Harpers

372 / CHAPTER 38molecules. This difference is exploited for clinical purposesbecause many effective antibiotics interact specificallywith the proteins and RNAs of prokaryotic ribosomesand thus inhibit protein synthesis. This results ingrowth arrest or death of the bacterium. The most usefulmembers of this class of antibiotics (eg, tetracyclines,lincomycin, erythromycin, and chloramphenicol)do not interact with components of eukaryoticribosomal particles and thus are not toxic to eukaryotes.Tetracycline prevents the binding of aminoacyl-tRNAsto the A site. Chloramphenicol and the macrolide classof antibiotics work by binding to 23S rRNA, which isinteresting in view of the newly appreciated role ofrRNA in peptide bond formation through its peptidyltransferaseactivity. It should be mentioned that theclose similarity between prokaryotic and mitochondrialribosomes can lead to complications in the use of someantibiotics.tRNANNHOCH 2 OH HH HNH OHO C CH CH 2OO –PON(CH 3 ) 2NNH 2OCH 3NNNO CH 2 OH HH HO OHO C CH CH 2NH 2NH 2Figure 38–11. The comparative structures of the antibioticpuromycin (top) and the 3′ terminal portion oftyrosinyl-tRNA (bottom).NNOHOther antibiotics inhibit protein synthesis on all ribosomes(puromycin) or only on those of eukaryoticcells (cycloheximide). Puromycin (Figure 38–11) is astructural analog of tyrosinyl-tRNA. Puromycin is incorporatedvia the A site on the ribosome into the carboxylterminal position of a peptide but causes the prematurerelease of the polypeptide. Puromycin, as atyrosinyl-tRNA analog, effectively inhibits protein synthesisin both prokaryotes and eukaryotes. Cycloheximideinhibits peptidyltransferase in the 60S ribosomalsubunit in eukaryotes, presumably by binding to anrRNA component.Diphtheria toxin, an exotoxin of Corynebacteriumdiphtheriae infected with a specific lysogenic phage, catalyzesthe ADP-ribosylation of EF-2 on the uniqueamino acid diphthamide in mammalian cells. Thismodification inactivates EF-2 and thereby specificallyinhibits mammalian protein synthesis. Many animals(eg, mice) are resistant to diphtheria toxin. This resistanceis due to inability of diphtheria toxin to cross thecell membrane rather than to insensitivity of mouseEF-2 to diphtheria toxin-catalyzed ADP-ribosylationby NAD.Ricin, an extremely toxic molecule isolated from thecastor bean, inactivates eukaryotic 28S ribosomal RNAby providing the N-glycolytic cleavage or removal of asingle adenine.Many of these compounds—puromycin and cycloheximidein particular—are not clinically useful buthave been important in elucidating the role of proteinsynthesis in the regulation of metabolic processes, particularlyenzyme induction by hormones.SUMMARY• The flow of genetic information follows the sequenceDNA → RNA → protein.• The genetic information in the structural region of agene is transcribed into an RNA molecule such thatthe sequence of the latter is complementary to that inthe DNA.• Several different types of RNA, including ribosomalRNA (rRNA), transfer RNA (tRNA), and messengerRNA (mRNA), are involved in protein synthesis.• The information in mRNA is in a tandem array ofcodons, each of which is three nucleotides long.• The mRNA is read continuously from a start codon(AUG) to a termination codon (UAA, UAG, UGA).• The open reading frame of the mRNA is the series ofcodons, each specifying a certain amino acid, that determinesthe precise amino acid sequence of the protein.• Protein synthesis, like DNA and RNA synthesis, followsa 5′ to 3′ polarity and can be divided into three