Agmatidine

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Agmatidine
Agmatidine.svg
Names
IUPAC name
N-(4-Carbamimidamidobutyl)-4-imino-1-(β-D-ribofuranosyl)-1,4-dihydro-2-pyrimidinamine
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
PubChem CID
  • InChI=1S/C14H25N7O4/c15-9-3-6-21(12-11(24)10(23)8(7-22)25-12)14(20-9)19-5-2-1-4-18-13(16)17/h3,6,8,10-12,22-24H,1-2,4-5,7H2,(H2,15,19,20)(H4,16,17,18)/t8-,10-,11-,12-/m1/s1
    Key: NHQSDCRALZPVAJ-HJQYOEGKSA-N
  • InChI=1/C14H25N7O4/c15-9-3-6-21(12-11(24)10(23)8(7-22)25-12)14(20-9)19-5-2-1-4-18-13(16)17/h3,6,8,10-12,22-24H,1-2,4-5,7H2,(H2,15,19,20)(H4,16,17,18)/t8-,10-,11-,12-/m1/s1
    Key: NHQSDCRALZPVAJ-HJQYOEGKBR
  • c1cn(c(nc1=N)NCCCCNC(=N)N)[C@H]2[C@@H]([C@@H]([C@H](O2)CO)O)O
Properties
C14H25N7O4
Molar mass 355.399 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Agmatidine (2-agmatinylcytidine, symbol C+ or agm2C) is a modified cytidine present in the wobble position of the anticodon of several archaeal AUA decoding tRNAs. Agmatidine is essential for correct decoding of the AUA codon in many archaea and is required for aminoacylation of tRNAIle2 with isoleucine.

Contents

Introduction

The genetic code describes how triplet codons on mRNA are translated into protein sequences by specific tRNA molecules which can base-pair with the codons. Precise decoding of the genetic code is a fundamental pre-requisite for long-term survival of all organisms. The nature of the anticodon decides the specificity of hydrogen bonding and hence the accuracy of decoding by tRNAs. To date, a variety of post-transcriptional modifications have been discovered which aid tRNAs in increasing their repertoire of hydrogen bonding capacities. These modifications usually occur on the first base on the anticodon (position 34 or the wobble base position) which base pairs with the third base on the codon and are critical in specific recognition of codons by tRNAs.

The wobble rules of Crick propose how a limited set of tRNAs can decode a wider set of codons by use of wobble base pairing. These rules have been successful in explaining how most of the genetic code is specifically translated by a limited number of tRNAs. For example, a single phenylalanine tRNA with G in the first anticodon position can base pair with either U or C (thus decoding UUU and UUC) and a single leucine tRNA with a modified U (2-thioU) in the anticodon can base pair with either A or G (thus decoding UUA and UUG).

The mechanism of AUA decoding

The mechanism of decoding in the box containing AUU, AUC, AUA (all coding for isoleucine) and AUG (coding for methionine) has remained a puzzle for scientists since long. AUU and AUC are decoded by a single isoleucine tRNA (tRNAIle1) which has G in the anticodon while AUA is decoded by a separate tRNA (tRNAIle2). How the second isoleucine tRNA decodes AUA without also decoding AUG has been a subject of much interest over the years.

Different classes of organisms solve the problem of AUA decoding differently. For example, in eukaryotes, a tRNA having inosine at position 34 (IAU anticodon) can decode all three isoleucine codons, while a tRNA having pseudouridine in the anticodon (ψAψ) anticodon can specifically read the AUA codon. In eubacteria, a tRNA having lysidine in the anticodon (LAU) can specifically decode AUA, but not AUG. However, the mechanism by which Archaea solve the problem of AUA decoding was not known till early 2010, when two groups simultaneously published reports that archaeal tRNAIle2 contains a modified cytidine at position 34, which was named agmatidine.

Structure and Biosynthesis

Agmatidine is similar to lysidine in that the C2-oxo group of cytidine is replaced by the aminoguanidine agmatine instead of by lysine in the case of lysidine. The modification is carried out by the enzyme tRNAIle2 2-agmatinylcytidine synthetase, a product of the gene tiaS present in many archaeal members. Agmatidine is generated in the cell by attachment of agmatine to the C2-oxo group of cytidine by TiaS. Agmatine in turn is a decarboxylation product of arginine (an aminoacid present in all cells).

