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PubMed1990

Nucleotide sequence and codon usage of the elongation factor Tu(EF-Tu) gene from Mycoplasma pneumoniae.

The Mycoplasma pneumoniae tuf gene, encoding the elongation factor protein Tu, was cloned and sequenced. The nucleotide sequence of the mycoplasmal gene showed about 60% homology to the sequences of tuf genes of other prokaryotes, yeast mitochondria and Euglena gracilis chloroplasts, and about 75% similarity was found when comparing the deduced amino acid sequences of the various Tu proteins. The relatively low G + C content (40%) of the M. pneumoniae DNA was reflected in a low G + C content (44.6%) of the tuf gene, and in a preferential use of adenine and uracil at the third position of codons, yet codon usage analysis revealed the presence of almost all of the codons of the genetic code in the mycoplasmal gene. Southern blot hybridization of digested DNAs of 11 Mollicutes species with the entire M. pneumoniae tuf gene and with its 5' part suggested the presence of one copy only of this gene in the representative species of the Mollicutes. In this respect, the Mollicutes resemble Gram-positive bacteria and differ from the Gram-negative bacteria, which carry two copies of the tuf gene.

Amino Acid Sequence↗
PubMed1991

The use of a rare codon specifically during development?

A range of circumstantial evidence suggests that in Streptomyces spp., genes required for vegetative growth do not contain the leucine codon TTA. Instead, the codon seems to be confined to a few genes necessary during differentiation, when the colonies begin to produce aerial hyphae and antibiotics. Thus, mutations in bldA, the structural gene for tRNATTALeu, do not retard vegetative growth, but they prevent normal aerial mycelium and antibiotic production. Most of the known TTA-containing genes specify regulatory or resistance proteins associated with antibiotic-production clusters. Possibly the ability to translate the UUA codons in mRNA from such genes is confined to late stages of colony development. Factors that might have contributed to the evolution of this unusual situation are discussed.

Base Sequence↗
PubMed1994

The cis-effect of a nascent peptide on its translating ribosome: influence of the cat-86 leader pentapeptide on translation termination at leader codon 6.

Inducible cat genes from Gram-positive bacteria are regulated by translation attenuation. The inducer chloramphenicol stalls a ribosome at a specific site in the leader of cat transcripts; this destabilizes a downstream stem-loop structure that normally sequesters the ribosome-binding site for the cat structural gene. The five-amino-acid peptide MVKTD that is synthesized when a ribosome has translated to the leader induction site is an inhibitor of peptidyl transferase in vitro. Thus, the peptide may be the in vivo determinant of the site of ribosome stalling. Here we provide evidence that the leader pentapeptide can exert a cis-effect on its translating ribosome in vivo. Converting leader codon 6 to the ochre codon results in expression of cat-86 in the absence of inducer. We term this autoinduction. Autoinduction is abolished by mutations that change the amino-acid sequence of the leader peptide but have no, or little, effect on the sequence of nucleotides at the leader stall site. In contrast, four nucleotide changes within the leader site occupied by the stalled ribosome that result in synonymous codon replacements do not diminish autoinduction. Our evidence indicates that the cat-86 leader pentapeptide can alter the function of its translating ribosome.

Amino Acid Sequence↗
PubMed1998

HFE codon 63/282 (H63D/C282Y) dimorphism in German patients with genetic hemochromatosis.

