Biosynthesis and biotechnological application of non-canonical amino acids: Complex and unclear.

Compared with the better-studied canonical amino acids, the distribution, metabolism and functions of natural non-canonical amino acids remain relatively obscure. Natural non-canonical amino acids have been mainly discovered in plants as secondary metabolites that perform diversified physiological functions. Due to their specific characteristics, a broader range of natural and artificial non-canonical amino acids have recently been applied in the development of functional materials and pharmaceutical products. With the rapid development of advanced methods in biotechnology, non-canonical amino acids can be incorporated into peptides, proteins and enzymes to improve the function and performance relative to their natural counterparts. Therefore, biotechnological application of non-canonical amino acids in artificial bio-macromolecules follows the central goal of synthetic biology to: create novel life forms and functions. However, many of the non-canonical amino acids are synthesized via chemo- or semi-synthetic methods, and few non-canonical amino acids can be synthesized using natural in vivo pathways. Therefore, further research is needed to clarify the metabolic pathways and key enzymes of the non-canonical amino acids. This will lead to the discovery of more candidate non-canonical amino acids, especially for those that are derived from microorganisms and are naturally bio-compatible with chassis strains for in vivo biosynthesis. In this review, we summarize representative natural and artificial non-canonical amino acids, their known information regarding associated metabolic pathways, their characteristics and their practical applications. Moreover, this review summarizes current barriers in developing in vivo pathways for the synthesis of non-canonical amino acids, as well as other considerations, future trends and potential applications of non-canonical amino acids in advanced biotechnology.

[1]  P. O. Larsen,et al.  Amino Acid Studies. Part II. Structure and Synthesis of Albizziine (L-2-Amino-3-ureidopropionic Acid), an Amino Acid from Higher Plants. , 1959 .

[2]  W. Chilton,et al.  A chloro amino acid from Amanita solitaria , 1972 .

[3]  R. Chaurasia,et al.  Lathyrism: has the scenario changed in 2013? , 2014, Neurological research.

[4]  T. Zabriskie,et al.  The enduracidin biosynthetic gene cluster from Streptomyces fungicidicus. , 2006, Microbiology.

[5]  Hyungdon Yun,et al.  Incorporating unnatural amino acids to engineer biocatalysts for industrial bioprocess applications , 2015, Biotechnology journal.

[6]  S. Hunt,et al.  The Non-Protein Amino Acids , 1985 .

[7]  M. Jensen,et al.  Tuning of Recombinant Protein Expression in Escherichia coli by Manipulating Transcription, Translation Initiation Rates, and Incorporation of Noncanonical Amino Acids. , 2017, ACS synthetic biology.

[8]  R. Wolfe,et al.  Homocysteine metabolism. , 1999, Annual review of nutrition.

[9]  G. Otting,et al.  Protein engineering with unnatural amino acids. , 2013, Current opinion in structural biology.

[10]  E. Rubenstein.  Misincorporation of the Proline Analog Azetidine-2-Carboxylic Acid in the Pathogenesis of Multiple Sclerosis: A Hypothesis , 2008, Journal of neuropathology and experimental neurology.

[11]  Michael C. Jewett,et al.  Non-standard amino acid incorporation into proteins using Escherichia coli cell-free protein synthesis , 2014, Front. Chem..

[12]  V. Noireaux,et al.  Cell-free expression with the toxic amino acid canavanine. , 2015, Bioorganic & medicinal chemistry letters.

[13]  C. Smolke,et al.  Complete biosynthesis of opioids in yeast , 2015, Science.

[14]  A. Chamberlin,et al.  Incorporation of Noncoded Amino Acids by In Vitro Protein Biosynthesis , 1999 .

[15]  J. Awapara,et al.  FREE γ-AMINOBUTYRIC ACID IN BRAIN , 1950 .

[16]  Steven Lee,et al.  Ramoplanin: A Lipoglycodepsipeptide Antibiotic , 2005, The Annals of pharmacotherapy.

