GENETIC CODING FOR PROTEIN STRUCTURE.
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Genetic Code↗
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The origin of the genetic code: amino acids as cofactors in an RNA world.
The genetic code, understood as the specific assignment of amino acids to nucleotide triplets, might have preceded the existence of translation. Amino acids became utilized as cofactors by ribozymes in a metabolically complex RNA world. Specific charging ribozymes linked amino acids to corresponding RNA handles, which could basepair with different ribozymes, via an anticodon hairpin, and so deliver the cofactor to the ribozyme. Growing of the 'handle' into a presumptive tRNA was possible while function was retained and modified throughout. A stereochemical relation between some amino acids and cognate anticodons/codons is likely to have been important in the earliest assignments. Recent experimental findings, including selection for ribozymes catalyzing peptide-bond formation and those utilizing an amino acid cofactor, hold promise that scenarios of this major transition can be tested.
Amino Acids↗
Genetic code deviations in the ciliates: evidence for multiple and independent events.
In several species of ciliates, the universal stop codons UAA and UAG are translated into glutamine, while in the euplotids, the glutamine codon usage is normal, but UGA appears to be translated as cysteine. Because the emerging position of this monophyletic group in the eukaryotic lineage is relatively late, this deviant genetic code represents a derived state of the universal code. The question is therefore raised as to how these changes arose within the evolutionary pathways of the phylum. Here, we have investigated the presence of stop codons in alpha tubulin and/or phosphoglycerate kinase gene coding sequences from diverse species of ciliates scattered over the phylogenetic tree constructed from 28S rRNA sequences. In our data set, when deviations occur they correspond to in frame UAA and UAG coding for glutamine. By combining these new data with those previously reported, we show that (i) utilization of UAA and UAG codons occurs to different extents between, but also within, the different classes of ciliates and (ii) the resulting phylogenetic pattern of deviations from the universal code cannot be accounted for by a scenario involving a single transition to the unusual code. Thus, contrary to expectations, deviations from the universal genetic code have arisen independently several times within the phylum.
Animals↗
Compliance of genetic code with base-composition deflecting pressure.
Gene DNAs of different organisms show a wide variation in their G+C content as much as 20% to 80%. This variation has been regarded as the result of the compliance of the genetic code with the base-composition-deflecting mutational pressure. To make possible a quantitative discussion of this genetic code's elasticity, we made a statistical study of the G+C frequency at the 1st, 2nd, and 3rd positions of codons: 4.5 x 10(6) codons in 11,981 protein coding regions in the DNA data base were analyzed. The data were examined quantitatively by using a species-independent universal equation which describes the base frequencies at the three codon sites in terms of the constraint parameters characteristic of the sites and an intersite interaction. By a best fitting procedure between theoretical curves and data points, the constraint parameters and the characteristic G+C contents to which the 1st and the 2nd site base compositions are bound were determined. The base substituting mutation of the coding sequence under the base-composition-deflecting pressure is divided into following three stages of the different compliance from the elastic one to the rigid: 1) the 3rd position of codons change by synonymous substitution; 2) the 1st and then 2nd positions change accompanying amino acid replacement; and 3) in the organisms exposed under an extremely high base composition deflecting pressure, the codon table is forced to be altered. The compliance parameters were derived quantitatively for the first two stages. In conclusion, a simultaneous analysis of data from organisms as divers as virus and man discovered that there is a set of constraints common to species, which governs the frequency of codon bases, and it can be described by a universal equation.
Animals↗
A comparison of proteins from Pyrococcus furiosus and Pyrococcus abyssi: barophily in the physicochemical properties of amino acids and in the genetic code.
A comparison is made between orthologous proteins from a nonbarophile (Pyrococcus furiosus) and a barophile (Pyrococcus abyssi) organism. The pattern of asymmetries in the amino acid substitution process identifies the amino acids arginine, serine, glycine, valine and aspartic acid as those having the most barophilic behaviour, and tyrosine and glutamine as the least barophilic. The construction of a hydrostatic pressure asymmetry index (PAI) which orders the amino acids from the most barophilic to the least barophilic makes it possible to visualise the amino acid properties that best explain barophily. The polarity of amino acids is positively correlated to the PAI values, i.e., on average, the more polar amino acids possess a higher PAI value, that is to say they are more barophilic. Moreover, the "size" of amino acids (molecular weight) is negatively correlated to the PAI value, that is to say that, on average, high PAI values are associated to "small" amino acids which are therefore more barophilic than "larger" ones. These two amino acid properties are the same ones that are known for having been important in affecting the origin of genetic code organisation. All the above, as well as the significant and positive correlation between the number of codons attributed to the amino acids in the genetic code and the PAI values, seem to favour the hypothesis that genetic code structuring took place under high hydrostatic pressure.
Amino Acids↗
A periodic pattern of mRNA secondary structure created by the genetic code.