Genetic hemochromatosis (GH) is closely associated with genes of the major histocompatibility complex (MHC) on chromosome 6. Recently, a candidate gene for GH, with structural similarities to MHC class I genes, designated HLA-H and presently named HFE, has been cloned. The HFE gene is localized telomeric to the MHC and several reports have indicated that the HFE gene is mutated in GH patients. In the present study we have analyzed the relationship of HFE gene variants and disease manifestation in GH patients and family members. Fifty-seven patients with GH, 73 family members and 153 healthy blood donors were studied for the amino acid dimorphism at codon 63 (His63Asp=H63D) and codon 282 (Cys282Tyr= C282Y) of the HFE gene. The codon 63 and 282 dimorphism were defined by PCR amplification of genomic DNA samples and restriction enzyme digestion using RsaI/SnaBI for C282Y and BclI/MboI for H63D. Ferritin, transferrin serum levels and total iron-binding capacity were determined prior to therapeutic intervention. The Tyr-282 substitution occurred in 53 (93%) of patients compared with 8 (5.2%) of controls (OR=169, P<0.0001). Fifty-one (90%) patients were Tyr-282 homozygous. In contrast, the Asp-63 substitution was present in 5 (8.8%) of the patients compared with 34 (22%) of controls (OR=0.39, P=NS) with none of the patients being homozygous. In Tyr-282 homozygous GH patients serum ferritin levels, transferrin saturation, liver iron and liver iron index were elevated significantly compared to Tyr-282-negative patients, whereas no difference was observed between Tyr/Cys-282 heterozygous and Tyr-282-negative patients.

Aspartic Acid↗
PubMed2004

Experimental reduction of codon bias in the Drosophila alcohol dehydrogenase gene results in decreased ethanol tolerance of adult flies.

The ethanol tolerance of adult transgenic flies of Drosophila containing between zero and ten unpreferred synonymous mutations that reduced codon bias in the alcohol dehydrogenase (Adh) gene was assayed. As the amino acid sequences of the ADH protein were identical in the four genotypes assayed, differences in ethanol tolerance were due to differences in the abundance of ADH protein, presumably driven by the effects of codon bias on translational efficiency. The ethanol tolerance of genotypes decreased with the number of unpreferred synonymous mutations, and a positive correlation between ADH protein abundance and ethanol tolerance was observed. This work confirms that the fitness effects of unpreferred synonymous mutations that reduce codon bias in a highly expressed gene are experimentally measurable in Drosophila melanogaster.

Alcohol Dehydrogenase↗
PubMed1975

Requirement for ribosome-releasing factor for the release of ribosomes at the termination codon.

With the use of 3H-labeled R 17 amB2 phage RNA having an UAG codon at the seventh triplet of the coat cistron, release of the RNA from ribosomes at the termination codon was studied. The ribosome-releasing factor previously described was shown to stimulate the process of mRNA release at the termination factor (RF-1). GTP was required for this process and guanosine 5'-(beta,gamma-methylene)triphosphate could not replace GTP. No apparent change of size of R 17 RNA was observed during the release of the R 17 RNA from the ribosomes. The ribosome-releasing factor is distinct from the known termination codon-specific factor such as RF-1.

Amino Acids↗
PubMed1984

Nucleotide sequence of the gene for the immunity protein to colicin A. Analysis of codon usage of immunity proteins as compared to colicins.

The nucleotide sequence of the structural gene for the immunity protein to colicin A (cai) has been established. This sequence consists of 534 base pairs. According to the predicted amino acid sequence, the polypeptide chain of this immunity protein comprises 178 amino acids and has a relative molecular mass of 20462. As expected from its localization in the inner membrane, large hydrophobic fragments are found along the polypeptide chain that also contains clusters of mostly positively charged residues. The cai like the ceiA genes encode proteins that are weakly expressed as compared to the corresponding colicins (A and E1). Codon usage reflects this difference. In contrast, the four genes for immunity to cloacin DF13 and to colicin E3 and for these bacteriocins, all of which are highly expressed and are organized in operon, display similar codon usage. These results are discussed with regards to the possible relationship between expressivity and codon usage.

Bacterial Proteins↗
PubMed1993

Nuclear magnetic resonance study of the codon-anticodon interaction in Bombyx mori tRNA(GCCGly).

