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PubMed2004

On the optimality of the genetic code, with the consideration of termination codons.

The existence of nonrandom patterns in codon assignments is supported by many statistical and biochemical studies. The canonical genetic code is known to be highly efficient in minimizing the effects of mistranslation errors and point mutations. For example, it is known that when an error induces the conversion of an amino acid to another, the biochemical properties of the resulting amino acid are usually very similar to that of the original. Prior studies include many attempts at quantitative estimation of the fraction of randomly generated codes which, based upon load minimization, score higher than the canonical genetic code. In this study, we took into consideration both the relative frequencies of amino acids and nonsense mistranslations, factors which had been previously ignored. Incorporation of these parameters, resulted in a fitness function (phi) which rendered the canonical genetic code to be highly optimized with respect to load minimization. Considering termination codons, we applied a biosynthetic version of the coevolution theory, however, with low significance. We employed a revised cost for the precursor-product pairs of amino acids and showed that the significance of this approach depends on the cost measure matrix used by the researcher. Thus, we have compared the two prominent matrices, point accepted mutations 74-100 (PAM(74-100)) and mutation matrix in our study.

Amino Acids↗
PubMed1978

On the physical basis for ambiguity in genetic coding interactions.

We report the relative stabilities, in the form of complex lifetimes, of complexes between the tRNAs complementary, or nearly so, in their anticodons. The results show striking parallels with the genetic coding rules, including the wobble interaction and the role of modified nucleotides S2U and V (a 5-oxyacetic acid derivative of U). One important difference between the genetic code and the pairing rules in the tRNA-tRNA interaction is the stability in the latter of the short wobble pairs, which the wobble hypothesis excludes. We stress the potential of U for translational errors, and suggest a simple stereochemical basis for ribosome-mediated discrimination against short wobble pairs. Surprisingly, the stability of anticodon-anticodon complexes does not vary systematically on base sequence. Because of the close similarity to the genetic coding rules, it is tempting to speculate that the interaction between two RNA loops may have been part of the physical basis for the evolutionary origin of the genetic code, and that this mechanism may still be utilized by folding the mRNA on the ribosome into a loop similar to the anticodon loop.

Base Sequence↗
PubMed1998

Reassigning cysteine in the genetic code of Escherichia coli.

We investigated directed deviations from the universal genetic code. Mutant tRNAs that incorporate cysteine at positions corresponding to the isoleucine AUU, AUC, and AUA and methionine AUG codons were introduced in Escherichia coli K12. Missense mutations at the cysteine catalytic site of thymidylate synthase were systematically crossed with synthetic suppressor tRNACys genes coexpressed from compatible plasmids. Strains harboring complementary codon/anticodon associations could be stably propagated as thymidine prototrophs. A plasmid-encoded tRNACys reading the codon AUA persisted for more than 500 generations in a strain requiring its suppressor activity for thymidylate biosynthesis, but was eliminated from a strain not requiring it. Cysteine miscoding at the codon AUA was also enforced in the active site of amidase, an enzyme found in Helicobacter pylori and not present in wild-type E. coli. Propagating the amidase missense mutation in E. coli with an aliphatic amide as nitrogen source required the overproduction of Cys-tRNA synthetase together with the complementary suppressor tRNACys. The toxicity of cysteine miscoding was low in all our strains. The small size and amphiphilic character of this amino acid may render it acceptable as a replacement at most protein positions and thus apt to overcome the steric and polar constraints that limit evolution of the genetic code.

Amidohydrolases↗
PubMed2006

GenDecoder: genetic code prediction for metazoan mitochondria.

Although the majority of the organisms use the same genetic code to translate DNA, several variants have been described in a wide range of organisms, both in nuclear and organellar systems, many of them corresponding to metazoan mitochondria. These variants are usually found by comparative sequence analyses, either conducted manually or with the computer. Basically, when a particular codon in a query-species is linked to positions for which a specific amino acid is consistently found in other species, then that particular codon is expected to translate as that specific amino acid. Importantly, and despite the simplicity of this approach, there are no available tools to help predicting the genetic code of an organism. We present here GenDecoder, a web server for the characterization and prediction of mitochondrial genetic codes in animals. The analysis of automatic predictions for 681 metazoans aimed us to study some properties of the comparative method, in particular, the relationship among sequence conservation, taxonomic sampling and reliability of assignments. Overall, the method is highly precise (99%), although highly divergent organisms such as platyhelminths are more problematic. The GenDecoder web server is freely available from http://darwin.uvigo.es/software/gendecoder.html.

Amino Acid Sequence↗
PubMed1999

Evolution of the genetic code: the nonsense, antisense, and antinonsense codes make no sense.

