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Aminoacyl tRNA synthetase

Aminoacyl tRNA synthetase

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An aminoacyl tRNA synthetase (aaRS) is an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 that catalyzes the esterification of a specific amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 or its precursor to one of all its compatible cognate tRNAs to form an aminoacyl-tRNA
Aminoacyl-tRNA
Aminoacyl-tRNA is tRNA to which its cognated amino acid is adhered. Its role is to deliver the amino acid to the ribosome where it will be incorporated into the polypeptide chain that is being produced...

. This is sometimes called "charging" the tRNA with the amino acid. Once the tRNA is charged, a ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....

 can transfer the amino acid from the tRNA onto a growing peptide, according to the genetic code
Genetic code
The genetic code is the set of rules by which information encoded in genetic material is translated into proteins by living cells....

.

Mechanism


The synthetase first binds ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

 and the corresponding amino acid or its precursor to form an aminoacyl-adenylate and release inorganic pyrophosphate
Pyrophosphate
In chemistry, the anion, the salts, and the esters of pyrophosphoric acid are called pyrophosphates. Any salt or ester containing two phosphate groups is called a diphosphate. As a food additive, diphosphates are known as E450.- Chemistry :...

 (PPi). The adenylate-aaRS complex then binds the appropriate tRNA molecule, and the amino acid is transferred from the aa-AMP to either the 2'- or the 3'-OH of the last tRNA base (A76) at the 3'-end. Some synthetases also mediate a proofreading reaction to ensure high fidelity of tRNA charging; if the tRNA is found to be improperly charged, the aminoacyl-tRNA bond is hydrolyzed.

Reaction


Reaction:
  1. amino acid + ATP → aminoacyl-AMP + PPi
  2. aminoacyl-AMP + tRNA → aminoacyl-tRNA + AMP


Sum of 1 and 2: amino acid + tRNA + ATP → aminoacyl-tRNA + AMP + PPi

Classes


There are two classes of aminoacyl tRNA synthetase:
  • Class I
    Aminoacyl tRNA synthetases, class I
    The aminoacyl-tRNA synthetases catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction. These proteins differ widely in size and oligomeric state, and have limited sequence homology. The 20 aminoacyl-tRNA synthetases are divided into two...

     has two highly conserved sequence motifs. It aminoacylates
    Aminoacylation
    Aminoacylation is the process of adding an aminoacyl group to a compound.-See also:*Acylation*tRNA aminoacylation*Transfer RNA-like structures...

     at the 2'-OH of an adenosine nucleotide
    Nucleotide
    Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...

    , and is usually monomeric or dimeric
    Protein dimer
    In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...

     (one or two subunits, respectively).
  • Class II
    Aminoacyl tRNA synthetases, class II
    Aminoacyl-tRNA synthetase, class II catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction. These proteins differ widely in size and oligomeric state, and have limited sequence homology.The 20 aminoacyl-tRNA synthetases are divided...

     has three highly conserved sequence motifs. It aminoacylates
    Aminoacylation
    Aminoacylation is the process of adding an aminoacyl group to a compound.-See also:*Acylation*tRNA aminoacylation*Transfer RNA-like structures...

     at the 3'-OH of the same adenosine, and is usually dimeric or tetrameric (two or four subunits, respectively). Although phenylalanine-tRNA synthetase is class II, it aminoacylates at the 2'-OH.


The amino acids are attached to the hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...

 (-OH) group of the adenosine via the carboxyl (-COOH) group.

Regardless of where the aminoacyl is initially attached to the nucleotide, the 2'-O-aminoacyl-tRNA will ultimately migrate to the 3' position via transesterification
Transesterification
In organic chemistry, transesterification is the process of exchanging the organic group R″ of an ester with the organic group R′ of an alcohol. These reactions are often catalyzed by the addition of an acid or base catalyst...

.