NMR spectra of Bombyx mori tRNA(GCCGly) were recorded in the GCC absence and presence of the oligonucleotide, GGCUp, which contains the codon sequence, GGC. The difference between the spectra with and without the codon oligonucleotide indicates the appearance of five new imino proton peaks. For the assignment of these peaks, G*GCUp, in which the 5'-terminal G was enriched with 95% 15N, was prepared (G*, 15N-labeled guanosine). In the imino proton spectrum of B. mori tRNA(GCCGly) on the addition of G*GCUp, the peak at 12 ppm became a doublet due to coupling with 15N nuclei. In the two-dimensional 1H-15N heteronuclear multiple-quantum correlation (HMQC) spectrum, only the peak at 12 ppm was observed, and thus it was assigned to the imino proton of the 5'-terminal G of GGCUp interacting with tRNA(GCCGly). Judging from the temperature effect and chemical shifts, the five new imino proton peaks are presumed to be due to three G.C base pairs, induced by the codon-anticodon interaction, and one U.U base pair, induced by an interaction between the 3' terminal U of GGCUp and U33 neighboring the anticodon. The binding of three trinucleotides (GGCp, GGUp and GCUp) to B. mori tRNA(GCCGly) was also investigated. Ultracentrifugation analysis showed that tRNA(GCCGly) underwent dimerization through the anticodon-anticodon interaction, but the dimerization was broken on addition of GGCUp. On 1H-NMR and ultracentrifugation analysis, it was found that GCUp not complementary to the anticodon also binds to the anticodon loop.

Animals↗
PubMedDate not supplied

Detection of hepatitis B virus precore stop codon mutants by selective amplification method: frequent detection of precore mutants in hepatitis B e antigen positive healthy carriers.

The precore region of hepatitis B virus (HBV) is indispensable for secretion of e antigen protein. Therefore, the precore stop codon mutants may play an important role in the process of e antigen seroconversion. However, the presence of the mutants in hepatitis B e antigen positive carriers has not been fully studied because of difficulties in detecting the mutants in the presence of large amounts of wild-type viruses. To overcome this, a sensitive method has been developed to detect the presence of G to A stop codon mutants at codon 28 of precore region. Primers for polymerase chain reaction (PCR) were devised to introduce restriction enzyme site Sty I for wild-type viruses and Dde I for the mutants. The amplification products with these primers were digested with Sty I to exclude the products from wild-type viruses. The remaining amplicon from precore mutants were re-amplified, and the presence of precore mutant was confirmed with Dde I digestion. The presence of precore mutants was examined in 61 HBV carriers by the method combining PCR and restriction enzyme digestion. Approximately 0.1% of precore mutant DNA among 10(6) copies of wild-type virus DNA was detectable by this method. The presence of the precore mutants was detected in seven of 10 (70%) e antigen positive asymptomatic carriers, and in 29 of 36 (81%) e antigen positive patients with chronic liver diseases, and in all 15 (100%) anti-e antibody positive patients with chronic liver diseases. This study revealed that a small amount of the precore mutants was present in the majority of HBV carriers.

Adult↗
PubMedDate not supplied

Association of p53 mutations and a codon 72 single nucleotide polymorphism with lower overall survival and responsiveness to adjuvant radiotherapy in endometrioid endometrial carcinomas.

p53 Genetic alterations are associated with advanced stage and aggressive tumors in a variety of human malignancies. The aim of this study was to examine p53 for genetic alterations and to evaluate the association of these alterations with clinical outcome and response to adjuvant radiotherapy in endometrioid endometrial carcinomas. p53 mutations in exons 2-11 were assessed in 59 endometrioid carcinomas by polymerase chain reaction-single-strand conformational polymorphism and sequence analysis. Twelve mutations (20.3%) and nine polymorphisms were identified. Seven of the nine polymorphisms were codon 72 single nucleotide polymorphisms (SNP) with an Arg/Pro allelotype. Women harboring either a mutation or an Arg/Pro allelotype at codon 72 had a lower overall survival rate than women whose tumors lacked alterations in the p53 gene (P= 0.0029). Women were stratified based on p53 genetic alterations (p53 mutation or p53 codon 72 SNP) and whether or not they received adjuvant radiation therapy. Women with p53 genetic alterations who did not receive adjuvant radiotherapy had the lowest survival rate (P= 0.0005). Treated women with p53 genetic alterations and untreated women with no p53 alteration had similar rates of survival. Among women with p53 alterations, adjuvant radiotherapy substantially increased survival (P= 0.035). In multivariate analyses, the group of women with p53 genetic alterations who did not receive adjuvant radiation therapy had a 5.9-fold increased risk of death (95% confidence interval: 1.5-22.7) compared to women whose tumors lacked p53 alterations and did not receive adjuvant radiation therapy.