Agmatidine formation occurs through a three-step mechanism. In step one, TiaS hydrolyzes the α-β phosphodiester bond of ATP to produce AMP and PPi. In step two, the C2 carbonyl oxygen of C34 attacks the γ-phosphorus atom to form the p-C34 intermediate, releasing β-Pi. This is in contrast to the mechanism of lysidine formation where the C2-oxo group is activated by adenylation instead of phosphorylation. In step three, the primary amino group of agmatine attacks the C2 carbon of the p-C34 intermediate to release γ-Pi and form agm2C. TiaS also autophosphorylates its Thr18 with the γ-phosphate of ATP, releasing AMP and β-Pi. This is known to be important for agm2C formation although its exact role is not clear.

Physiology

Conjugation of agmatine moiety at the C2 carbon of C34 induces a tautomeric conversion of C34 which alters its hydrogen bonding pattern, enabling it to pair with adenosine instead of guanosine. The modification is essential for decoding of AUA codons and a tRNA without the modification is not aminoacylated with isoleucine. Moreover, it has been shown that agmatine is an essential metabolite for the viability of Thermococcus kodakaraensis.

The currently sequenced euryarchaeal and crenarchaeal genomes contain only one annotated isoleucine tRNA and three tRNAs with the CAU anticodon (annotated as methionine tRNAs). Therefore, it is very likely that most if not all of these archaeal clades use agmatidine modification to selectively read AUA codons.[ citation needed ] However, currently sequenced genomes from nanoarchaea and korarchaea contain two isoleucine tRNAs, one of which has UAU anticodon (which is probably converted into ψAψ in-vivo). Therefore, it is thought that these classes of archaea follow a eukaryote-like strategy to solve the AUA decoding problem. [1]

Related Research Articles

<span class="mw-page-title-main">Protein biosynthesis</span> Assembly of proteins inside biological cells

Protein biosynthesis is a core biological process, occurring inside cells, balancing the loss of cellular proteins through the production of new proteins. Proteins perform a number of critical functions as enzymes, structural proteins or hormones. Protein synthesis is a very similar process for both prokaryotes and eukaryotes but there are some distinct differences.

<span class="mw-page-title-main">Ribosome</span> Synthesizes proteins in cells

Ribosomes are macromolecular machines, found within all cells, that perform biological protein synthesis. Ribosomes link amino acids together in the order specified by the codons of messenger RNA molecules to form polypeptide chains. Ribosomes consist of two major components: the small and large ribosomal subunits. Each subunit consists of one or more ribosomal RNA molecules and many ribosomal proteins. The ribosomes and associated molecules are also known as the translational apparatus.

<span class="mw-page-title-main">Methionine</span> Sulfur-containing amino acid

Methionine is an essential amino acid in humans.

<span class="mw-page-title-main">Pyrrolysine</span> Chemical compound

Pyrrolysine is an α-amino acid that is used in the biosynthesis of proteins in some methanogenic archaea and bacteria; it is not present in humans. It contains an α-amino group and a carboxylic acid group. Its pyrroline side-chain is similar to that of lysine in being basic and positively charged at neutral pH.

<span class="mw-page-title-main">Translation (biology)</span> Cellular process of protein synthesis

In biology, translation is the process in living cells in which proteins are produced using RNA molecules as templates. The generated protein is a sequence of amino acids. This sequence is determined by the sequence of nucleotides in the RNA. The nucleotides are considered three at a time. Each such triple results in addition of one specific amino acid to the protein being generated. The matching from nucleotide triple to amino acid is called the genetic code. The translation is performed by a large complex of functional RNA and proteins called ribosomes. The entire process is called gene expression.

<span class="mw-page-title-main">Transfer RNA</span> RNA that facilitates the addition of amino acids to a new protein

Transfer RNA is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length. In a cell, it provides the physical link between the genetic code in messenger RNA (mRNA) and the amino acid sequence of proteins, carrying the correct sequence of amino acids to be combined by the protein-synthesizing machinery, the ribosome. Each three-nucleotide codon in mRNA is complemented by a three-nucleotide anticodon in tRNA. As such, tRNAs are a necessary component of translation, the biological synthesis of new proteins in accordance with the genetic code.