According to the molecular recognition theory, the complementarity of the sense and nonsense DNA strands is reflected in a complementarity of polypeptides and the corresponding nonsense polypeptides. A comparison of the sense and nonsense code matrices, and of the antisense and antinonsense code matrices, either by visual inspection or by comparing the corresponding hydrophobicity matrices (e.g. by simply adding them together), revealed no complementarity of these pairs of matrices in terms of possible attractive physical forces. Instead, it was evident that the codes divide the amino acids into two major groups: hydrophilic and hydrophobic, a division which is directly correlated with the folding property of proteins. A simple primordial genetic code distinguishing between these two types of amino acids would have been capable of generating three-dimensionally folded peptides, which could stabilize coding RNAs by forming ribonucleoprotein complexes. This evolutionary scheme is reflected in the present organisation of information processing and storage in essentially all organisms. RNAs are processed and translated into proteins by ribonucleoproteins, while other steps in information retrieval and processing, such as DNA replication, transcription, protein folding and posttranslational processing, are catalyzed by proteins. This shows that the evolution of DNA as an information storage medium was a secondary event, unrelated to the evolution of the genetic code. From the primordial hydrophilic/hydrophobic (f.ex. Leu/Arg) code, evolution proceeded by introduction of a catalytic amino acid (Ser). The further evolution of the code has mainly served to increase the number of functional hydrophilic amino acids, since there has not been a great advantage in increasing the number of structural, hydrophobic amino acids. At some stage during the evolution of the genetic code, double-stranded DNA was introduced as a maximally safe genetic copy of RNA. This required the action of highly specific enzymes, and was therefore preceded by the refinement of the genetic code. As a conclusion of this evolutionary scheme, it can be inferred that, in general only the sense strand encodes proteins.

Codon, Nonsense↗
PubMed1987

Beta-turn-driven early evolution: the genetic code and biosynthetic pathways.

The physicochemical properties of beta-turns suggest their biological importance prior to the formation of the genetic code. These properties include ones potentially affecting the preference for either L- or D-amino acids. The abundance of certain amino acids in beta-turns is correlated with their assignment to a small, well-defined part of the genetic code and with their role as metabolic precursors for other amino acids. It is proposed that in the prebiotic environment, beta-turns became objects of selection that influenced the evolution of the genetic code and biosynthetic pathways for amino acids.

Biological Evolution↗
PubMed1998

Rhyme or reason: RNA-arginine interactions and the genetic code.

Theories about the origin of the genetic code require specific recognition between nucleic acids and amino acids at some stage of the code's evolution. A statistical analysis of arginine-binding RNA aptamers now offers the opportunity to test such interactions and provides the strongest support for an intrinsic affinity between any amino acid and its codons.

Animals↗
PubMed1995

Evolution of the aminoacyl-tRNA synthetases and the origin of the genetic code.

The aminoacyl-tRNA synthetases exist as two enzyme families which were apparently generated by divergent evolution from two primordial synthetases. The two classes of enzymes exhibit intriguing familial relationships, in that they are distributed nonrandomly within the codon-amino acid matrix of the genetic code. For example, all XCX codons code for amino acids handled by class II synthetases, and all but one of the XUX codons code for amino acids handled by class I synthetases. One interpretation of these patterns is that the synthetases coevolved with the genetic code. The more likely explanation, however, is that the synthetases evolved in the context of an already-established genetic code--a code which developed earlier in an RNA world. The rules which governed the development of the genetic code, and led to certain patterns in the coding catalog between codons and amino acids, would also have governed the subsequent evolution of the synthetases in the context of a fixed code, leading to patterns in synthetase distribution such as those observed. These rules are (1) conservative evolution of amino acid and adapter binding sites and (2) minimization of the disruptive effects on protein structure caused by codon meaning changes.

Amino Acids↗
PubMed2006

Potential automata. Application to the genetic code III.

In previous notes, we have described both mathematical properties of potential (n-switches) and potential-Hamiltonian (Liénard systems) continuous differential systems, and also biological applications, especially those concerning primitive cyclic RNAs related to the genetic code. In the present note, we give a general definition of a potential automaton, and we show that a discrete Hopfield-like system already introduced by Goles et al. is a good candidate for such a potential automaton: it has a Lyapunov functional that decreases on its trajectories and whose time derivative is just its discrete velocity. Then we apply this new notion of potential automaton to the genetic code. We show in particular that the consideration of only physicochemical properties of amino-acids, like their molecular weight, hydrophobicity and ability to create hydrogen bonds suffices to build a potential decreasing on trajectories corresponding to the synonymy classes of the genetic code. Such an 'a minima' construction reinforces the classical stereochemical hypothesis about the origin of the genetic code and authorizes new views about the optimality of its synonymy classes.

Amino Acids↗
PubMed1985

Genetic code redundancy and the evolutionary stability of protein secondary structure.