Single-stranded mRNA molecules form secondary structures through complementary self-interactions. Several hypotheses have been proposed on the relationship between the nucleotide sequence, encoded amino acid sequence and mRNA secondary structure. We performed the first transcriptome-wide in silico analysis of the human and mouse mRNA foldings and found a pronounced periodic pattern of nucleotide involvement in mRNA secondary structure. We show that this pattern is created by the structure of the genetic code, and the dinucleotide relative abundances are important for the maintenance of mRNA secondary structure. Although synonymous codon usage contributes to this pattern, it is intrinsic to the structure of the genetic code and manifests itself even in the absence of synonymous codon usage bias at the 4-fold degenerate sites. While all codon sites are important for the maintenance of mRNA secondary structure, degeneracy of the code allows regulation of stability and periodicity of mRNA secondary structure. We demonstrate that the third degenerate codon sites contribute most strongly to mRNA stability. These results convincingly support the hypothesis that redundancies in the genetic code allow transcripts to satisfy requirements for both protein structure and RNA structure. Our data show that selection may be operating on synonymous codons to maintain a more stable and ordered mRNA secondary structure, which is likely to be important for transcript stability and translation. We also demonstrate that functional domains of the mRNA [5'-untranslated region (5'-UTR), CDS and 3'-UTR] preferentially fold onto themselves, while the start codon and stop codon regions are characterized by relaxed secondary structures, which may facilitate initiation and termination of translation.
3' Untranslated Regions↗
Codon reassignment and the evolving genetic code: problems and pitfalls in post-genome analysis.
The in silico translation of open reading frames, using the 'universal genetic code', must be approached with caution. The uncovering of a number of codon reassignments in nuclear and organellar genomes highlights the importance of experimentally confirming the assignments of all 64 codons for the species whose genome is under investigation. Such alterations to codon meaning also suggest that the genetic code is not 'frozen' and continues to evolve.
Codon↗
Speculations on the evolution of the genetic code IV. The evolution of the aminoacyl-tRNA synthetases.
An evolutionary scheme is postulated in which a primitive code, involving only guanine and cytosine, would code for glycine(GG.), alanine(GC.), arginine(CG.) and proline(CC.). There evolves from this primitive code families of related amino acids as the code expands. The evolution of the aminoacyl-tRNA synthetases are considered to be indicators for the evolution of the genetic code. The postulated model for the evolution of the genetic code is used to give an evolutionary interpretation to the recent work on the structure and sequences of the aminoacyl-tRNA synthetases.
Amino Acid Sequence↗
Genetic code ambiguity. Cell viability related to the severity of editing defects in mutant tRNA synthetases.
The rules of the genetic code are established in reactions that aminoacylate tRNAs with specific amino acids. Ambiguity in the code is prevented by editing activities whereby incorrect aminoacylations are cleared by specialized hydrolytic reactions of aminoacyl tRNA synthetases. Whereas editing reactions have long been known, their significance for cell viability is still poorly understood. Here we investigated in vitro and in vivo four different mutations in the center for editing that diminish the proofreading activity of valyl-tRNA synthetase (ValRS). The four mutant enzymes were shown to differ quantitatively in the severity of the defect in their ability to clear mischarged tRNA in vitro. Strikingly, in the presence of excess concentrations of alpha-aminobutyrate, one of the amino acids that is misactivated by ValRS, growth of bacterial strains bearing these mutant alleles is arrested. The concentration of misactivated amino acid required for growth arrest correlates inversely in a rank order with the degree of the editing defect seen in vitro. Thus, cell viability depends directly on the suppression of genetic code ambiguity by these specific editing reactions and is finely tuned to any perturbation of these reactions.
Amino Acid Sequence↗
The genetic code as a periodic table: algebraic aspects.
The systematics of indices of physico-chemical properties of codons and amino acids across the genetic code are examined. Using a simple numerical labelling scheme for nucleic acid bases, A=(-1,0), C=(0,-1), G=(0,1), U=(1,0), data can be fitted as low order polynomials of the six coordinates in the 64-dimensional codon weight space. The work confirms and extends the recent studies by Siemion et al. (1995. BioSystems 36, 231-238) of the conformational parameters. Fundamental patterns in the data such as codon periodicities, and related harmonics and reflection symmetries, are here associated with the structure of the set of basis monomials chosen for fitting. Results are plotted using the Siemion one-step mutation ring scheme, and variants thereof. The connections between the present work, and recent studies of the genetic code structure using dynamical symmetry algebras, are pointed out.
Amino Acids↗
Amino acid biogenesis, evolution of the genetic code and aminoacyl-tRNA synthetases.
