiltschi B (2012) Expressed protein modifications: making synthetic proteins. Methods Mol Biol 813:211–225PubMedCrossRefGoogle Scholar
  223. Wiltschi B, Wenger W, Nehring S, Budisa N (2008) Expanding the genetic code of Saccharomyces cerevisiae with methionine analogues. Yeast 25(11):775–786PubMedCrossRefGoogle Scholar
  224. Wolschner C, Giese A, Kretzschmar HA, Huber R, Moroder L, Budisa N (2009) Design of anti- and pro-aggregation variants to assess the effects of methionine oxidation in human prion protein. Proc Natl Acad Sci USA 106(19):7756–7761PubMedCentralPubMedCrossRefGoogle Scholar
  225. Wu N, Deiters A, Cropp TA, King D, Schultz PG (2004) A genetically encoded photocaged amino acid. J Am Chem Soc 126(44):14306–14307PubMedCrossRefGoogle Scholar
  226. Wu IL, Patterson MA, Carpenter Desai HE, Mehl RA, Giorgi G, Conticello VP (2013) Multiple site-selective insertions of noncanonical amino acids into sequence-repetitive polypeptides. ChemBioChem 14(8):968–978PubMedCentralPubMedCrossRefGoogle Scholar
  227. Wu JCY, Hutchings CH, Lindsay MJ, Werner CJ, Bundy BC (2015) Enhanced enzyme stability through site-directed covalent immobilization. J Biotechnol 193:83–90PubMedCrossRefGoogle Scholar
  228. Xiao H, Chatterjee A, Choi S-H, Bajjuri KM, Sinha SC, Schultz PG (2013) Genetic incorporation of multiple unnatural amino acids into proteins in mammalian cells. Angew Chem Int Ed Engl 52(52):14080–14083PubMedCrossRefGoogle Scholar
  229. Xie J, Wang L, Wu N, Brock A, Spraggon G, Schultz PG (2004) The site-specific incorporation of p-iodo-L-phenylalanine into proteins for structure determination. Nat Biotechnol 22(10):1297–1301PubMedCrossRefGoogle Scholar
  230. Yoo TH, Link AJ, Tirrell DA (2007) Evolution of a fluorinated green fluorescent protein. Proc Natl Acad Sci USA 104(35):13887–13890PubMedCentralPubMedCrossRefGoogle Scholar
  231. Yoon Byung C, Jung H, Dwivedy A, O’hare Catherine M, Zivraj Krishna H, Holt Christine E (2012) Local translation of extranuclear lamin B promotes axon maintenance. Cell 148(4):752–764PubMedCentralPubMedCrossRefGoogle Scholar
  232. Yoshioka H, Nakatsu K, Sato M, Tatsuno T (1973) The molecular structure of cyclochlorotine, a toxic chlorine-containing cyclic pentapeptide. Chem Lett 2(12):1319–1322CrossRefGoogle Scholar
  233. Young TS, Ahmad I, Brock A, Schultz PG (2009) Expanding the genetic repertoire of the methylotrophic yeast Pichia pastoris. Biochemistry 48(12):2643–2653PubMedCrossRefGoogle Scholar
  234. Young DD, Young TS, Jahnz M, Ahmad I, Spraggon G, Schultz PG (2011) An evolved aminoacyl-tRNA synthetase with atypical polysubstrate specificity. Biochemistry 50(11):1894–1900PubMedCentralPubMedCrossRefGoogle Scholar
  235. Yu Z, Pan Y, Wang Z, Wang J, Lin Q (2012) Genetically encoded cyclopropene directs rapid, photoclick-chemistry-mediated protein labeling in mammalian cells. Angew Chem Int Ed Engl 51(42):10600–10604PubMedCentralPubMedCrossRefGoogle Scholar
  236. Zhang Z, Wang L, Brock A, Schultz PG (2002) The selective incorporation of alkenes into proteins in Escherichia coli. Angew Chem Int Ed Engl 41(15):2840–2842PubMedCrossRefGoogle Scholar
  237. Zhang Z, Alfonta L, Tian F et al (2004) Selective incorporation of 5-hydroxytryptophan into proteins in mammalian cells. Proc Natl Acad Sci USA 101(24):8882–8887PubMedCentralPubMedCrossRefGoogle Scholar
  238. Zhang Y, Fomenko D, Gladyshev V (2005a) The microbial selenoproteome of the Sargasso Sea. Genome Biol 6(4):R37PubMedCentralPubMedCrossRefGoogle Scholar
  239. Zhang Y, Baranov PV, Atkins JF, Gladyshev VN (2005b) Pyrrolysine and selenocysteine use dissimilar decoding strategies. J Biol Chem 280(21):20740–20751PubMedCrossRefGoogle Scholar
  240. Zheng S, Kwon I (2012) Manipulation of enzyme properties by noncanonical amino acid incorporation. Biotechnol J 7(1):47–60PubMedCrossRefGoogle Scholar

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© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Austrian Centre of Industrial Biotechnology – ACIBGrazAustria

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