Pyrrolysine

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"Pyl" redirects here. For other uses, see Pyl (disambiguation).
Not to be confused with Pyrolysis.
Pyrrolysine
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
  • InChI=1S/C12H21N3O3/c1-8-5-7-14-10(8)11(16)15-6-3-2-4-9(13)12(17)18/h7-10H,2-6,13H2,1H3,(H,15,16)(H,17,18)/t8-,9+,10-/m1/s1 checkY
    Key: ZFOMKMMPBOQKMC-KXUCPTDWSA-N checkY
  • InChI=1/C12H21N3O3/c1-8-5-7-14-10(8)11(16)15-6-3-2-4-9(13)12(17)18/h7-10H,2-6,13H2,1H3,(H,15,16)(H,17,18)/t8-,9+,10-/m1/s1
    Key: ZFOMKMMPBOQKMC-KXUCPTDWBO
  • C[C@@H]1CC=N[C@H]1C(=O)NCCCC[C@@H](C(=O)O)N
  • Zwitterion: O=C(NCCCC[C@@H](C(=O)[O-])[NH3+])[C@@H]1/N=C\C[C@H]1C
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).
☒N verify (what is checkY☒N ?)

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

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

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

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

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

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

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

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. ISBN 978-0-85404-182-4
    .
  2. ^ "Nomenclature and Symbolism for Amino Acids and Peptides". IUPAC-IUB Joint Commission on Biochemical Nomenclature. 1983. Archived from the original on 9 October 2008. Retrieved 5 March 2018.
  3. ^ Richard Cammack, ed. (2009). "Newsletter 2009". Biochemical Nomenclature Committee of IUPAC and NC-IUBMB. Pyrrolysine. Archived from the original on 2017-09-12. Retrieved 2012-04-16.
  4. ^
    PMID 20847933
    .
  5. S2CID 28593085
    .
  6. ^
    S2CID 35519996
    .
  7. PMID 16096277
    .
  8. PMID 21455182
    .
  9. PMID 15380192
    .
  10. PMID 19063902
    .
  11. PMID 19156778
    .
  12. PMID 19378306
    .
  13. ^
    PMID 15788401
    .
  14. PMID 17967457
    .
  15. PMID 17626042
    .
  16. PMID 17204561
    .
  17. ^
    PMID 36152750
    .
  18. PMID 17360621
    .
  19. PMID 19118381
    .
  20. PMID 19271184
    .
  21. PMID 15314242
    .
  22. S2CID 26445329
    .

Further reading

External links
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