Chemistry:Pyrrolysine

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Pyrrolysine
Pyrrolysine.svg
Pyrrolysine-from-PDB-3D-bs-17.png
Names
IUPAC name
Pyrrolysine[1]
Systematic IUPAC name
N6-{[(2R,3R)-3-methyl-3,4-dihydro-2H-pyrrol-2-yl]carbonyl}-L-lysine
Other names
(2S)-2-amino-6-{[(2R,3R)-3-methyl-3,4-dihydro-2H-pyrrole-2-carbonyl]-amino}-hexanoic acid
N6-(4-methyl-1,2-didehydropyrrolidine-5-carboxyl)-L-lysine
monomethylamine methyltransferase cofactor lysine adduct
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
KEGG
UNII
Properties
C12H21N3O3
Molar mass 255.313 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
Tracking categories (test):

Pyrrolysine (symbol Pyl or O;[2] encoded by the 'amber' stop codon UAG) is an α-amino acid that is used in the biosynthesis of proteins in some methanogenic archaea and bacteria;[3][4] it is not present in humans. It contains an α-amino group (which is in the protonated –NH+3 form under biological conditions), a carboxylic acid group (which is in the deprotonated –COO− form under biological conditions). Its pyrroline side-chain is similar to that of lysine in being basic and positively charged at neutral pH.[citation needed]

Genetics

Nearly all genes are translated using only 20 standard amino acid building blocks. Two unusual genetically-encoded amino acids are selenocysteine and pyrrolysine. Pyrrolysine was discovered in 2002 at the active site of methyltransferase enzyme from a methane-producing archeon, Methanosarcina barkeri.[5][6] This amino acid is encoded by UAG (normally a stop codon), and its synthesis and incorporation into protein is mediated via the biological machinery encoded by the pylTSBCD cluster of genes.[4]

Composition

As determined by X-ray crystallography[6] and MALDI mass spectrometry, pyrrolysine is made up of 4-methylpyrroline-5-carboxylate in amide linkage with the εN of lysine.[7]

Synthesis

Pyrrolysine is synthesized in vivo by joining two molecules of L-lysine. One molecule of lysine is first converted to (3R)-3-methyl-D-ornithine, which is then ligated to a second lysine. An NH2 group is eliminated, followed by cyclization and dehydration step to yield L-pyrrolysine.[8]

Catalytic function

The extra pyrroline ring is incorporated into the active site of several methyltransferases, where it is believed to rotate relatively freely. It is believed that the ring is involved in positioning and displaying the methyl group of methylamine for attack by a corrinoid cofactor. The proposed model is that a nearby carboxylic acid bearing residue, glutamate, becomes protonated, and the proton can then be transferred to the imine ring nitrogen, exposing the adjacent ring carbon to nucleophilic addition by methylamine. The positively charged nitrogen created by this interaction may then interact with the deprotonated glutamate, causing a shift in ring orientation and exposing the methyl group derived from the methylamine to the binding cleft where it can interact with corrinoid. In this way a net CH+3 is transferred to the cofactor's cobalt atom with a change of oxidation state from I to III. The methylamine-derived ammonia is then released, restoring the original imine.[6]

Genetic coding

Unlike posttranslational modifications of lysine such as hydroxylysine, methyllysine, and hypusine, pyrrolysine is incorporated during translation (protein synthesis) as directed by the genetic code, just like the standard amino acids. It is encoded in mRNA by the UAG codon, which in most organisms is the 'amber' stop codon. This requires only the presence of the pylT gene, which encodes an unusual transfer RNA (tRNA) with a CUA anticodon, and the pylS gene, which encodes a class II aminoacyl-tRNA synthetase that charges the pylT-derived tRNA with pyrrolysine.