[17]  P. Schultz,et al.  Incorporation of fluorotyrosines into ribonucleotide reductase using an evolved, polyspecific aminoacyl-tRNA synthetase. , 2011, Journal of the American Chemical Society.

[18]  F. Heitz,et al.  How can the aromatic side-chains modulate the conductance of the gramicidin channel? A new approach using non-coded amino acids. , 2009, International journal of peptide and protein research.

[19]  Kate Samardzic,et al.  Toxic Nonprotein Amino Acids , 2015 .

[20]  J. Connor,et al.  Characterization of L-homocysteate-induced currents in Purkinje cells from wild-type and NMDA receptor knockout mice. , 1999, Journal of neurophysiology.

[21]  S. Yadav,et al.  Self-assembled dehydropeptide nano carriers for delivery of ornidazole and curcumin. , 2017, Colloids and surfaces. B, Biointerfaces.

[22]  A. Lipka,et al.  Accumulation of 5-hydroxynorvaline in maize (Zea mays) leaves is induced by insect feeding and abiotic stress , 2014, Journal of experimental botany.

[23]  J. Sansano,et al.  Asymmetric synthesis of α-amino acids from α,β-(Z)-didehydroamino acid derivatives with 1,2,3,6-tetrahydropyrazin-2-one structure , 2001 .

[24]  D. D. Van Slyke,et al.  The source and state of the hydroxylysine of collagen. , 1955, The Journal of biological chemistry.

[25]  A. Williams,et al.  Design, synthesis and characterization of linear unnatural amino acids for skin moisturization , 2016, International journal of cosmetic science.

[26]  J. Keasling.  Synthetic biology and the development of tools for metabolic engineering. , 2012, Metabolic engineering.

[27]  T. Barrette,et al.  Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. , 2007, Neoplasia.

[28]  Cohen Gn,et al.  Total replacement of methionine by selenomethionine in the proteins of Escherichia coli , 1957 .

[29]  G. Salvesen,et al.  Synthesis of a HyCoSuL peptide substrate library to dissect protease substrate specificity , 2017, Nature Protocols.

[30]  S. Seah,et al.  Functional Characterization of an Aminotransferase Required for Pyoverdine Siderophore Biosynthesis in Pseudomonas aeruginosa PAO1 , 2004, Journal of bacteriology.

[31]  O. Calderini,et al.  CYP72A67 Catalyzes a Key Oxidative Step in Medicago truncatula Hemolytic Saponin Biosynthesis. , 2015, Molecular plant.

[32]  R. Pi,et al.  Downregulation of Nrf2/HO-1 pathway and activation of JNK/c-Jun pathway are involved in homocysteic acid-induced cytotoxicity in HT-22 cells. , 2013, Toxicology letters.

[33]  M. Xian,et al.  The metabolism and biotechnological application of betaine in microorganism , 2016, Applied Microbiology and Biotechnology.

[34]  Millard J. Horn,et al.  ISOLATION OF A NEW SULFUR-CONTAINING AMINO ACID (LANTHIONINE) FROM SODIUM CARBONATE-TREATED WOOL , 1941 .

[35]  B. Maes,et al.  The first one-pot synthesis of L-7-iodotryptophan from 7-iodoindole and serine, and an improved synthesis of other L-7-halotryptophans. , 2014, Organic letters.

[36]  Sylvie Garneau-Tsodikova,et al.  Protein posttranslational modifications: the chemistry of proteome diversifications. , 2005, Angewandte Chemie.

[37]  C. Döbler,et al.  Synthesis of non-proteinogenic (D)- or (L)-amino acids by asymmetric hydrogenation , 1996, Amino Acids.

[38]  M. J. Sloan,et al.  Enzymatic synthesis of aza-l-tryptophans: The preparation of 5- and 6-Aza-l-tryptophan , 1992 .