<span class="mw-page-title-main">Wobble base pair</span> RNA base pair that does not follow Watson-Crick base pair rules

A wobble base pair is a pairing between two nucleotides in RNA molecules that does not follow Watson-Crick base pair rules. The four main wobble base pairs are guanine-uracil (G-U), hypoxanthine-uracil (I-U), hypoxanthine-adenine (I-A), and hypoxanthine-cytosine (I-C). In order to maintain consistency of nucleic acid nomenclature, "I" is used for hypoxanthine because hypoxanthine is the nucleobase of inosine; nomenclature otherwise follows the names of nucleobases and their corresponding nucleosides. The thermodynamic stability of a wobble base pair is comparable to that of a Watson-Crick base pair. Wobble base pairs are fundamental in RNA secondary structure and are critical for the proper translation of the genetic code.

<span class="mw-page-title-main">RNA editing</span> Molecular process

RNA editing is a molecular process through which some cells can make discrete changes to specific nucleotide sequences within an RNA molecule after it has been generated by RNA polymerase. It occurs in all living organisms and is one of the most evolutionarily conserved properties of RNAs. RNA editing may include the insertion, deletion, and base substitution of nucleotides within the RNA molecule. RNA editing is relatively rare, with common forms of RNA processing not usually considered as editing. It can affect the activity, localization as well as stability of RNAs, and has been linked with human diseases.

<span class="mw-page-title-main">Start codon</span> First codon of a messenger RNA translated by a ribosome

The start codon is the first codon of a messenger RNA (mRNA) transcript translated by a ribosome. The start codon always codes for methionine in eukaryotes and archaea and a N-formylmethionine (fMet) in bacteria, mitochondria and plastids.

<span class="mw-page-title-main">T arm</span> Region on a tRNA molecule

The T-arm or T-loop is a specialized region on the tRNA molecule which acts as a special recognition site for the ribosome to form a tRNA-ribosome complex during protein biosynthesis or translation (biology).

A release factor is a protein that allows for the termination of translation by recognizing the termination codon or stop codon in an mRNA sequence. They are named so because they release new peptides from the ribosome.

<span class="mw-page-title-main">Queuine</span> Chemical compound

Queuine (Q) is a hypermodified nucleobase found in the first position of the anticodon of tRNAs specific for Asn, Asp, His, and Tyr, in most eukaryotes and prokaryotes. Because it is utilized by all eukaryotes but produced exclusively by bacteria, it is a putative vitamin.

Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation that results in the production of multiple, unique proteins from a single mRNA. The process can be programmed by the nucleotide sequence of the mRNA and is sometimes affected by the secondary, 3-dimensional mRNA structure. It has been described mainly in viruses, retrotransposons and bacterial insertion elements, and also in some cellular genes.

<span class="mw-page-title-main">Expanded genetic code</span> Modified genetic code

An expanded genetic code is an artificially modified genetic code in which one or more specific codons have been re-allocated to encode an amino acid that is not among the 22 common naturally-encoded proteinogenic amino acids.

<span class="mw-page-title-main">Queuosine</span> Chemical compound

Queuosine is a modified nucleoside that is present in certain tRNAs in bacteria and eukaryotes. It contains the nucleobase queuine. Originally identified in E. coli, queuosine was found to occupy the first anticodon position of tRNAs for histidine, aspartic acid, asparagine and tyrosine. The first anticodon position pairs with the third "wobble" position in codons, and queuosine improves accuracy of translation compared to guanosine. Synthesis of queuosine begins with GTP. In bacteria, three structurally unrelated classes of riboswitch are known to regulate genes that are involved in the synthesis or transport of pre-queuosine1, a precursor to queuosine: PreQ1-I riboswitches, PreQ1-II riboswitches and PreQ1-III riboswitches.

<span class="mw-page-title-main">Lysidine (nucleoside)</span> Chemical compound

Lysidine is an uncommon nucleoside, rarely seen outside of tRNA. It is a derivative of cytidine in which the carbonyl is replaced by the amino acid lysine. The first position, i.e. the wobble base, in the anti-codon of the eubacterial isoleucine-specific tRNA pertaining to the AUA codon is typically changed from a cytidine which would pair with guanosine to a lysidine which will base pair with adenosine. Lysidine improves translation fidelity because uridine cannot be used at this position even though it is a conventional partner for adenosine since it will also "wobble base pair" with guanosine. Lysidine is denoted as L or k2C.