This novel tRNA-aaRS pair ("orthogonal pair") is independent of other synthetases and tRNAs in Escherichia coli, and further possesses some flexibility in the range of amino acids processed, making it an attractive tool to allow the placement of a possibly wide range of functional chemical groups at arbitrarily specified locations in modified proteins.[9][10] For example, the system provided one of two fluorophores incorporated site-specifically within calmodulin to allow the real-time examination of changes within the protein by FRET spectroscopy,[11] and site-specific introduction of a photocaged lysine derivative.[12] (See Expanded genetic code)

It was originally proposed that a specific downstream sequence "PYLIS", forming a stem-loop in the mRNA, forced the incorporation of pyrrolysine instead of terminating translation in methanogenic archaea. This would be analogous to the SECIS element for selenocysteine incorporation.[13] However, the PYLIS model has lost favor in view of the lack of structural homology between PYLIS elements and the lack of UAG stops in those species.[14]

Evolution

The pylT (tRNA) and pylS (aa-tRNA synthase) genes are part of an operon of Methanosarcina barkeri, with homologues in other sequenced members of the Methanosarcinaceae family: M. acetivorans, M. mazei, and M. thermophila. Pyrrolysine-containing proteins are known to include monomethylamine methyltransferase (mtmB), dimethylamine methyltransferase (mtbB), and trimethylamine methyltransferase (mttB). Homologs of pylS and pylT have also been found in an Antarctic archaeon, Methanosarcina barkeri and a Gram-positive bacterium, Desulfitobacterium hafniense.[13][15] The other genes of the Pyl operon mediate pyrrolysine biosynthesis, leading to description of the operon as a "natural genetic code expansion cassette".[16]

A number of evolutionary scenarios have been proposed for the pyrrolysine system. The current (2022) view, given available sequences for tRNA and Pyl-tRNA (PylRS) synthase genes, is that:[17]

  • tRNA(Pyl) diverged from tRNA(Phe) some time between the divergence of the three domains (~LUCA) and the divergence of archaeal phyla, but was lost in non-archaeal lineages;[17]
  • PylRS originated within a common ancestor of all archaea. A number of domain organizations of PylRS is known: pylS itself consists of an N-terminal tRNA-binding domain and a C-terminal synthase domain, but other organizations consist of two domains in separate proteins or a protein made up of a lone C-terminal domain. The CTD probably originated from PheRS. The NTD is an archaeal innovation with no known relative. The ancestral PylRS probably adopted the "two separate proteins" configuration.[17]
  • The "genetic code expansion cassette" was later transferred into various bacteria. This cassette's PylRS has a split-domain configuration.[17]

Earlier evolutionary scenarios were limited by the taxonomic range of known synthases:

  • In 2007, when use of the amino acid appeared confined to the Methanosarcinaceae, the system was described as a "late archaeal invention" by which a 21st amino acid was added to the genetic code.[18] It is now known that a wide range of prokaryotes have these two genes.[17]
  • In 2009, structure comparison suggested that PylRS may have originated in the LUCA, but it only persisted in organisms using methylamines as energy sources.[19] It is now known that some non-methanogens also have these two genes, but the dating was not too far off.[17]
  • In 2009, it was suggested that the system could have migrated into bacteria by horizontal gene transfer.[20] This is probably true based on the 2022 study, though the paper originally assumed a link to methanogenesis.[17]

Potential for an alternative translation

The tRNA(CUA) can be charged with lysine in vitro by the concerted action of the M. barkeri Class I and Class II lysyl-tRNA synthetases, which do not recognize pyrrolysine. Charging a tRNA(CUA) with lysine was originally hypothesized to be the first step in translating UAG amber codons as pyrrolysine, a mechanism analogous to that used for selenocysteine. More recent data favor direct charging of pyrrolysine on to the tRNA(CUA) by the protein product of the pylS gene, leading to the suggestion that the LysRS1:LysRS2 complex may participate in a parallel pathway designed to ensure that proteins containing the UAG codon can be fully translated using lysine as a substitute amino acid in the event of pyrrolysine deficiency.[21] Further study found that the genes encoding LysRS1 and LysRS2 are not required for normal growth on methanol and methylamines with normal methyltransferase levels, and they cannot replace pylS in a recombinant system for UAG amber stop codon suppression.[22]