Structures


Both classes of aminoacyl-tRNA synthetases are multidomain proteins. In a typical scenario, an aaRS consists of a catalytic domain (where both the above reactions take place) and an anticodon binding domain (which interacts mostly with the anticodon region of the tRNA and ensures binding of the correct tRNA to the amino acid). In addition, some aaRSs have additional RNA binding domains and editing domains that cleave incorrectly paired aminoacyl-tRNA molecules.

The catalytic domains of all the aaRSs of a given class are found to be homologous to one another, whereas class I and class II aaRSs are unrelated to one another. The class I aaRSs have the ubiquitous Rossmann fold
Rossmann fold
The Rossmann fold is a protein structural motif found in proteins that bind nucleotides, especially the cofactor NAD. The structure with two repeats is composed of six parallel beta strands linked to two pairs of alpha helices in the topological order beta-alpha-beta-alpha-beta...

 and have the antiparallel beta-strands architecture, whereas the class II aaRSs have a unique fold made up of antiparallel beta-strands.

The alpha helical
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...

 anticodon binding domain of Arginyl, Glycyl and Cysteinyl-tRNA synthetases is known as the DALR domain after characteristic conserved
Conserved sequence
In biology, conserved sequences are similar or identical sequences that occur within nucleic acid sequences , protein sequences, protein structures or polymeric carbohydrates across species or within different molecules produced by the same organism...

 amino acids.

Evolution


Most of the aaRSs of a given specificity are evolutionarily closer to one another than to aaRSs of another specificity. However, AsnRS and GlnRS group within AspRS and GluRS, respectively. Most of the aaRSs of a given specificity also belong to a single class. However, there are two distinct versions of the LysRS - one belonging to the class I family and the other belonging to the class II family.

In addition, the molecular phylogenies of aaRSs are often not consistent with accepted organismal phylogenies, e.g. they violate the so-called canonical phylogenetic pattern shown by most other enzymes for the three domains of life - Archaea
Archaea
The Archaea are a group of single-celled microorganisms. A single individual or species from this domain is called an archaeon...

, Bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...

, and Eukarya. Furthermore, the phylogenies inferred for aaRSs of different amino acids often do not agree with one another. These are two clear indications that horizontal transfer has occurred several times during the evolutionary history of aaRSs (Carl R. Woese, Gary J. Olsen, Michael Ibba, and Dieter Söll. Microbiology and Molecular Biology Reviews, March 2000, p. 202-236, Vol. 64, No. 1: Aminoacyl-tRNA Synthetases, the Genetic Code, and the Evolutionary Process).

Expanding the genetic code via mutant aminoacyl tRNA synthetases


In some of the aminoacyl tRNA synthetases, the cavity that holds the amino acid can be mutated and modified to carry artificial, unnatural amino acids synthesized in the lab, and to attach them to specific tRNAs. This expands the genetic code, beyond the twenty amino acids universal in nature, to include an unnatural amino acid as well. The unnatural amino acid is coded by an otherwise non-coding base triplet such as the amber stop codon
Stop codon
In the genetic code, a stop codon is a nucleotide triplet within messenger RNA that signals a termination of translation. Proteins are based on polypeptides, which are unique sequences of amino acids. Most codons in messenger RNA correspond to the addition of an amino acid to a growing polypeptide...

. The organism that expresses the mutant synthetase can then be genetically programmed to incorporate the unnatural amino acid into any desired position in any protein of interest, allowing chemists to probe, or change, the protein's function. For instance, one can start with the gene for a protein that binds a certain sequence of DNA, and, by directing an unnatural amino acid with a reactive side-chain into the binding site, create a new protein that cuts the DNA at the target-sequence, rather than binding it.

By mutating aminoacyl tRNA synthetases, chemists have expanded the genetic codes of various organisms to include lab-synthesized amino acids with all kinds of useful properties: photoreactive, metal-chelating, xenon-chelating, crosslinking, color-changing, spin-resonant, fluorescent, biotinylated, and redox-active amino acids.

Prediction Server


External links