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The circularDNA of c/>X174 contains nine genes (A to J). Gene Blies within the sequence of gene A but uses a different reading frame. Similarly, gene E lies withingene D and also uses a different reading frame (seeFig. 26-11). The unshaded segments are untranslated spacer regions.Reading frame for gene DReading frame for gene E5'Although only one reading frame is generally used to encode aprotein and genes do not overlap, there are a few interesting exceptions.
In several viruses the same DNA base sequence codes for twodifferent proteins by employing two different reading frames. The discovery of such "genes within genes" arose from the observation that theDNA of bacteriophage c/>X174, which contains 5,386 nucleotide residues, is not long enough to code for the nine different proteins that areknown to be the products of the </>X174 DNA genome, unless the genesoverlap. The entire nucleotide sequence of the c/>X174 chromosome wascompared with the amino acid sequences of the proteins encoded by the(f)X114 genes; this indicated several overlapping gene sequences.
Figure 26-10 shows that genes B and E are nested within A and D, respectively. There are also five cases (not shown) in which the initiationcodon of one gene overlaps the termination codon of the other gene.Figure 26-11 shows how genes D and E share a segment of DNA butuse different reading frames; a similar situation exists for genes A andB. The sum of all the nested and overlapping sequences accounts completely for the surprisingly small size of the c/>X174 genome comparedwith the number of amino acid residues in the nine proteins for whichit codes.Val Glu Ala Cys Val Tyr Gly Thr Leu - Asp Phe|G U U\\G~A G\\G C U][U G C|[G U U[[U A "tj|[G G U[|A C GJlC U~G||G A C l | U U U|[G - - - 3G U U G A G G CFigure 26—11 Portion of the nucleotide sequence ofthe mRNA transcript of gene D of <£X174 DNA,showing how gene E, which is nested within geneD, is coded by a different reading frame from thatused by gene D.U U G C G U UU [A U G|[G U Aj[C~G Cl|U G G]|A C U|[U U G [ - - Met — Val — Arg — Trp — Thr — LeuThis discovery was quickly followed by similar observations inother viral DNAs, including those of phage A, the cancer-causing simian virus 40 (SV40), RNA phages such as Q/3 and Q17, and phage G4, aclose relative of c/>X174.
Phage G4 is remarkable in that at least onecodon is shared by three different genes. It has been suggested thatoverlapping genes or genes within genes may be found only in virusesbecause the fixed, small size of the viral capsid requires economical useof a limited amount of DNA to code for the variety of proteins needed toinfect a host cell and replicate within it. Also, because viruses reproduce (and therefore evolve) faster than their host cells, they may represent the ultimate in biological streamlining.The genetic code is nearly universal.
With the intriguing exception of a few minor variations that have been found in mitochondria,some bacteria, and some single-celled eukaryotes (Box 26-2, p. 906),amino acid codons are identical in all species that have been examined.Human beings, E. coli, tobacco plants, amphibians, and viruses sharethe same genetic code. Thus it would appear that all life forms had acommon evolutionary ancestor with a single genetic code that has beenvery well preserved throughout the course of biological evolution.The genetic code tells us how protein sequence information isstored in nucleic acids and provides some clues about how that information is translated into protein. We now turn to the molecular mechanisms of the translation process.Chapter 26 Protein MetabolismProtein SynthesisAs we have seen for DNA and RNA, the synthesis of polymeric biomolecules can be separated into initiation, elongation, and terminationstages.
Protein synthesis is no exception. The activation of amino acidprecursors prior to their incorporation into polypeptides and the posttranslational processing of the completed polypeptide constitute twoimportant and especially complex additional stages in the synthesis ofproteins, and therefore require separate discussion. The cellular components required for each of the five stages inE. coli and other bacteriaare listed in Table 26-6. The requirements in eukaryotic cells are quitesimilar. An overview of these stages will provide a useful outline forthe discussion that follows.Table 26—6 Components required for the five major stages in proteinsynthesis in E.
coliStageNecessary components1. Activation ofamino acids20 amino acids20 aminoacyl-tRNA synthetases20 or more tRNAsATPMg2+mRNAiV-Formylmethionyl-tRNAInitiation codon in mRNA (AUG)30S ribosomal subunit50S ribosomal subunitInitiation factors (IF-1, IF-2, IF-3)GTPMg2+Functional 70S ribosome (initiation complex)Aminoacyl-tRNAs specified by codonsElongation factors (EF-Tu, EF-Ts, EF-G)Peptidyl transferaseGTPMg2+Termination codon in mRNAPolypeptide release factors (RFb RF2, RF3)ATPSpecific enzymes and cofactors for removal ofinitiating residues and signal sequences, additionalproteolytic processing, modification of terminalresidues, attachment of phosphate, methyl, carboxyl,carbohydrate, or prosthetic groups2.
Initiation3. Elongation4. Terminationand release5. Folding andprocessingStage 1: Activation of Amino Acids During this stage, which takesplace in the cytosol, not on the ribosomes, each of the 20 amino acids iscovalently attached to a specific tRNA at the expense of ATP energy.These reactions are catalyzed by a group of Mg 2+ -dependent activatingenzymes called aminoacyl-tRNA synthetases, each specific for oneamino acid and its corresponding tRNAs. Where two or more tRNAsexist for a given amino acid, one aminoacyl-tRNA synthetase generallyaminoacylates all of them. Aminoacylated tRNAs are commonly referred to as being "charged."906Part IV Information PathwaysBOX 26-2Natural Variations in the Genetic CodeIn biochemistry, as in other disciplines, exceptionsto general rules can be problematic for educatorsand frustrating for students.
At the same time theyteach us that life is complex and inspire us tosearch for more surprises. Understanding the exceptions can even reinforce the original rule in surprising ways.It would seem that there is little room for variation in the genetic code. Recall from Chapters 6and 7 that even a single amino acid substitutioncan have profoundly deleterious effects on thestructure of a protein. Suppose that somewherethere was a bacterial cell in which one of the codons specifying alanine suddenly began specifyingarginine; the resulting substitution of arginine foralanine at multiple positions in scores of proteinswould unquestionably be lethal.
Variations in thecode occur in some organisms nonetheless, andthey are both interesting and instructive. The veryrarity of these variations and the types of variations that occur together provide powerful evidence for a common evolutionary origin of all livingthings.The mechanism for altering the code is straightforward: changes must occur in one or moretRNAs, with the obvious target for alterationsbeing the anticodon. This will lead to the systematic insertion of an amino acid at a codon that doesnot specify that amino acid in the normal code (Fig.26-7).
The genetic code, in effect, is defined by theanticodons on tRNAs (which determine where anamino acid is placed in a growing polypeptide) andby the specificity of the enzymes—aminoacyl-tRNA synthetases—that charge the tRNAs(which determine the identity of the amino acidattached to a given tRNA).Because of the catastrophic effects most suddencode changes would have on cellular proteins, onemight predict that code alterations would occuronly in cases where relatively few proteins wouldbe affected. This could happen in small genomesencoding only a few proteins. The biological consequences of a code change could also be limited byrestricting changes to the three termination codons, because these do not generally occur withingenes (see Box 26-1 for exceptions to this rule).
Achange that converts a termination codon to acodon specifying an amino acid will affect termination in the products of only a subset of genes, andsometimes the effects in those genes will be minorbecause some genes have multiple (redundant) termination codons. This pattern is in fact observed.Changes in the genetic code are very rare. Mostof the characterized code variations occur in mitochondria, whose genomes encode only 10 to 20 proteins.
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