References

  1. ↑ International Union of Pure and Applied Chemistry (2014). Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013. The Royal Society of Chemistry. pp. 1392. doi:10.1039/9781849733069. ISBN 978-0-85404-182-4. 
  2. ↑ "Nomenclature and Symbolism for Amino Acids and Peptides". IUPAC-IUB Joint Commission on Biochemical Nomenclature. 1983. http://www.chem.qmul.ac.uk/iupac/AminoAcid/AA1n2.html. 
  3. ↑ Richard Cammack, ed (2009). "Newsletter 2009". Biochemical Nomenclature Committee of IUPAC and NC-IUBMB. Pyrrolysine. http://www.chem.qmul.ac.uk/iubmb/newsletter/2009.html#item35. 
  4. ↑ 4.0 4.1 Rother, Michael; Krzycki, Joseph A. (2010-01-01). "Selenocysteine, Pyrrolysine, and the Unique Energy Metabolism of Methanogenic Archaea". Archaea 2010: 1–14. doi:10.1155/2010/453642. ISSN 1472-3646. PMID 20847933. 
  5. ↑ Srinivasan, G; James, C. M.; Krzycki, J. A. (2002-05-24). "Pyrrolysine encoded by UAG in Archaea: charging of a UAG-decoding specialized tRNA". Science 296 (5572): 1459–1462. doi:10.1126/science.1069588. PMID 12029131. Bibcode: 2002Sci...296.1459S. 
  6. ↑ 6.0 6.1 6.2 Hao, Bing; Gong; Ferguson; James; Krzycki; Chan (2002-05-24). "A New UAG-Encoded Residue in the Structure of a Methanogen Methyltransferase". Science 296 (5572): 1462–1466. doi:10.1126/science.1069556. PMID 12029132. Bibcode: 2002Sci...296.1462H. 
  7. ↑ Soares, J. A.; Zhang, L; Pitsch, R. L.; Kleinholz, N. M.; Jones, R. B.; Wolff, J. J.; Amster, J; Green-Church, K. B. et al. (2005-11-04). "The residue mass of L-pyrrolysine in three distinct methylamine methyltransferases". The Journal of Biological Chemistry 280 (44): 36962–36969. doi:10.1074/jbc.M506402200. PMID 16096277. 
  8. ↑ Gaston, Marsha A.; Zhang; Green-Church; Krzycki (March 31, 2011). "The complete biosynthesis of the genetically encoded amino acid pyrrolysine from lysine". Nature 471 (7340): 647–50. doi:10.1038/nature09918. PMID 21455182. Bibcode: 2011Natur.471..647G. 
  9. ↑ Hao, B; Zhao, G; Kang, P. T.; Soares, J. A.; Ferguson, T. K.; Gallucci, J; Krzycki, J. A.; Chan, M. K. (September 2004). "Reactivity and chemical synthesis of L-pyrrolysine – the 22nd genetically encoded amino acid". Chemistry & Biology 11 (9): 1317–24. doi:10.1016/j.chembiol.2004.07.011. PMID 15380192. 
  10. ↑ Li, W. T.; Mahapatra, A; Longstaff, D. G.; Bechtel, J; Zhao, G; Kang, P. T.; Chan, M. K.; Krzycki, J. A. (January 2009). "Specificity of pyrrolysyl-tRNA synthetase for pyrrolysine and pyrrolysine analogs". Journal of Molecular Biology 385 (4): 1156–64. doi:10.1016/j.jmb.2008.11.032. PMID 19063902. 
  11. ↑ Fekner, T; Li, X; Lee, M. M.; Chan, M. K. (2009). "A pyrrolysine analogue for protein click chemistry". Angewandte Chemie International Edition in English 48 (9): 1633–5. doi:10.1002/anie.200805420. PMID 19156778. 
  12. ↑ Chen, P. R.; Groff, D; Guo, J; Ou, W; Cellitti, S; Geierstanger, B. H.; Schultz, P. G. (2009). "A facile system for encoding unnatural amino acids in mammalian cells". Angewandte Chemie International Edition in English 48 (22): 4052–5. doi:10.1002/anie.200900683. PMID 19378306. 
