Ribosomal Carbon

Abstract

Genetic code refers to the assignment of the codons to the amino acids, thus being the cornerstone template underling the translation process. Genetic code is largely invariant throughout all extant organisms; hence, it is often referred to as the "universal" or "canonical" genetic code. However, a number of extant deviations exist, in both nuclear and organelle (notably, mitochondrial) genomes. These are known as "deviant" or "non-canonical" codes. The emergence of the non-canonical codes posits a number of intriguing questions in regard to the origins and evolution of the universal genetic code and, importantly, has practical implications as certain human mitochondrial diseases have been shown to be linked to the mitochondrial code deviations and translational errors. On a fundamental level, universality (and presumed optimality) of the genetic code is a principal notion underlying its origins, evolution and functionality.

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Translation

A. Liljas, in Encyclopedia of Genetics, 2001

Genetic Code

The genetic code is the universal dictionary by which genetic information is translated into the functional machinery of living organisms, the proteins. The words or 'codons' of the genetic message are three nucleotides long. Since there are four different nucleotides used in messenger RNA (mRNA), this results in a dictionary of 64 words. There are 20 amino acids that are normally used in proteins and which are translated. In addition the translation needs a definition of 'start' and 'stop.' The start codon defines the start of translation as well as the reading frame (the sequence of nucleotide triplets) that is to be translated. The start or initiator codon is identical to the methionine codon. Special mechanisms are used to identify the correct initiation site; in addition there are three stop codons. Thus 61 codons are available for 20 amino acids, and hence the genetic code is degenerate. In the case of leucine, serine, and arginine, there are as many as six codons, whereas methionine and tryptophan have only one codon.

The universal genetic code deviates slightly in mitochondria, where a few codons are translated in alternative ways. The most prevalent are methionine and tryptophan, which have two codons instead of the usual one. Different organisms use the degenerate genetic code differently. The usage of the codons is coupled to the availability to tRNAs that can translate them. Thus the codon usage can differ to the extent that a gene that is transferred from one organism to another cannot be translated unless the new organism is supplemented with extra tRNAs.

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Peptide, Protein and Enzyme Design

C. Hu, J. Wang, in Methods in Enzymology, 2016

4 Synthetic Chemistry-Guided Unnatural Amino Acid Design

Genetic code expansion enables the usage of unnatural chemical groups, which are widely used in organic chemistry but is rare in organisms. At least three advantages can be achieved by doing that. First, the protein scaffold provides a secondary coordination sphere for the organic catalyst, which may enhance their performance, including turnover numbers and enantioselectivity (Durrenberger & Ward, 2014). Second, the structure containing unnatural organic amino acid is genetically encoded. As a consequence, its self-assembly can be easily amplified or improved by directed evolution. Finally, adding unnatural organic molecules enables researchers to solve biological chemistry problems by organic chemical methods, which may be helpful in green chemistry and synthetic biology.

Some unnatural amino acids were inspired by organic chemistry studies. Thus, some unnatural organic molecules and powerful and highly developed synthetic chemistry methods can be introduced to molecular biology (Mann, 1989). In order to be properly incorporated, those organic molecules are required to be converted into an unnatural amino acid first. Based on their structure features, they can be converted into either a "tyrosine" or a "lysine". For instance, if the molecule contained an aromatic ring, it would be suitable for mimicking tyrosine. The tyrosine type unnatural amino acid often contains an aromatic ring that bears the unnatural chemical groups, and a covalently linked aliphatic amino acid part (usually alanine) as the amino acid back bone. On the other hand, a lysine host is more suitable for flexible aliphatic chemical groups. The lysine mimic is usually composed of the unnatural aliphatic chemical groups and a lysine molecule. Usually they are covalently connected by an amide bond or carbamate.

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Amino Acids, Peptides, Porphyrins, and Alkaloids

Dolph L. Hatfield, ... Byeong jae Lee, in Comprehensive Natural Products Chemistry, 1999

4.14.4 Universality of UGA as a Codon for Sec

The genetic code was previously thought to be used in the same way by all organisms and therefore was considered to be universal. However, it is now known that many changes have occurred in the genetic code during evolution65,66 and thus, it has been described as the "almost universal genetic code".73 In the present discussion of the assignment of Sec to the universal genetic code, the code will be referred to as the almost universal genetic code.73