<span class="mw-page-title-main">Wybutosine</span> Chemical compound

In biochemistry, wybutosine (yW) is a heavily modified nucleoside of phenylalanine transfer RNA that stabilizes interactions between the codons and anti-codons during protein synthesis. Ensuring accurate synthesis of protein is essential in maintaining health as defects in tRNA modifications are able to cause disease. In eukaryotic organisms, it is found only in position 37, 3'-adjacent to the anticodon, of phenylalanine tRNA. Wybutosine enables correct translation through the stabilization of the codon-anticodon base pairing during the decoding process.

TRNAMet cytidine acetyltransferase (EC 2.3.1.193, YpfI, TmcA) is an enzyme with systematic name acetyl-CoA:(elongator tRNAMet)-cytidine34 N4-acetyltransferase (ATP-hydrolysing). This enzyme catalyses the following chemical reaction

TRNAIle-lysidine synthase (EC 6.3.4.19, TilS, mesJ (gene), yacA (gene), isoleucine-specific transfer ribonucleate lysidine synthetase, tRNAIle-lysidine synthetase) is an enzyme with systematic name L-lysine:(tRNAIle2)-cytidine34 ligase (AMP-forming). This enzyme catalyses the following chemical reaction

References

  1. Mandal, Debabrata; Köhrer, Caroline; Su, Dan; Russell, Susan P.; Krivos, Kady; Castleberry, Colette M.; Blum, Paul; Limbach, Patrick A.; Söll, Dieter; RajBhandary, Uttam L. (2010). "Agmatidine, a modified cytidine in the anticodon of archaeal tRNAIle, base pairs with adenosine but not with guanosine". Proceedings of the National Academy of Sciences. 107 (7): 2872–2877. Bibcode:2010PNAS..107.2872M. doi: 10.1073/pnas.0914869107 . PMC   2840323 . PMID   20133752.
  2. Ikeuchi, Yoshiho; Kimura, Satoshi; Numata, Tomoyuki; Nakamura, Daigo; Yokogawa, Takashi; Ogata, Toshihiko; Wada, Takeshi; Suzuki, Takeo; Suzuki, Tsutomu (2010). "Agmatine-conjugated cytidine in a tRNA anticodon is essential for AUA decoding in archaea". Nature Chemical Biology. 6 (4): 277–282. doi:10.1038/nchembio.323. PMID   20139989.
  3. Hendrickson, Tamara L (2010). "The genetic code: An archaeal path to literacy". Nature Chemical Biology. 6 (4): 248–249. doi:10.1038/nchembio.335. PMID   20300092.
  4. Terasaka, Naohiro; Kimura, Satoshi; Osawa, Takuo; Numata, Tomoyuki; Suzuki, Tsutomu (2011). "Biogenesis of 2-agmatinylcytidine catalyzed by the dual protein and RNA kinase TiaS". Nature Structural & Molecular Biology. 18 (11): 1268–1274. doi:10.1038/nsmb.2121. PMID   22002222. S2CID   10913903.
  5. Osawa, Takuo; Inanaga, Hideko; Kimura, Satoshi; Terasaka, Naohiro; Suzuki, Tsutomu; Numata, Tomoyuki (2011). "Crystallization and preliminary X-ray diffraction analysis of an archaeal tRNA-modification enzyme, TiaS, complexed with tRNAIle2 and ATP". Acta Crystallographica Section F. 67 (11): 1414–1416. doi:10.1107/S1744309111034890. PMC   3212464 . PMID   22102245.
  6. Osawa, Takuo; Kimura, Satoshi; Terasaka, Naohiro; Inanaga, Hideko; Suzuki, Tsutomu; Numata, Tomoyuki (2011). "Structural basis of tRNA agmatinylation essential for AUA codon decoding". Nature Structural & Molecular Biology. 18 (11): 1275–1280. doi:10.1038/nsmb.2144. PMID   22002223. S2CID   27881269.
  1. ↑ Suzuki, Tsutomu; Numata, Tomoyuki (February 2015). "Convergent evolution of AUA decoding in bacteria and archaea". RNA Biology. 11 (12): 1586–1596. doi: 10.4161/15476286.2014.992281 . PMC   4615378 . PMID   25629511.
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