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Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002.

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Biochemistry. 5th edition.

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Section 5.5Amino Acids Are Encoded by Groups of Three Bases Starting from a Fixed Point

The genetic code is the relation between the sequence of bases in DNA (or its RNA transcripts) and the sequence of amino acids in proteins. Experiments by Francis Crick, Sydney Brenner, and others established the following features of the genetic code by 1961:

1.

Three nucleotides encode an amino acid. Proteins are built from a basic set of 20 amino acids, but there are only four bases. Simple calculations show that a minimum of three bases is required to encode at least 20 amino acids. Genetic experiments showed that an amino acid is in fact encoded by a group of three bases, or codon.

2.

The code is nonoverlapping. Consider a base sequence ABCDEF. In an overlapping code, ABC specifies the first amino acid, BCD the next, CDE the next, and so on. In a nonoverlapping code, ABC designates the first amino acid, DEF the second, and so forth. Genetics experiments again established the code to be nonoverlapping.

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3.

The code has no punctuation. In principle, one base (denoted as Q) might serve as a “comma” between groups of three bases.

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This is not the case. Rather, the sequence of bases is read sequentially from a fixed starting point, without punctuation.

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4.

The genetic code is degenerate. Some amino acids are encoded by more than one codon, inasmuch as there are 64 possible base triplets and only 20 amino acids. In fact, 61 of the 64 possible triplets specify particular amino acids and 3 triplets (called stop codons) designate the termination of translation. Thus, for most amino acids, there is more than one code word.

5.5.1. Major Features of the Genetic Code

All 64 codons have been deciphered (Table 5.4). Because the code is highly degenerate, only tryptophan and methionine are encoded by just one triplet each. The other 18 amino acids are each encoded by two or more. Indeed, leucine, arginine, and serine are specified by six codons each. The number of codons for a particular amino acid correlates with its frequency of occurrence in proteins.

Table 5.4. The genetic code.

Table 5.4

The genetic code.

Codons that specify the same amino acid are called synonyms. For example, CAU and CAC are synonyms for histidine. Note that synonyms are not distributed haphazardly throughout the genetic code (depicted in Table 5.4). An amino acid specified by two or more synonyms occupies a single box (unless it is specified by more than four synonyms). The amino acids in a box are specified by codons that have the same first two bases but differ in the third base, as exemplified by GUU, GUC, GUA, and GUG. Thus, most synonyms differ only in the last base of the triplet. Inspection of the code shows that XYC and XYU always encode the same amino acid, whereas XYG and XYA usually encode the same amino acid. The structural basis for these equivalences of codons will become evident when we consider the nature of the anticodons of tRNA molecules (Section 29.3.9).

What is the biological significance of the extensive degeneracy of the genetic code? If the code were not degenerate, 20 codons would designate amino acids and 44 would lead to chain termination. The probability of mutating to chain termination would therefore be much higher with a nondegenerate code. Chain-termination mutations usually lead to inactive proteins, whereas substitutions of one amino acid for another are usually rather harmless. Thus, degeneracy minimizes the deleterious effects of mutations. Degeneracy of the code may also be significant in permitting DNA base composition to vary over a wide range without altering the amino acid sequence of the proteins encoded by the DNA. The G + C content of bacterial DNA ranges from less than 30% to more than 70%. DNA molecules with quite different G + C contents could encode the same proteins if different synonyms of the genetic code were consistently used.

5.5.2. Messenger RNA Contains Start and Stop Signals for Protein Synthesis

Messenger RNA is translated into proteins on ribosomes, large molecular complexes assembled from proteins and ribosomal RNA. How is mRNA interpreted by the translation apparatus? As already mentioned, UAA, UAG, and UGA designate chain termination. These codons are read not by tRNA molecules but rather by specific proteins called release factors (Section 29.4.4). Binding of the release factors to the ribosomes releases the newly synthesized protein. The start signal for protein synthesis is more complex. Polypeptide chains in bacteria start with a modified amino acid—namely, formylmethionine (fMet). A specific tRNA, the initiator tRNA, carries fMet. This fMet-tRNA recognizes the codon AUG or, less frequently, GUG. However, AUG is also the codon for an internal methio-nine residue, and GUG is the codon for an internal valine residue. Hence, the signal for the first amino acid in a prokaryotic polypeptide chain must be more complex than that for all subsequent ones. AUG (or GUG) is only part of the initiation signal (Figure 5.32). In bacteria, the initiating AUG (or GUG) codon is preceded several nucleotides away by a purine-rich sequence that base-pairs with a complementary sequence in a ribosomal RNA molecule (Section 29.3.4). In eukaryotes, the AUG closest to the 5′ end of an mRNA molecule is usually the start signal for protein synthesis. This particular AUG is read by an initiator tRNA conjugated to methionine. Once the initiator AUG is located, the reading frame is established—groups of three nonoverlapping nucleotides are defined, beginning with the initiator AUG codon.

Figure 5.32. Initiation of Protein Synthesis.

Figure 5.32

Initiation of Protein Synthesis. Start signals are required for the initiation of protein synthesis in (A) prokaryotes and (B) eukaryotes.

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5.5.3. The Genetic Code Is Nearly Universal

Image tree.jpg Is the genetic code the same in all organisms? The base sequences of many wild-type and mutant genes are known, as are the amino acid sequences of their encoded proteins. In each case, the nucleotide change in the gene and the amino acid change in the protein are as predicted by the genetic code. Furthermore, mRNAs can be correctly translated by the proteinsynthesizing machinery of very different species. For example, human hemoglobin mRNA is correctly translated by a wheat germ extract, and bacteria efficiently express recombinant DNA molecules encoding human proteins such as insulin. These experimental findings strongly suggested that the genetic code is universal.

A surprise was encountered when the sequence of human mitochondrial DNA became known. Human mitochondria read UGA as a codon for tryptophan rather than as a stop signal (Table 5.5). Furthermore, AGA and AGG are read as stop signals rather than as codons for arginine, and AUA is read as a codon for methionine instead of isoleucine. Mitochondria of other species, such as those of yeast, also have genetic codes that differ slightly from the standard one. The genetic code of mitochondria can differ from that of the rest of the cell because mitochondrial DNA encodes a distinct set of tRNAs. Do any cellular protein-synthesizing systems deviate from the standard genetic code? Ciliated protozoa differ from most organisms in reading UAA and UAG as codons for amino acids rather than as stop signals; UGA is their sole termination signal. Thus, the genetic code is nearly but not absolutely universal. Variations clearly exist in mitochondria and in species, such as ciliates, that branched off very early in eukaryotic evolution. It is interesting to note that two of the codon reassignments in human mitochondria diminish the information content of the third base of the triplet (e.g., both AUA and AUG specify methionine). Most variations from the standard genetic code are in the direction of a simpler code.

Table 5.5. Distinctive codons of human mitochondria.

Table 5.5

Distinctive codons of human mitochondria.

Why has the code remained nearly invariant through billions of years of evolution, from bacteria to human beings? A mutation that altered the reading of mRNA would change the amino acid sequence of most, if not all, proteins synthesized by that particular organism. Many of these changes would undoubtedly be deleterious, and so there would be strong selection against a mutation with such pervasive consequences.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2002, W. H. Freeman and Company.
Bookshelf ID: NBK22358

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