Sec tRNAs that decode UGA in protein synthesis are widespread in nature.5,6,8 Initially, a Sec-tRNA that decodes UGA in protein synthesis was identified intracellularly in E. coli21 and in mammals.23 These studies clearly established the existence of selenocysteyl-tRNA[Ser]Sec and provided strong evidence that the Sec moiety in selenoproteins must arise by direct incorporation of Sec and not by posttranslational modification. The gene encoding Sec tRNA[Ser]Sec was subsequently found to be ubiquitous in the subkingdom Eubacteria74 and tRNA[Ser]Sec or its gene was found to be ubiquitous in the animal kingdom.75 Sec-tRNAs that decode UGA were also found in two very diverse protists, Tetrahymena borealis and Thalassiosira pseudoonana,76 in a higher plant, Beta vulgaris, and in a filamentous fungus, Gliocladium virens.77 Several potential Sec-containing protein genes (i.e., genes that contained TGA in an open reading frame) and a Sec tRNA gene were found in the genome sequence of the archaeon, Methanococcus jannaschii.78 Each of these studies shows that UGA as a codon for Sec occurs in representative organisms from all five life kingdoms, Monera (with its two subkingdoms, Eubacteria and Archaebacteria), Protists, Plants, Animals, and Fungi (see Figure 3 for the delineation of organisms into five life kingdoms).79 Therefore, Sec should be assigned to UGA in the almost universal genetic code5 as shown in Figure 4.

Figure 3. Evolutionary tree showing the distribution of Sec in nature.

Figure 4. The almost universal genetic code showing the inclusion of Sec as the 21st amino acid.

In addition to UGA, AUG also has a dual function in the almost universal genetic code (see Figure 4).67,69 AUG serves both as a codon that initiates protein synthesis and a codon for methionine at internal positions of protein. The dual role of AUG has been known since the code was first deciphered67,68 and thus it is not surprising that a second codon, UGA, also has a dual function. Furthermore, the fact that two codons have now been identified in the almost universal genetic code with multiple functions raises the possibility that other codewords may also exist with multiple roles.

The genome of Saccharomyces cerevisiae has been sequenced.80 This organism does not appear to encode a Sec tRNA[Ser]Sec gene or any potential selenoprotein genes.8 A S. cerevisiae homologue of the glutathione peroxidase gene in mammals was found to contain a cysteine codon (TGT) at the position where the mammalian gene encodes Sec (codon TGA). Thus, this organism appears to lack the biosynthetic pathways for specific site incorporation of Sec into protein found in other life forms.8 This observation reflects genetic diversity and should not affect our proposal that Sec belongs in the almost universal genetic code. Other yeast forms, such as Candida albicans, are known to encode variations in the almost universal genetic code in their genomes.65,66,81

The fact that S. cerevisiae does not appear to have the system for incorporating Sec into specific sites of protein demonstrates that this means of utilizing selenium is not essential to life. Furthermore, E. coli mutants lacking the ability to incorporate Sec into specific sites of protein can grow normally under certain conditions.82 Do these findings imply that the incorporation of Sec into specific sites of protein is not important in nature? In mammalian systems, the synthesis of specific selenoproteins is essential to sustain life as removal of the Sec tRNA[Ser]Sec gene from the mouse genome by gene replacement or "gene knockout" is embryonically lethal.83 In E. coli, the selenoprotein, formate dehydrogenase, is required to detoxify formate under aerobic growth conditions.82 The ability to incorporate Sec into specific selenoproteins is, therefore, not essential to sustain life in E. coli, but provides these organisms with a selective advantage. Thus, the ability to synthesize specific selenoproteins is essential to some life forms, while it appears to provide only a selective advantage to others. In addition, since this process is widespread in nature, it must then be important as a requirement and/or as a selective advantage to virtually all organisms.

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Codon Usage and Translational Selection

R. Hershberg, in Encyclopedia of Evolutionary Biology, 2016

Abstract

The genetic code is redundant, meaning that most amino acids are encoded by more than one codon. Codons encoding the same amino acid are referred to as synonymous codons. Different synonymous codons are not used equally within the protein-coding sequences of a genome. Rather, a phenomenon of codon bias, by which certain synonymous codons are consistently over represented relative to others, is ubiquitous across living organisms. In this article we discuss the neutral and selective causes of codon bias, focusing on translation optimization considerations as a major source of selection on codon usage.

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Translation

A. Liljas, in Brenner's Encyclopedia of Genetics (Second Edition), 2013

The Genetic Code

The genetic code is the universal dictionary by which the genetic information is translated into the functional machinery of living organisms, the proteins. The words or the codons of the genetic message are three nucleotides long. Since there are four different nucleotides (A, C, G, U) used in the messenger RNA (mRNA), this leads to a dictionary of 64 words. Translation needs a definition of start and stop. The start codon at the same time defines the reading frame of the sequence of nucleotide triplets that are to be translated. The start or initiator codon is identical to the methionine codon. Special mechanisms are used to identify the correct initiation site. In addition, there are three stop codons. Thus 61 codons are available for 20 amino acids that are normally translated and used in proteins. Thus the genetic code is degenerate. In the case of leucine, serine, and arginine, there are as many as six codons, whereas methionine and tryptophan have only one codon each.