[39]  R. Phillips,et al.  High-efficiency incorporation in vivo of tyrosine analogues with altered hydroxyl acidity in place of the catalytic tyrosine-14 of Delta 5-3-ketosteroid isomerase of Comamonas (Pseudomonas) testosteroni: effects of the modifications on isomerase kinetics. , 1998, Biochemistry.

[40]  G. Zenebe,et al.  Neurolathyrism: two Ethiopian case reports and review of the literature , 2012, Journal of Neurology.

[41]  S. Gronowitz,et al.  Enzymatic synthesis of Thia-L-tryptophans , 1995 .

[42]  A. Stempel,et al.  ANTIMETABOLITES PRODUCED BY MICROORGANISMS. II , 1971 .

[43]  I. Izzo,et al.  Asymmetric synthesis of N, O-diprotected (2S, 3S)-N-methyl-δ-hydroxyisoleucine, noncoded amino acid of halipeptin A , 2004 .

[44]  Y. Wang,et al.  CYP76AH1 catalyzes turnover of miltiradiene in tanshinones biosynthesis and enables heterologous production of ferruginol in yeasts , 2013, Proceedings of the National Academy of Sciences.

[45]  G. Rosenthal.  l-Canavanine: a higher plant insecticidal allelochemical , 2001, Amino Acids.

[46]  C. Walsh,et al.  Nonproteinogenic amino acid building blocks for nonribosomal peptide and hybrid polyketide scaffolds. , 2013, Angewandte Chemie.

[47]  Metal complexation induces antibiotic activity in S-ethyl-l-cysteine sulfoxide , 2018, Inorganica Chimica Acta.

[48]  K. Niehaus,et al.  Genome wide transcription start sites analysis of Xanthomonas campestris pv. campestris B100 with insights into the gum gene cluster directing the biosynthesis of the exopolysaccharide xanthan. , 2016, Journal of biotechnology.

[49]  Biotechnological approaches to enhance the biosynthesis of ginkgolides and bilobalide in Ginkgo biloba , 2013, Phytochemistry Reviews.

[50]  K. Walker,et al.  Taxol biosynthesis: tyrocidine synthetase A catalyzes the production of phenylisoserinyl CoA and other amino phenylpropanoyl thioesters. , 2012, Chemistry & biology.

[51]  Tilmann Weber,et al.  Characterization of the ‘pristinamycin supercluster’ of Streptomyces pristinaespiralis , 2011, Microbial biotechnology.

[52]  C. Wingren,et al.  Site-specific photocoupling of pBpa mutated scFv antibodies for use in affinity proteomics. , 2017, Biochimica et biophysica acta. Proteins and proteomics.

[53]  F. Clerici,et al.  Non-standard amino acids and peptides: From self-assembly to nanomaterials , 2016 .

[54]  Hyungdon Yun,et al.  Unnatural amino acid mutagenesis-based enzyme engineering. , 2015, Trends in biotechnology.

[55]  S. Hashimoto,et al.  Construction of a novel hydroxyproline-producing recombinant Escherichia coli by introducing a proline 4-hydroxylase gene. , 2000, Journal of bioscience and bioengineering.

[56]  S. Hatanaka.  Amino acids from mushrooms. , 1992, Fortschritte der Chemie organischer Naturstoffe = Progress in the chemistry of organic natural products. Progres dans la chimie des substances organiques naturelles.

[57]  Zhiyan Huang,et al.  Formal total synthesis of (−)-kainic acid , 2016 .

[58]  G. Rosenthal.  The Biological Effects and Mode of Action of L-Canavanine, a Structural Analogue of L-Arginine , 1977, The Quarterly Review of Biology.

[59]  Lei Zhang,et al.  Design, Synthesis, and Preliminary Activity Evaluation of Novel Peptidomimetics as Aminopeptidase N/CD13 Inhibitors , 2011, Archiv der Pharmazie.

[60]  H. Wiesinger.  5 Arginine, Citrulline, and Ornithine , 2007 .

[61]  Andrew B. Martin,et al.  Generation of a bacterium with a 21 amino acid genetic code. , 2003, Journal of the American Chemical Society.

