Codon combinations, Table

The codon combinations are shown in Table 14.2. A codon can be the DNA sequence in the coding strand or, alternatively, the related sequence found in mRNA. The table shows the mRNA sequences, since we shall be using these during consideration of protein synthesis. The DNA sequences merely have thymine (T) in place of uracil (U), as appropriate. The sequence is always listed from the 5 -end to the 3 -end. 

The general nature of the genetic code was suggested by the structure of DNA. Both DNA and proteins are linear polymers. Thus, it was logical to suppose that the sequence of the bases in DNA codes for the sequence of amino acids. There are only four bases in DNA but 20 different amino acids in proteins at the time of their synthesis. It is obvious that each amino acid must be specified by some combination of more than one base. While 16 pairs of bases are possible, this is still too few to specify 20 different amino acids. Therefore, it appeared that at least a triplet group of three nucleotides would be required to code for one amino acid.371 Sixty-four (43) such triplet codons exist, as is indicated in Tables 5-5 and 5-6. 

Table 6.1 shows the relationship between the codon sequence in mRNA and its corresponding amino acid in the new protein. Because there are 64 (43) different anticodon combinations and only 20 encoded amino acids, some different anticodon sequences encode for the same amino acid. Generally, all the anticodons matching a given amino acid will have the same first two nucleotides. Exceptions are arginine, serine, and isoleucine. For example, the codon for proline will always start with CC, but the arginine codon may start with either AG or CG. The 3 end of the tRNA anticodon pairs with the 5 end of the mRNA codon. In other words, the codon and anticodon align and bind in an antiparallel fashion. 

The corresponding combinatorial problem was solved by Golomb et al. (1958). The five basic dictionaries obtained in this way are given in Table 43, where the symbols a, b, c, and d stand for the four different bases appearing in the codons. Within each dictionary, the twenty nonoverlapping triplets are obtained by taking all the possible combinations of the first, second, and third letters within each subset. Derived sets of triplets may be obtained by taking the symmetric combinations, etc. 

The question then arises regarding the way in which four different bases (or nucleotides) determine the sequence (code) for 20 amino acids. A code based on two bases is not sufficient since such pairs yield only 16 possible combinations (4 x 4). A minimum of three bases is necessary. The triplet code give 64 possible combinations (4 x 4 x 4). As we shall see, each triplet represents a particular amino acid. Some amino acids are actually coded by only one triplet codon, whereas others are coded by several. The code is said to be degenerate (Table 6-7). 

Zidovudine is FDA-approved for the treatment of adults and children with HIV infection and for preventing mother-to-child transmission it also is recommended for postexposure prophylaxis in HIV-exposed healthcare workers, also in combination with other antiretroviral agents. The standard of care for treatment-naive patients (Table 50-lB) is to combine zidovudine with a potent protease inhibitor and another nucleoside analog or with an NNRTl and another nucleoside analog. The Met-to-Val substitution at reverse transcriptase codon 184 associated with use of lamivudine greatly restores sensitivity to zidovudine, and these drugs are often used in combination. 

The triplets of nucleotides (the codons) on mRNA are the genetic code (see Table 25.2). The code must be in the form of three bases, not one or two, because there are 20 different amino acids used in protein synthesis but there are only four different bases in mRNA. If only two bases were used, there would be only 4, or 16, possible combinations, a number too small to accommodate all of the possible amino acids. However, with a three-base code, 4, or 64, different sequences are possible. This is far more than... 

Formation of the SOS initiation complex. Recognition of the START codon (AUG) in mRNA is assisted by the preceding Kozak sequence (Table 71.3) before the pre-initiation complex is formed. Finally, the 60S ribosomal subunit combines with the 40S subunit to form the SOS initiation complex. 

These procedures have permitted researchers to determine the base composition and the base sequence of the codons for a large number of amino acids and to establish that the code is degenerate, universal, operates in vivo, and is not overlapping. The accepted code for each amino acid is presented in Table 2-4. There are 64 sequence combinations of trinucleotides when four different bases are used to build the triplet. A brief look at Table 2-4 shows that 60 of the 64 combinations are involved in amino acid coding. Two sequences have no known coding properties (CUA and CUG) and are therefore called nonsense codons. The intercalation of such a triplet into the sequence of messenger RNA is responsible for nonsense mutation. UAA and UAG are now known to be involved in punctuation. 

Figure 12.14. The RNA codons for mRNA read from DNA and are installed on the ribosome to be read by tRNA bringing the amino acids to the ribosome for peptide (protein) synthesis. Note that AUG is both the start codon (and thus requires the tRNA anticodon of UAC for the first amino acid, methionine [Met, M]) as well as the codon for methionine (Met, M) that might be found elsewhere, and that UAA, UGA, and UAG are stop codons. Note, too, that this 4 X 16 array, with 64 combinations, is redundant for the 20 amino acids, and thus some amino acids are specified in more than one way, while the start codon is unique. Information in this table was obtained from Nirenberg, M Leder, R Bernfield, M. Brimacombe, R. Trupin, I Rottman, F. O Neal, C. Nat. Acad. Sd. U.S., 1965,53,1161 and subsequent work.

As described above, DNA determines the structure of mRNA. The mRNA has 64 possible triplet codons. However, there are only 20 amino acids. The code is actually highly degenerate most amino acid residues are designated by more than one triplet. Only Trp and Met are designated by single codons. Table 14.7 (95) provides the genetic code of protein biosynthesis. Note that three combinations indicate a termination of the translation and the carboxyl end of the protein chain. 

Codons have now been determined for all 20 amino acids. A total of 64 codons is possible from the triplet combinations of A, G, C, and U (see Table 18.11). Three of these, UGA, UAA, and UAG, are stop signals that code for the termination of protein synthesis. All the other codons specify amino acids one amino acid can have several codons. For example, glycine has four codons GGU, GGC, GGA, and GGG. The triplet AUG has two roles in protein synthesis. At the beginning of an mRNA, the codon AUG signals the start of protein synthesis. In the middle of a series of codons, AUG codes for the amino acid methionine. 

Protein synthesis starts with mRNA, a transcript of a piece of a single strand of partly nnwonnd DNA (Fignre 26-14). Its chain is mnch shorter than that of DNA, and it does not stay bonnd to the DNA bnt breaks away as its synthesis is finished. The mRNA is the template responsible for the correct seqnencing of the amino acid units in proteins. How does mRNA do that Each sequence of three bases, called a codon, specifies a particular amino acid (Table 26-3). Simple permntation of this three-base code with a total of four bases gives 4 = 64 possible distinct sequences. That number is more than enongh, because only 20 different amino acids are needed for protein synthesis. This might seem like overkill, but consider that the next lower alternative—namely, a two-base code—wonld give only 4 = 16 combinations, too few for the number of different amino acids found in natnral proteins. 

---