The codon usage is coupled to the availability of tRNAs that can translate them. The codon usage can differ to the extent that if a gene is transferred from one organism to another, it may not be possible to translate unless the gene is altered to match the codon usage of the recipient organism.

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Messenger RNA

A. Liljas, in Brenner's Encyclopedia of Genetics (Second Edition), 2013

The Genetic Code

The genetic code is the universal dictionary by which the genetic information is translated into the functional machinery of living organisms, the proteins. The words or the codons of the genetic message are three nucleotides long. Since there are four different nucleotides used in the messenger RNA (mRNA; A, C, G, and U), this leads to a dictionary of 64 code words. A total of 20 amino acids is normally used in proteins, but translation also needs a definition of a start and a stop of the message. The start codon, AUG, defines the reading frame of the sequence of nucleotide triplets that will be translated. However, the start or initiator codon is identical to the methionine codon. Special mechanisms are used to identify the correct initiation site. With the three stop codons – UAA, UAG, and UGA – there are 61 codons available for the 20 amino acids. Therefore, the genetic code is degenerate. There are as many as six codons corresponding to leucine, serine, and arginine, whereas methionine and tryptophane have only one codon each.

Traditional Interpretation of Silent Mutations

The genetic code uses 64 three-nucleotide codons to encode the 20 common amino acids used in protein synthesis. For most amino acids, this extra coding capability allows for more than one codon to encode the same amino acid. A silent mutation, therefore, is a point mutation where one nucleotide in a genetic sequence is replaced with another nucleotide, altering the corresponding codon to another codon for the same amino acid. This is in contrast to missense mutations, where the mutation changes the codon to one amino acid for another amino acid, and nonsense mutations, where the mutation changes the codon to one of the three termination codons.

Silent mutations produce no change to the encoded amino acid sequence and traditionally are not thought to affect the final protein product. For example, the codon CUU codes for the amino acid leucine. Any mutation in the third position of the nucleic acid sequence, that is, to CUC, CUA, or CUG, will also correspond to leucine. Silent mutations (also referred to as synonymous mutations) can also be described as single-nucleotide polymorphisms (SNPs) that result in no change to the amino acid sequence because of codon redundancy or degeneracy in the genetic code. Because the protein products of silent mutations are not changed, silent mutations are usually considered to be neutral in terms of evolution since there is no negative or positive selection at the phenotypic level against or for the mutation. This has led to the use of silent mutations in determining evolutionary distances between species, a use often described as a genetic clock.

With the advent of DNA sequencing, especially whole-genome sequencing, the definition of a silent mutation could be broadened to include noncoding regions as well. Noncoding genome sequences are areas of the genome that contain sequences that do not produce proteins. Changes to this area of the genetic sequence, therefore, have no effect on the sequence of proteins. These regions do include important regulatory regions since mutations in these can affect the expression of proteins while not altering the protein's sequence. Likewise, genes for functional RNA molecules are not protein encoding, sensu stricto, but changes in tRNAs, ribosomal RNAs, or regulatory RNA molecules through mutations can have far-reaching effects on protein synthesis and gene expression. Sequence changes in introns may also affect expression of the coding sequences in which the introns are located. Some sources now include these changes as a kind of silent mutation, making synonymous mutations a subset of silent mutations. It is fair to argue, however, that mutations outside of coding regions are mutations that fall outside of the categories of silent, missense, and nonsense mutations. Missense and nonsense mutations are linked to the genetic code and coding sequences so that limiting the definition of silent mutations to changes within coding sequences maintains a single conceptual framework for all three. For the remainder of this article, we shall limit our discussion of silent mutations to synonymous mutations, that is, mutations that do not alter codon meaning but are within codon sequences.

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Codon Usage Bias

P.M. Sharp, in Brenner's Encyclopedia of Genetics (Second Edition), 2001

Introduction

The genetic code is degenerate: except for Met and Trp, all amino acids are encoded by more than one nucleotide triplet (codon). The number of alternative, or synonymous, codons varies from two to six, with the synonyms generally differing at their third position. It might be expected that alternative synonymous codons would be used in roughly equal frequencies, but this is not so. Most genes from most species exhibit biased codon usage. Different species have different codon usage profiles, and codon usage often varies significantly among genes from the same genome.

The pattern of synonymous codon usage must reflect the combined influences of mutation, natural selection, and random genetic drift. Investigations of codon usage have provided interesting insights into basic aspects of cell biochemistry, genetics, and evolutionary biology. The results can also have useful applications.

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