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. Till 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.

All of 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 all members of nanoarchaea and korarchaea use agmatidine modification to selectively read AUA codons. 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.

Related Research Articles

Methionine Sulfur-containing amino acid

Methionine is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical role in the metabolism and health of many species, including humans. It is encoded by the codon AUG.

Pyrrolysine 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, a carboxylic acid group. Its pyrroline side-chain is similar to that of lysine in being basic and positively charged at neutral pH.

Translation (biology) Cellular process of protein synthesis

In molecular biology and genetics, translation is the process in which ribosomes in the cytoplasm or endoplasmic reticulum synthesize proteins after the process of transcription of DNA to RNA in the cell's nucleus. The entire process is called gene expression.

Transfer RNA 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, that serves as the physical link between the mRNA and the amino acid sequence of proteins. Transfer RNA (tRNA) does this by carrying an amino acid to the protein synthesizing machinery of a cell called the ribosome. Complementation of a 3-nucleotide codon in a messenger RNA (mRNA) by a 3-nucleotide anticodon of the tRNA results in protein synthesis based on the mRNA code. As such, tRNAs are a necessary component of translation, the biological synthesis of new proteins in accordance with the genetic code.

Wobble base pair 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.

The Shine–Dalgarno (SD) sequence is a ribosomal binding site in bacterial and archaeal messenger RNA, generally located around 8 bases upstream of the start codon AUG. The RNA sequence helps recruit the ribosome to the messenger RNA (mRNA) to initiate protein synthesis by aligning the ribosome with the start codon. Once recruited, tRNA may add amino acids in sequence as dictated by the codons, moving downstream from the translational start site.

RNA editing 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.

Start codon First codon of a messenger RNA transcript 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. The most common start codon is AUG.

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.

Queuine 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.

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.

Expanded genetic code 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.

Queuosine 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.

Lysidine (nucleoside) 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 third position in the anti-codon of the Isoleucine-specific tRNA, is typically changed from a cytidine which would pair with guanosine to a lysidine which will base pair with adenosine. Uridine could not be used at this position even though it is a conventional partner for adenosine since it will also "wobble base pair" with guanosine. So lysidine allows better translation fidelity. Lysidine is denoted as L or k2C.

Wybutosine 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.

tRNA (cytidine56-2'-O)-methyltransferase is an enzyme with systematic name S-adenosyl-L-methionine:tRNA (cytidine56-2'-O)-methyltransferase. This enzyme catalyses the following chemical reaction

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

Degeneracy or redundancy of codons is the redundancy of the genetic code, exhibited as the multiplicity of three-base pair codon combinations that specify an amino acid. The degeneracy of the genetic code is what accounts for the existence of synonymous mutations.

Éric Westhof is a French biochemist born in Uccle (Belgium) on July 25, 1948. He is a member of the Academie des sciences, head of Education and Training (DEF) and a member of the Board of Directors of the "La Main à la pâte" Foundation. He is professor emeritus of structural biochemistry at the University of Strasbourg at the Institute of Molecular and Cellular Biology.

References

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