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PubMed1994

Codon context and protein synthesis: enhancements of the genetic code.

The sequence around stop codons strongly affects termination efficiency and the probability of alternative events to termination such as frameshifting and stop codon readthrough. Where tRNA suppressors of nonsense codons are present, both the efficiency of suppression and of the termination process appear to be affected by stop codon context. Since context can affect suppressor tRNA function directly, an influence on sense codon translation or suppression might be expected, but has not yet been clearly demonstrated. Statistical analyses of coding sequences indicate non-random contexts for both stop and sense codons, and non-random occurrence of codon pairs. Highly expressed genes show clear preferences among stop codons and their contexts, whereas inefficient stop signals are exploited in a variety of recoding processes.

Codon↗

PubMed1983

Membership mutation of the genetic code: loss of fitness by tryptophan.

Bacillus subtilis strain QB928, a tryptophan-auxotroph, was serially mutated to yield strain HR15. For QB928, tryptophan functioned as a competent amino acid and 4-fluorotryptophan as merely an inferior analogue. For HR15, these roles were reversed. The tryptophan/4-fluorotryptophan growth ratio decreased by a factor of 2 X 10(4) in the transition from QB928 to HR15.

Bacillus subtilis↗

PubMed2001

Expanding the genetic code: selection of efficient suppressors of four-base codons and identification of "shifty" four-base codons with a library approach in Escherichia coli.

Naturally occurring tRNA mutants are known that suppress +1 frameshift mutations by means of an extended anticodon loop, and a few have been used in protein mutagenesis. In an effort to expand the number of possible ways to uniquely and efficiently encode unnatural amino acids, we have devised a general strategy to select tRNAs with the ability to suppress four-base codons from a library of tRNAs with randomized 8 or 9 nt anticodon loops. Our selectants included both known and novel suppressible four-base codons and resulted in a set of very efficient, non-cross-reactive tRNA/four-base codon pairs for AGGA, UAGA, CCCU and CUAG. The most efficient four-base codon suppressors had Watson-Crick complementary anticodons, and the sequences of the anticodon loops outside of the anticodons varied with the anticodon. Additionally, four-base codon reporter libraries were used to identify "shifty" sites at which +1 frameshifting is most favorable in the absence of suppressor tRNAs in Escherichia coli. We intend to use these tRNAs to explore the limits of unnatural polypeptide biosynthesis, both in vitro and eventually in vivo. In addition, this selection strategy is being extended to identify novel five- and six-base codon suppressors.

Amino Acid Sequence↗

PubMed1985

Streptomycin-induced, third-position misreading of the genetic code.

Streptomycin was used to increase the frequency of errors in protein synthesis in vivo. In the system under study two misreading errors were observed. Both involved the erroneous insertion of lysine at asparagine codons, because of misreading of a pyrimidine as a purine at the 3' position of the codon. Streptomycin increased the errors at the two codons AAU and AAC to the same extent, thereby maintaining the error ratio found for basal level mistranslation.

Autoradiography↗

PubMed1985

A change in the genetic code in Mycoplasma capricolum.

Mycoplasma capricolum was previously found to use UGA instead of UGG as its codon for tryptophan and to contain 75% A + T in its DNA. The codon change could have been due to mutational pressure to replace C + G by A + T, resulting in the replacement of UGA stop codons by UAA, change of the anticodon in tryptophan tRNA from CCA to UCA, and replacement of UGG tryptophan codons by UGA. None of these changes should have been deleterious.

Anticodon↗

PubMed1972

Selective condensation of aminoacyl adenylates by nucleoproteinoid microparticles (prebiotic-lysine-model system-genetic code).

Microparticles composed of each of four enzymically synthesized homopolynucleotides and the same lysine-rich proteinoid have been found to influence the condensation of the AMP-anhydrides of each of four amino acids. The conditions of preparation of the particles and other variables of the experiments control the types of reaction. When a specified set of conditions was identified empirically, the incorporation favored the amino acids whose present-day codons are related to the homopolynucleotide in the particle.

Adenine Nucleotides↗

PubMed1978

Speculations on the evolution of the genetic code. II.