Adult↗
PubMedDate not supplied

Analysis of p53 codon 72 polymorphism and its association with human papillomavirus 16 and 18 E6 in Chinese cervical lesions.

The aim of this study was to analysis the relationship between p53 codon 72 polymorphism with human papillomavirus (HPV) 16 and 18 E6 in Chinese cervical cancer. A total of 81 cervical squamous cancer (specimens of G1, G2, and G3 are 13, 24, and 44, respectively; and of stage IB, IIA, IIB, and IIIA are 15, 37, 24, and 5, respectively), 18 cervical adenocarcinoma, 88 cervical intraepithelial neoplasm (CIN) (specimens of CIN II and III are 30 and 58), and 60 normal cervical specimens were included in this study. Polymerase chain reaction was used to examine p53 genotypes and HPV 16 and 18 E6. The frequencies of p53 Arg homozygosity in cervical squamous cancer, cervical adenocarcinoma, and CIN (II-III) were 58.02%, 55.55%, and 59.09%, respectively, that was much higher than that of p53 Arg/Pro heterozygosity (30.86%, 27.78%, and 21.59%) and of p53 Pro homozygosity (11.12%, 16.67%, and 19.32%) in each groups and higher than the frequency of p53 Arg homozygosity in normal samples (23.33%). There is no statistic difference in the normal samples for the frequency of p53 Arg homozygosity, p53 Arg/Pro heterozygosity, and p53 Pro homozygosity (23.33%, 40.00%, and 36.67%, respectively). The frequency of p53 Arg homozygosity in high risk (HR)-HPV E6-positive cervical squamous cancer samples (64.06%) is much higher than that in (HR)-HPV E6-negative cervical squamous cancer samples (35.29%) and in HR-HPV E6-positive normal samples (33.33%). No difference of p53 codon 72 polymorphism was found according to FIGO staging and grades. In conclusion, based on the findings of this study, it is suggested that p53 Arg homozygosity could act as a potential risk factor for the tumorigenesis of the cervix. p53 codon 72 polymorphism has no relation with the FIGO staging and grades of cervical cancer. p53 Arg homozygosity and HR-HPV E6 positive simultaneously can predict the fate of cervical lesions.

Alleles↗
PubMed1999

p53 and p21/Waf1 protein expression and K-ras codon 12 mutation in carcinoma of the papilla of Vater.

OBJECTIVE: There have been few studies on the molecular biological characteristics of carcinoma of the papilla of Vater. In this study, p53 and p21/Waf1 expression and K-ras codon 12 mutation in carcinoma of the papilla of Vater were investigated. METHODS: Thirty-seven cases of carcinoma of the papilla of Vater were studied. Macroscopically, the carcinoma was ulcerative in 15 cases and nonulcerative in 22 cases. Histologically, nine were intestinal type, 27 were pancreaticobiliary type, and one was undifferentiated. Formalin-fixed, paraffin-embedded sections were immunohistochemically stained for p53 and p21. K-ras codon 12 mutation was detected with the two-step polymerase chain reaction-restriction fragment length polymorphism method, followed by direct sequencing. RESULTS: p53 overexpression was found in 17 of 37 cases (46%) and was more frequent in the ulcerative type than in the nonulcerative type (67% vs 32%, p < 0.05). p21/Waf1 protein expression was found in 15 of 37 cases (41%), and was not correlated with that of p53. K-ras codon 12 mutation was found in 14 of 37 cases (38%), and was more frequently detected in the intestinal type than in the pancreaticobiliary type (66% vs 30%, p < 0.05). On direct sequencing, the mutations were mainly GGT to GAT (9/14) and GGT to GTT (4/14). The type of mutation did not correlate with the histological type. CONCLUSIONS: In carcinoma of the papilla of Vater, p53 overexpression may play a role in tumor ulceration. p21/Waf1 expression is induced via a p53-independent pathway. Carcinomas of the intestinal and pancreaticobiliary types may develop via different mechanisms, and K-ras mutation is mainly associated with the intestinal type.