  13. ↑ 13.0 13.1 Reviewed in Zhang, Y; Baranov, P. V.; Atkins, J. F.; Gladyshev, V. N. (May 27, 2005). "Pyrrolysine and selenocysteine use dissimilar decoding strategies". Journal of Biological Chemistry 280 (21): 20740–20751. doi:10.1074/jbc.M501458200. PMID 15788401. 
  14. ↑ Namy, Olivier; Zhou, Yu; Gundllapalli, Sarath; Polycarpo, Carla R.; Denise, Alain; Rousset, Jean-Pierre; Söll, Dieter; Ambrogelly, Alexandre (November 2007). "Adding pyrrolysine to the Escherichia coli genetic code". FEBS Letters 581 (27): 5282–5288. doi:10.1016/j.febslet.2007.10.022. PMID 17967457. 
  15. ↑ Zhang, Y; Gladyshev, V. N. (2007). "High content of proteins containing 21st and 22nd amino acids, selenocysteine and pyrrolysine, in a symbiotic deltaproteobacterium of gutless worm Olavius algarvensis". Nucleic Acids Research 35 (15): 4952–4963. doi:10.1093/nar/gkm514. PMID 17626042. 
  16. ↑ Longstaff, D. G.; Larue, R. C.; Faust, J. E.; Mahapatra, A; Zhang, L; Green-Church, K. B.; Krzycki, J. A. (2007-01-16). "A natural genetic code expansion cassette enables transmissible biosynthesis and genetic encoding of pyrrolysine". Proceedings of the National Academy of Sciences of the United States of America 104 (3): 1021–6. doi:10.1073/pnas.0610294104. PMID 17204561. Bibcode: 2007PNAS..104.1021L. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 Guo, LT; Amikura, K; Jiang, HK; Mukai, T; Fu, X; Wang, YS; O'Donoghue, P; Söll, D et al. (November 2022). "Ancestral archaea expanded the genetic code with pyrrolysine.". The Journal of Biological Chemistry 298 (11): 102521. doi:10.1016/j.jbc.2022.102521. PMID 36152750. 
  18. ↑ Ambrogelly, A; Gundllapalli, S; Herring, S; Polycarpo, C; Frauer, C; Söll, D (2007-02-27). "Pyrrolysine is not hardwired for cotranslational insertion at UAG codons". Proceedings of the National Academy of Sciences of the United States of America 104 (9): 3141–3146. doi:10.1073/pnas.0611634104. PMID 17360621. Bibcode: 2007PNAS..104.3141A. 
  19. ↑ Nozawa, K; O'Donoghue, P; Gundllapalli, S; Araiso, Y; Ishitani, R; Umehara, T; Söll, D; Nureki, O (2009-02-26). "Pyrrolysyl-tRNA synthetase:tRNAPyl structure reveals the molecular basis of orthogonality". Nature 457 (7233): 1163–1167. doi:10.1038/nature07611. PMID 19118381. Bibcode: 2009Natur.457.1163N. 
  20. ↑ Fournier, G (2009). "Horizontal gene transfer and the evolution of methanogenic pathways". Horizontal Gene Transfer. Methods in Molecular Biology. 532. pp. 163–79. doi:10.1007/978-1-60327-853-9_9. ISBN 978-1-60327-852-2. 
  21. ↑ Polycarpo, C; Ambrogelly, A; Bérubé, A; Winbush, S. M.; McCloskey, J. A.; Crain, P. F.; Wood, J. L.; Söll, D (2004-08-24). "An aminoacyl-tRNA synthetase that specifically activates pyrrolysine". Proceedings of the National Academy of Sciences of the United States of America 101 (34): 12450–12454. doi:10.1073/pnas.0405362101. PMID 15314242. Bibcode: 2004PNAS..10112450P. 
  22. ↑ Mahapatra, A; Srinivasan, G; Richter, K. B.; Meyer, A; Lienard, T; Zhang, J. K.; Zhao, G; Kang, P. T. et al. (June 2007). "Class I and class II lysyl-tRNA synthetase mutants and the genetic encoding of pyrrolysine in Methanosarcina spp". Molecular Microbiology 64 (5): 1306–18. doi:10.1111/j.1365-2958.2007.05740.x. PMID 17542922. 

Further reading

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