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). From each of these amino acids and their codons, there evolves a family of related amino acids as the code expands. The four families are: (1) alanine valine, leucine, isoleucine, phenylalanine, tyrosine, methionine and tryptophane; (2) proline, threonine and serine; (3) arginine, lysine, and histidine; (4) glycine, serine cysteine, glutamic acid, glutamine, aspartic acid and asparagine. Except for the glycine relation to glutamic acid and aspartic acid, all amino acids are related by chemical similarities in their side chains. Glycine not having a side chain would permit a more complex set of substitutions.

Amino Acids↗

PubMed1995

Multisite oligonucleotide-mediated mutagenesis: application to the conversion of a mitochondrial gene to universal genetic code.

Using multisite oligonucleotide-mediated mutagenesis in conjunction with a mutagenesis selection procedure and rapid screening by allele-specific oligonucleotide hybridization has allowed us to develop a reliable protocol that enables a large number of base changes to be introduced rapidly into a piece of DNA, with the minimum number of manipulations. We have applied this protocol to generate synthetic versions of four mouse mitochondrial genes capable of being expressed in the nucleus/cytosol.

Amino Acid Sequence↗

PubMed2000

Synthesis of 6-(2-thienyl)purine nucleoside derivatives toward the expansion of the genetic code.

Unnatural bases specifically pairing with pyridin-2-one, 2-amino-6-(2-thienyl) purine and 2-amino-6-(2-furanyl)purine, were newly designed to replace 2-amino-6-(N,N-dimethylamino)purine. It was expected that these novel purine analogues, as compared with 2-amino-6-(N,N-dimethylamino)purine, might reduce the interference in the stacking interactions with the neighboring bases in a duplex and improve the efficiency of the enzymatic incorporation of the nucleoside triphosphate of pyridin-2-one opposite these unnatural bases. The syntheses of these nucleoside derivatives and the DNA fragments were examined.

Base Pairing↗

PubMed1979

A different genetic code in human mitochondria.

Comparison of the human mitochrondial DNA sequence of the cytochrome oxidase subunit II gene and the sequence of the corresponding beef heart protein shows that UGA is used as a tryptophan codon and not as a termination codon and suggests that AUA may be a methionine and not an isoleucine codon. The cytochrome oxidase II gene is contiguous at its 5' end with a tRNAAsp gene and there are only 25 bases at its 3' end before a tRNALys gene. These tRNA'S are different from all other known tRNA sequences.

Aspartic Acid↗

PubMed2002

Addition of a photocrosslinking amino acid to the genetic code of Escherichiacoli.

Benzophenones are among the most useful photocrosslinking agents in biology. We have evolved an orthogonal aminoacyl-tRNA synthetase/tRNA pair that makes possible the in vivo incorporation of p-benzoyl-l-phenylalanine into proteins in Escherichia coli in response to the amber codon, TAG. This unnatural amino acid was incorporated with high translational efficiency and fidelity into the dimeric protein glutathione S-transferase. Irradiation resulted in efficient crosslinking (>50%) of the protein subunits. This methodology may prove useful for discovering and defining protein interactions in vitro and in vivo.

Amino Acids↗

PubMed1969

Demonstration of the universality of the genetic code in vivo by comparison of the coat proteins synthesized in different plants by tobacco mosaic virus RNA.

The amino acid sequence of the coat protein of tobacco mosaic virus (TMV) synthesized in the garden zinnia (Compositae family) is compared with that synthesized in tobacco (Solanaceae family) by using the same preparation of TMV-RNA as messenger. The Compositae family is the most advanced group, and the Solanaceae family is a relatively advanced group in the plant kingdom. Both amino acid sequences are identical, including acetylserine as the N-terminal amino acid. This gives direct evidence that the RNA codon in vivo in the plant kingdom is universal between Compositae and Solanaceae families.

Amino Acid Sequence↗

PubMed1998

Genetic code origins: tRNAs older than their synthetases?

We present a phylogenetic analysis to determine whether a given tRNA molecule was established in evolution before its cognate aminoacyl-tRNA synthetase. The earlier appearance of tRNA versus their metabolically related enzymes is a prediction of the RNA world theory, but the available synthetase and tRNA sequences previously had not allowed a formal comparison of their relative time of appearance. Using data recently obtained from the emerging genome projects, our analysis points to the extant forms of lysyl-tRNA synthetase being preceded in evolution by the establishment of the identity of lysine tRNA.