Adult↗
PubMed1998

Codon usage in Actinobacillus actinomycetemcomitans.

The codon usage patterns of 21 genes encompassing 5800 codons from Actinobacillus actinomycetemcomitans were analyzed. A. actinomycetemcomitans genes could be divided into two groups based on their function and G + C content. One group included those genes encoding basic cellular functions. This group displayed an average G + C content of 48%. A second group comprised genes encoding the leukotoxin determinant, an insertion sequence and a plasmid. This group displayed an average G + C content of 36%. These findings suggest that portions of the A. actinomycetemcomitans genome may have been acquired by horizontal gene transfer from one or more distantly related species. We present a table of A. actinomycetemcomitans codon usage. These data may be used to establish standards for computer programs that predict A. actinomycetemcomitans protein coding regions and may be useful in designing degenerate oligonucleotide probes.

Adolescent↗
PubMed1998

Phylogenetic position and codon usage of two centrin genes from the rumen ciliate protozoan, Entodinium caudatum.

A lambda phage cDNA expression library was constructed from washed suspensions of the rumen ciliate protozoan, Entodinium caudatum, which had been maintained in an isolated, monofaunated sheep. The library was screened using an anti-E. caudatum antiserum raised in rabbits against sonically disrupted protozoa, DNA sequences for two centrins or caltractins, a subfamily of the EF-hand Ca(2+)-modulated proteins which are closely related, highly conserved cytoskeletal proteins, were identified and characterised. Their phylogenetic position was established relative to other centrin gene sequences. The two proteins showed homology to Paramecium tetraurelia centrins: 50 and 52% identities and 71 and 75% similarities in the protein sequence, over 99 and 110 amino acids fragments. Codon usage and indices revealed the E. caudatum follows universal codon usage, but with a restricted number of codons, and has a low G&C content.

Animals↗
PubMed1991

Spontaneous neurodegeneration in transgenic mice with prion protein codon 101 proline----leucine substitution.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is an autosomal, dominantly inherited, human neurodegenerative disease that can sometimes be transmitted to non-human primates and rodents through intracerebral inoculation of brain homogenates from patients. Recent studies of GSS demonstrated significant genetic linkage between GSS and a leucine substitution at codon 102 of the human prion protein (PrP) gene. Transgenic mice were created to test the biologic activity of this mutation. Spontaneous neurologic disease with spongiform degeneration developed in one of three lines of transgenic mice containing murine PrP genes with a leucine substitution at codon 101 (homologous to codon 102 in humans). Transmission studies of brain homogenates from affected mice are in progress. These results indicate that some of the clinical and pathologic features of GSS can be reproduced in a transgenic mouse paradigm; this represents the first time a dominantly inherited, neurodegenerative process similar to a human disease has been genetically modeled in an experimental animal (Hsiao and Prusiner 1990).

Amino Acid Sequence↗
PubMed1995

Predominance of codon 215 mutation in reverse transcriptase-coding region of 3'-azido-3'-deoxythymidine (AZT)-resistant HIV-1 isolates after long-term AZT therapy.