The aminoacyl-tRNA synthetases (aaRSs) ensure the fidelity of the translation of the genetic code, covalently attaching appropriate amino acids to the corresponding nucleic acid adaptor molecules-tRNA. The fundamental role of aminoacylation reaction catalysed by aaRSs implies that representatives of the family are thought to be among the earliest proteins to appear. Based on sequence analysis and catalytic domain structure, aaRSs have been partitioned into two classes of 10 enzymes each. However, based on the structural and sequence data only, it will not be easily understood that the present partitioning is not governed by chance. Our findings suggest that organization of amino acid biosynthetic pathways and clustering of aaRSs into different classes are intimately related to one another. A plausible explanation for such a relationship is dictated by early link between aaRSs and amino acids biosynthetic proteins. The aaRSs catalytic cores are highly relevant to the ancient metabolic reactions, namely, amino acids and cofactors biosynthesis. In particular we show that class II aaRSs mostly associated with the primordial amino acids, while class I aaRSs are usually related to amino acids evolved lately. Reasoning from this we propose a possible chronology of genetic code evolution.
Amino Acids↗
Evolution of a genetic code simulated with the computer.
A simple selforganizing model system of molecules is considered and it is demonstrated by a computer simulation, that a genetic code of 16 elements (aminoacids) can gradually be formed by such a system in the course of many generations. By a number of rare chance events, each suppressing other events of equal a priori probability, a single code results out of an immense number of possible codes of the same a priori probability. The result is discussed in relation to the uniqueness of the genetic code in living systems. The computer simulation emphasizes a particular step in a model pathway discussed elsewhere consisting of many assumed physicochemical steps leading to a genetic apparatus.
Base Sequence↗
On the optimization of the physicochemical distances between amino acids in the evolution of the genetic code.
Using the simulated annealing technique we re-examine the role played by the minimization of the physicochemical distances between amino acids during the origin of the organization of the genetic code. The results are discussed in the context of the various hypotheses proposed to explain how amino acids were allocated in the genetic code.
Amino Acid Sequence↗
An expanding genetic code.
More than 30 novel amino acids have been genetically encoded in response to unique triplet and quadruplet codons including fluorescent, photoreactive and redox active amino acids, glycosylated and heavy atom derived amino acids in addition to those with keto, azido and acetylenic chains. In this article, we describe recent advances that make it possible to add new building blocks systematically to the genetic codes of bacteria, yeast and mammalian cells. Taken together these tools will enable the detailed investigation of protein structure and function, which is not possible with conventional mutagenesis. Moreover, by lifting the constraints of the existing 20-amino-acid code, it should be possible to generate proteins and perhaps entire organisms with new or enhanced properties.
Amino Acids↗
Neural network model of the genetic code is strongly correlated to the GES scale of amino acid transfer free energies.
A neural network trained to classify the 61 nucleotide triplets of the genetic code into 20 amino acid categories develops in its internal representation a pattern matching the relative cost of transferring amino acids with satisfied backbone hydrogen bonds from water to an environment of dielectric constant of roughly 2.0. Such environments are typically found in lipid membranes or in the interior of proteins. In learning the mapping between the codons and the categories, the network groups the amino acids according to the scale of transfer free energies developed by Engelman, Goldman and Steitz. Several other scales based on internal preference statistics also agree reasonably well with the network grouping. The network is able to relate the structure of the genetic code to quantifications of amino acid hydrophobicity-hydrophilicity more systematically than the numerous attempts made earlier. Due to its inherent non-linearity, the code is also shown to impose decisive constraints on algorithmic analysis of the protein coding potential of DNA.
Amino Acid Sequence↗
The origin of the genetic code.
A new approach to the origin of the genetic code is proposed based on some regularities in the nucleotide distribution pattern of the code. The relative amounts of various amino acids in primitive proteins were possibly different from those in organisms living today. The primordial ratio was supposed to shift to the modern one guided by the action of primitive nucleotides. Each primitive tRNA had a discriminator site and, distinguished from it, an anticodon site. It also postulated that primordially each amino acid could correspond to a wide variety of codons. During the course of the evolutionary change, a selective mechanism worked among the protobionts so that less frequent nucleotides became associated with more abundant amino acids in the primordial conditions,thus finally leading to the present codon catalogue.
Amino Acids↗
Genetic code: aspects of organization.
The pattern of organization of the genetic code decreases to a minimum the phenotypic effects of mutation and of base-pairing errors in protein synthesis. Single base changes, especially transitions, usually cause either no amino acid change or the change to a chemically similar amino acid. The degree of degeneracy of the codons for an amino acid is correlated with their guanine-cytosine content. The code gives greater protection (by both degeneracy and guaninecytosine content of codons) to those amino acids that appear more frequently in proteins. Increased reliability of the protein-synthesis system afforded by this pattern of organization nay have determined the fitness of the present code.
Amino Acid Sequence↗
[Hidden symmetry of the genetic code and laws of amino acid interaction].
Natural amino acids having common antiamino acids are divided into families and groups according to the algorithm of the genetic code (a-n-n-a, amino acid-codon-anticodon-antiamino acid). Members of these groups are placed symmetrically in the structure of the genetic code. In the course of evolution, those point mutations are predominantly accepted retained. In homologous proteins of phylogenetically related organisms which lend to amino acids belonging to one family or group and having common antiamino acids. This assumption is in agreement with L. B. Mekler's theory (1969) of the amino acid interaction code a-a.
Amino Acid Sequence↗