[62]  J. C. Cook,et al.  Structures of the didemnins, antiviral and cytotoxic depsipeptides from a Caribbean tunicate , 1981 .

[63]  R. Phillips,et al.  Enzymatic synthesis of aza-l-tyrosines. , 2001, Bioorganic & medicinal chemistry letters.

[64]  Kechun Zhang,et al.  Expanding metabolism for total biosynthesis of the nonnatural amino acid L-homoalanine , 2010, Proceedings of the National Academy of Sciences.

[65]  L. Lai,et al.  Rational Design of Selective Allosteric Inhibitors of PHGDH and Serine Synthesis with Anti-tumor Activity. , 2017, Cell chemical biology.

[66]  R. Dean,et al.  Metabolism of protein-bound DOPA in mammals. , 2000, The international journal of biochemistry & cell biology.

[67]  M. Drew,et al.  Amyloid-like fibril-forming supramolecular β-sheets from a β-turn forming tripeptide containing non-coded amino acids: the crystallographic signature , 2003 .

[68]  J. Liao,et al.  An evolutionary strategy for isobutanol production strain development in Escherichia coli. , 2011, Metabolic engineering.

[69]  Robert H. White.  The biosynthesis of cysteine and homocysteine in Methanococcus jannaschii. , 2003, Biochimica et biophysica acta.

[70]  R. Dodge,et al.  The synthesis of [14 C]4-acetylphenylalanine, effect on cell viability, and assessment of protein incorporation in male rat hepatocytes. , 2017, Journal of labelled compounds & radiopharmaceuticals.

[71]  P. Spencer,et al.  Lathyrus sativus (grass pea) and its neurotoxin ODAP. , 2006, Phytochemistry.

[72]  Nediljko Budisa,et al.  Azatryptophans endow proteins with intrinsic blue fluorescence , 2008, Proceedings of the National Academy of Sciences.

[73]  X. Wang,et al.  Core-shell magnetic molecularly imprinted polymers used rhodamine B hydroxyproline derivate as template combined with in situ derivatization for the specific measurement of L-hydroxyproline. , 2018, Journal of chromatography. A.

[74]  Zhengwu Shen,et al.  Two unusual isoflavonoids from Campylotropis hirtella – A new biosynthesis route of flavonoids , 2017 .

[75]  S. Yokoyama,et al.  Site‐specific incorporation of photofunctional nonnatural amino acids into a polypeptide through in vitro protein biosynthesis , 1994, FEBS letters.

[76]  Chaoyin Chen,et al.  Enhancement of triterpenoid saponins biosynthesis in Panax notoginseng cells by co-overexpressions of 3-hydroxy-3-methylglutaryl CoA reductase and squalene synthase genes , 2017 .

[77]  Nediljko Budisa,et al.  Recent advances in genetic code engineering in Escherichia coli. , 2012, Current opinion in biotechnology.

[78]  Sinisa Hrvatin,et al.  Cloning and characterization of the biosynthetic gene cluster for kutznerides , 2007, Proceedings of the National Academy of Sciences.

[79]  M. Kito,et al.  Some Properties of the Theanine Synthesizing Enzyme in Tea Seedlings , 1965 .

[80]  J. Meinwald,et al.  Grass roots chemistry: meta-Tyrosine, an herbicidal nonprotein amino acid , 2007, Proceedings of the National Academy of Sciences.

[81]  J. H. Pereira,et al.  Structure of a three-domain sesquiterpene synthase: a prospective target for advanced biofuels production. , 2011, Structure.

[82]  J. Keasling,et al.  Engineering Cellular Metabolism , 2016, Cell.

[83]  Birgit Wiltschi,et al.  Protein Building Blocks and the Expansion of the Genetic Code , 2016 .

[84]  L. Fowden.  Non-protein amino acids of plants , 1981 .

[85]  P. Nunn,et al.  Toxicity of Non-protein Amino Acids to Humans and Domestic Animals , 2010, Natural product communications.