Among human immunodeficiency type 1 viruses (HIV-1) isolated during long-term 3'-azido-3'-deoxythymidine (AZT) therapy, 4 condoms (Asp67, Lys70, Thr215, and Lys219) in the HIV-1-reverse transcriptase (RT)-coding region have been considered to be related to the AZT resistance of HIV-1. Therefore we determined these mutation patterns in HIV-1 isolates from patients undergoing long-term AZT treatment. In 41 clones of HIV-1 from 7 patients, the Thr215 mutation was the most predominant (97.6%), and more frequent than Asp67 (48.8%), Lys70 (31.7%) and Lys219 (9.8%) mutations. All 22 clones from isolates cultured in the presence of 1 microM AZT Thr215 mutation; such a high frequency was not found for the other 3 codon mutations. In a clinical follow-up study, Thr215 mutation appeared in the late stage of AZT treatment parallel with the emergence of AZT insusceptibility. It is worth noting that this Thr215 mutation to Tyr or Phe is a 2-nucleotide mutation in contrast to the 1-nucleotide mutations seen in the other 3 codons. Isolates with the single amino acid change of Thr215 of the RT-coding region obtained after long-term AZT treatment grew in the presence of 1 microM AZT. This single amino acid mutation in the Thr215 codon is the most important factor in AZT resistance.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Resistance to 2',3'-dideoxycytidine conferred by a mutation in codon 65 of the human immunodeficiency virus type 1 reverse transcriptase.

A human immunodeficiency virus type 1 variant resistant to zalcitabine (2',3'-dideoxycytidine [ddC]) was selected by sequential passage in the presence of increasing concentrations of ddC in peripheral blood mononuclear cell cultures. A mutation causing a lysine-to-arginine substitution was noted in reverse transcriptase (RT) codon 65 of this ddC-selected virus. A cloned mutant virus with this codon 65 mutation was constructed by using a novel PCR approach for site-directed mutagenesis. Characterization of this virus confirmed that the RT Lys-65-->Arg substitution was necessary and sufficient for a fourfold increase in the ddC 50% inhibitory concentration, as well as for resistance to didanosine (2',3'-dideoxyinosine [ddI]). Lys-65-->Arg and virus resistance to ddC and ddI also developed during therapy in isolates from one ddC-treated patient and two ddI-treated patients. Recombinant-expressed codon 65 mutant RT enzyme was resistant to ddCTP and ddATP in cell-free polymerase assays. Results of mutant enzyme studies are consistent with Lys-65-->Arg leading to changes in binding of the triphosphate forms of these nucleoside analogs to the RT. These data have implications for future studies of ddC resistance, particularly those aimed at defining its clinical relevance.

Arginine↗
PubMed2003

Effect of codon optimization on expression levels of a functionally folded malaria vaccine candidate in prokaryotic and eukaryotic expression systems.

We have produced two synthetic genes that code for the F2 domain located within region II of the 175-kDa Plasmodium falciparum erythrocyte binding antigen (EBA-175) to determine the effects of codon alteration on protein expression in homologous and heterologous host systems. EBA-175 plays a key role in the process of merozoite invasion into erythrocytes through a specific receptor-ligand interaction. The F2 domain of EBA-175 is the ligand that binds to the glycophorin A receptor on human erythrocytes and is therefore a target of vaccine development efforts. We designed synthetic genes based on P. falciparum, Escherichia coli, and Pichia codon usage and expressed recombinant F2 in E. coli and Pichia pastoris. Compared to the expression of the native F2 sequence, conversion to prokaryote (E. coli)- or eukaryote (Pichia)-based codon usage dramatically improved the levels of recombinant protein expression in both E. coli and P. pastoris. The majority of the protein expressed in E. coli, however, was produced as inclusion bodies. The protein expressed in P. pastoris, on the other hand, was expressed as a secreted, soluble protein. The P. pastoris-produced protein was superior to that produced in E. coli based on its ability to bind to red blood cells. Consistent with these observations, the antibodies generated against the Pichia-produced protein prevented the binding of recombinant EBA to red blood cells. These antibodies recognize EBA-175 present on merozoites as well as in sporozoites by immunofluorescence. Our results suggest that the Pichia-based EBA-F2 vaccine construct has further potential to be developed for clinical use.

Animals↗