The genetic code has an inherent bias towards some amino acids because of the variable number of synonymous codons per amino acid. The extent to which these biases are expressed in protein secondary structure is described through the analysis of the overall amino acid compositions of the alpha-helix, beta-sheet, beta-turn and random coil segments elucidated by X-ray crystallography. Given the concept of neutral mutation in proteins, the allocation of synonyms in the genetic code appears to protect secondary structures from amino acid changes and discourages the appearance of chemically complex residues. The level of protection is similar for each structural form, despite their clear preferences for certain amino acids. The organization of the code is therefore relevant to the preservation of conformation seen in the evolution of many protein families.

Amino Acids↗
PubMed2007

Natural expansion of the genetic code.

At the time of its discovery four decades ago, the genetic code was viewed as the result of a "frozen accident." Our current knowledge of the translation process and of the detailed structure of its components highlights the roles of RNA structure (in mRNA and tRNA), RNA modification (in tRNA), and aminoacyl-tRNA synthetase diversity in the evolution of the genetic code. The diverse assortment of codon reassignments present in subcellular organelles and organisms of distinct lineages has 'thawed' the concept of a universal immutable code; it may not be accidental that out of more than 140 amino acids found in natural proteins, only two (selenocysteine and pyrrolysine) are known to have been added to the standard 20-member amino acid alphabet. The existence of phosphoseryl-tRNA (in the form of tRNACys and tRNASec) may presage the discovery of other cotranslationally inserted modified amino acids.

Amino Acyl-tRNA Synthetases↗
PubMed2000

Changes in mitochondrial genetic codes as phylogenetic characters: two examples from the flatworms.

Shared molecular genetic characteristics other than DNA and protein sequences can provide excellent sources of phylogenetic information, particularly if they are complex and rare and are consequently unlikely to have arisen by chance convergence. We have used two such characters, arising from changes in mitochondrial genetic code, to define a clade within the Platyhelminthes (flatworms), the Rhabditophora. We have sampled 10 distinct classes within the Rhabditophora and find that all have the codon AAA coding for the amino acid Asn rather than the usual Lys and AUA for Ile rather than the usual Met. We find no evidence to support claims that the codon UAA codes for Tyr in the Platyhelminthes rather than the standard stop codon. The Rhabditophora are a very diverse group comprising the majority of the free-living turbellarian taxa and the parasitic Neodermata. In contrast, three other classes of turbellarian flatworm, the Acoela, Nemertodermatida, and Catenulida, have the standard invertebrate assignments for these codons and so are convincingly excluded from the rhabditophoran clade. We have developed a rapid computerized method for analyzing genetic codes and demonstrate the wide phylogenetic distribution of the standard invertebrate code as well as confirming already known metazoan deviations from it (ascidian, vertebrate, echinoderm/hemichordate).

Amino Acid Sequence↗
PubMed2002

Accurate translation of the genetic code depends on tRNA modified nucleosides.

Transfer RNA molecules translate the genetic code by recognizing cognate mRNA codons during protein synthesis. The anticodon wobble at position 34 and the nucleotide immediately 3' to the anticodon triplet at position 37 display a large diversity of modified nucleosides in the tRNAs of all organisms. We show that tRNA species translating 2-fold degenerate codons require a modified U(34) to enable recognition of their cognate codons ending in A or G but restrict reading of noncognate or near-cognate codons ending in U and C that specify a different amino acid. In particular, the nucleoside modifications 2-thiouridine at position 34 (s(2)U(34)), 5-methylaminomethyluridine at position 34 (mnm(5)U(34)), and 6-threonylcarbamoyladenosine at position 37 (t(6)A(37)) were essential for Watson-Crick (AAA) and wobble (AAG) cognate codon recognition by tRNA(UUU)(Lys) at the ribosomal aminoacyl and peptidyl sites but did not enable the recognition of the asparagine codons (AAU and AAC). We conclude that modified nucleosides evolved to modulate an anticodon domain structure necessary for many tRNA species to accurately translate the genetic code.

Adenosine↗
PubMed2003

Crystal structures that suggest late development of genetic code components for differentiating aromatic side chains.

Early forms of the genetic code likely generated "statistical" proteins, with similar side chains occupying the same sequence positions at different ratios. In this scenario, groups of related side chains were treated by aminoacyl-tRNA synthetases as a single molecular species until a discrimination mechanism developed that could separate them. The aromatic amino acids tryptophan, tyrosine, and phenylalanine likely constituted one of these groups. A crystal structure of human tryptophanyl-tRNA synthetase was solved at 2.1 A with a tryptophanyl-adenylate bound at the active site. A cocrystal structure of an active fragment of human tyrosyl-tRNA synthetase with its cognate amino acid analog was also solved at 1.6 A. The two structures enabled active site identifications and provided the information for structure-based sequence alignments of approximately 45 orthologs of each enzyme. Two critical positions shared by all tyrosyl-tRNA synthetases and tryptophanyl-tRNA synthetases for amino acid discrimination were identified. The variations at these two positions and phylogenetic analyses based on the structural information suggest that, in contrast to many other amino acids, discrimination of tyrosine from tryptophan occurred late in the development of the genetic code.

Adenosine Monophosphate↗