Amino Acyl-tRNA Synthetases↗

PubMed2003

Using a solid-phase ribozyme aminoacylation system to reprogram the genetic code.

Here, we report a simple and economical tRNA aminoacylation system based upon a resin-immobilized ribozyme, referred to as Flexiresin. This catalytic system features a broad spectrum of activities toward various phenylalanine (Phe) analogs and suppressor tRNAs. Most importantly, it allows users to perform the tRNA aminoacylation reaction and isolate the aminoacylated tRNAs in a few hours. We coupled the Flexiresin system with a high-performance cell-free translation system and demonstrated protein mutagenesis with seven different Phe analogs in parallel. Thus, the technology developed herein provides a new tool that significantly simplifies the procedures for the synthesis of aminoacyl-tRNAs charged with nonnatural amino acids, which makes the nonnatural amino acid mutagenesis of proteins more user accessible.

Acylation↗

PubMed1989

Evolution of the mitochondrial genetic code. II. Reassignment of codon AUA from isoleucine to methionine.

The reassignment of codon AUA from isoleucine to methionine during mitochondrial evolution may be explained by the codon reassignment (capture) hypothesis without assuming direct replacement of isoleucine by methionine in mitochondrial proteins. According to this hypothesis, codon AUA would have disappeared from the reading frames of messenger RNA. AUA codons would have mutated mainly to AUU isoleucine codons because of constraints resulting from elimination of tRNA Ile with anticodon *CAU (in which *C is lysidine). Later, tRNA Met (CAU) would have undergone structural changes enabling it to pair with both AUG and AUA. AUA codons, formed by mutations of other codons, including AUG, would have reappeared and would have been translated as methionine.

Animals↗

PubMed1984

Aminoacyl-nucleotide reactions: studies related to the origin of the genetic code and protein synthesis.

In the present paper, we report on the effect of pH and carbonate on the hydrolysis rate constants of N-blocked and free aminoacyl adenylate anhydrides. Whereas the hydrolysis of free aminoacyl adenylates seems principally catalyzed by OH-, the hydrolysis of the N-blocked species is also catalyzed by H+, giving this compound a U-shaped hydrolysis vs. pH curve. Furthermore, at pH's less than 8, carbonate has an extreme catalytic effect on the hydrolysis of free aminoacyl-AMP anhydride, but essentially no effect on the hydrolysis of N-blocked aminoacyl-AMP anhydride. Furthermore, the N-blocked aminoacyl-AMP anhydride is a very efficient generator of peptides using free glycine as acceptor. The possible significance of the observations to prebiological peptide synthesis is discussed.

Adenosine Monophosphate↗

PubMed1985

Conservation of the secondary structure of protein during evolution and the role of the genetic code.

In this communication we demonstrate, in a group of modern proteins, following an algorithm described by Argyle (1980), that the ordination of the amino acids in terms of the most frequent substitutions agrees with the conservation of the alpha-helix, beta-sheet, and beta-turn formation tendencies during evolution. The same correspondence has been demonstrated for the conservation of the physico-chemical properties in the amino acid substitutions. Both parameters are similar in showing higher correlation with the most frequent amino acid substitutions than with the feasibility of changes at the level of the respective codons. Some kind of restrictions for the expression of the genomic changes, due to the conservation of the secondary structure of proteins and/or the physicochemical properties of the substituted amino acids, could account for the differences found between the distribution of the amino acid substitutions and the most probable codon changes.

Amino Acids↗

PubMedDate not supplied

[Evolution of the genetic code and earliest proteins. Reconstruction from the current sequences].

One would expect that present-day protein sequences have changed many times during their evolution, at every point, so that there is no chance to recognize in the sequences any traces of their ancient organization. It turns out to be not true. Massive analysis of complete genomes of bacteria allows one to derive, according to very specific predictions, distinct features of very early sequences and to outline the history of evolution protein. Modern proteins appear to have evolved from short peptides of mixed sequences of two alphabet types. They were then closed to sequences of optimal size from which modern folds/domains and multidomain proteins were formed. The reconstruction of amino acid and codon chronology is described. A specific idea on the nature and evolutionary significance of gene splicing is suggested. The gene splicing, while obeying the rules of basic structural organization of proteins, offers accessibility to regions of sequence space that could not be reached by mutational changes typical for prokaryotes.

Amino Acid Sequence↗