[86]  C. Walsh,et al.  Biosynthesis of L-p-hydroxyphenylglycine, a non-proteinogenic amino acid constituent of peptide antibiotics. , 2000, Chemistry & biology.

[87]  L. Navrátilová,et al.  Synthesis of readily available fluorophenylalanine derivatives and investigation of their biological activity. , 2017, Bioorganic chemistry.

[88]  N. Morin,et al.  Production of L-dihydroxyphenylalanine in Escherichia coli with the tyrosine phenol-lyase gene cloned from Erwinia herbicola , 1993, Applied and environmental microbiology.

[89]  B. Trost,et al.  The direct catalytic asymmetric aldol reaction. , 2010, Chemical Society reviews.

[90]  R. Marchiosi,et al.  The role of L-DOPA in plants , 2014, Plant signaling & behavior.

[91]  J. Southard,et al.  Presence of L-canavanine in Hedysarum alpinum seeds and its potential role in the death of Chris McCandless. , 2015, Wilderness & environmental medicine.

[92]  Peter G Schultz,et al.  Adding new chemistries to the genetic code. , 2010, Annual review of biochemistry.

[93]  R. Phillips.  Synthetic applications of tryptophan synthase , 2004 .

[94]  Bas Pieters,et al.  Substrate scope for trimethyllysine hydroxylase catalysis. , 2016, Chemical communications.

[95]  K. Numata,et al.  Chemoenzymatic synthesis of polypeptides containing the unnatural amino acid 2-aminoisobutyric acid. , 2017, Chemical communications.

[96]  W. König,et al.  Hydroxyproline-containing and glycine-rich cell wall polypeptides are widespread in the green algae , 1994 .

[97]  Shufeng Zhou,et al.  Electrochemical Sensors for Nitric Oxide Detection in Biological Applications , 2014 .

[98]  Robin L Brabham,et al.  Pyrrolysine Amber Stop‐Codon Suppression: Development and Applications , 2017, Chembiochem : a European journal of chemical biology.

[99]  Paul Tempst,et al.  PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. , 2002, Molecular cell.

[100]  P. Schultz,et al.  Genetic incorporation of unnatural amino acids into proteins in mammalian cells , 2007, Nature Methods.

[101]  Gerald Striedner,et al.  High-level biosynthesis of norleucine in E. coli for the economic labeling of proteins. , 2016, Journal of biotechnology.

[102]  David Eisen,et al.  Orchestrating the biosynthesis of an unnatural pyrrolysine amino Acid for its direct incorporation into proteins inside living cells. , 2015, Chemistry.

[103]  Xiaowei Wang,et al.  Transcriptional responses of invasive and indigenous whiteflies to different host plants reveal their disparate capacity of adaptation , 2015, Scientific Reports.

[104]  G. Cohen,et al.  Biosynthesis by Escherichia coli of active altered proteins containing selenium instead of sulfur. , 1957, Biochimica et biophysica acta.

[105]  Nediljko Budisa,et al.  Biocatalysis with Unnatural Amino Acids: Enzymology Meets Xenobiology. , 2017, Angewandte Chemie.

[106]  D. Morse,et al.  γ-Aminobutyric Acid, a Neurotransmitter, Induces Planktonic Abalone Larvae to Settle and Begin Metamorphosis , 1979, Science.

[107]  Matthew D. Schultz,et al.  RF1 Knockout Allows Ribosomal Incorporation of Unnatural Amino Acids at Multiple Sites , 2011, Nature chemical biology.

[108]  Li Li,et al.  Improved synthesis of unnatural amino acids for peptide stapling , 2017 .

[109]  K. Soda,et al.  Applications of stereoselectivity of enzymes: synthesis of optically active amino acids and alpha-hydroxy acids, and stereospecific isotope-labeling of amino acids, amines and coenzymes. , 1986, Advances in biochemical engineering/biotechnology.

[110]  E. Roberts,et al.  gamma-Aminobutyric acid in brain: its formation from glutamic acid. , 1950, The Journal of biological chemistry.

[111]  J. Moss,et al.  ADP-ribosylation of human defensin HNP-1 results in the replacement of the modified arginine with the noncoded amino acid ornithine , 2009, Proceedings of the National Academy of Sciences.

[112]  D. Bagchi,et al.  Safety of 5-hydroxy-L-tryptophan. , 2004, Toxicology letters.

[113]  Yi Lu,et al.  Biosynthetic approach to modeling and understanding metalloproteins using unnatural amino acids , 2017, Science China Chemistry.

[114]  G. Colombo,et al.  Probing the hirudin-thrombin interaction by incorporation of noncoded amino acids and molecular dynamics simulation. , 2002, Biochemistry.

[115]  M. Xian,et al.  Fatty acid from the renewable sources: a promising feedstock for the production of biofuels and biobased chemicals. , 2014, Biotechnology advances.

[116]  C. Walsh.  Blurring the lines between ribosomal and nonribosomal peptide scaffolds. , 2014, ACS chemical biology.

[117]  P. Adiga,et al.  The Isolation and Characterization of β-N-Oxalyl-L-α,β-Diaminopropionic Acid: A Neurotoxin from the Seeds of Lathyrus sativus* , 1964 .

[118]  D. Dhavale,et al.  Chiron approach towards the synthesis of (2S,3R)-3-hydroxyornithine, (2S,3R)-3-hydroxylysine and tetrahydroazepine core of (−)-balanol , 2016 .

[119]  A. van der Vaart,et al.  Right-Handed Helical Foldamers Consisting of De Novo d-AApeptides. , 2017, Journal of the American Chemical Society.

[120]  K. Walker,et al.  Whole-cell biocatalytic production of variously substituted β-aryl- and β-heteroaryl-β-amino acids. , 2016, Journal of biotechnology.

[121]  Hiroaki Suga,et al.  A RaPID way to discover nonstandard macrocyclic peptide modulators of drug targets. , 2017, Chemical communications.

[122]  Aaron W Feldman,et al.  A Semi-Synthetic Organism that Stores and Retrieves Increased Genetic Information , 2017, Nature.

[123]  K. Park,et al.  Enhancement of γ-aminobutyric acid production in Chungkukjang by applying a Bacillus subtilis strain expressing glutamate decarboxylase from Lactobacillus brevis , 2006, Biotechnology Letters.

[124]  H. Neumann,et al.  The use of unnatural amino acids to study and engineer protein function. , 2016, Current opinion in structural biology.

[125]  T. Maier,et al.  Semisynthetic production of unnatural L-α-amino acids by metabolic engineering of the cysteine-biosynthetic pathway , 2003, Nature Biotechnology.

[126]  J. M. Rogers,et al.  Discovering functional, non-proteinogenic amino acid containing, peptides using genetic code reprogramming. , 2015, Organic & biomolecular chemistry.

[127]  D. Baker,et al.  Urea cycle metabolism: effects of supplemental ornithine or citrulline on performance, tissue amino acid concentrations and enzymatic activity in young pigs fed arginine-deficient diets. , 1987, Journal of animal science.

[128]  H. Ashihara,et al.  Biosynthesis of theanine (γ-ethylamino-l-glutamic acid) in seedlings of Camellia sinensis , 2008 .

[129]  G. Cohen,et al.  Amino acid analog incorporation into bacterial proteins. , 1959, Biochimica et biophysica acta.

[130]  Nediljko Budisa,et al.  Coupling Bioorthogonal Chemistries with Artificial Metabolism: Intracellular Biosynthesis of Azidohomoalanine and Its Incorporation into Recombinant Proteins , 2014, Molecules.

[131]  C. Hirayama,et al.  Urinary hydroxyproline and hydroxylysine excretions in relation to hepatic hydroxyproline content in chronic liver disease. , 1989, Clinical biochemistry.

[132]  G. Holmes,et al.  Effect of temperature on kainic acid-induced seizures , 1993, Brain Research.