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Inhibitors of Protein Synthesis Volume 40, Supplement FEBS LETTERS 23 March 1974 INHIBITORS OF PROTEIN SYNTHESIS D. VAZQUEZ Instituto de Biologia Celular, Velazquez 144, Madrid-6, Spain Received 16 January 1974 1. Introduction the specific aminoacyl-tRNA synthetase, is a complex reaction involving the steps of activation and transfer: Studies on the mode of action of protein synthesis inhibitors can be chronologically divided into two Activation: periods. The first period covers the years 1951-1960 Amino -adid1 + Enzyme I t ATP Ms Enzyme 1- and the second from 1961 until 1973. We make this chronological distinction because specific inhibition aminoacyll -AMP + PPi of bacterial protein synthesis by antibiotics (chlor- amphenicol and chlortetracycline) was first described Transfer: in 195 1 [ 1,2] and confirmed in a ribosomal amino acid incorporation system directed by a specific syn- Enzyme 1-aminoacyl 1-AMP + tRNA 1 2 aminoacyl 1- thetic polynucleotide as mRNA, in 1961 [3] . Since tRNAi t Enzyme, + AMP 1961 studies on the mechanisms of antibiotic action have been so widely developed [4-6; reviews] that it Inhibitors of these reactions have been recently became practically impossible to cover the subject in reviewed [ 131. A number of amino acid analogues a single contribution, and protein synthesis inhibitors have been reported as inhibitors of the activation have usually been dealt with for the last eight years reaction by the corresponding aminoacyl-tRNA syn- either in independent contributions or even in entire thetases. Included in this group are 7-azatryptophan, volumes [7- 121. This study will be concerned main- tryptazan, 6-fluorotryptophan and 5-fluorotryp- ly with advances in our knowledge of the mode of tophan [ 141, norvaline, cu-amino-/3-chlorobutyrate, action, selectivity, and specificity of inhibitors of cw-aminobutyrate, selenomethionine, ethionine, nor- protein synthesis over the last ten years. However, a leucine [15-l 71, a number of tyrosine analogues complete survey of the literature would not be [18], the methyl and ethyl esters of serine [ 191 and possible in such a brief contribution as this. certain lysine analogues [20]. Some competitive The process of protein biosynthesis can be arbi- inhibitors of certain amino acid(s) in the activation trarily divided, for didactic purposes, into (a) steps step become attached to tRNA in the transfer reac- taking place prior to translation and (b) steps in the tion and abnormal proteins are formed in subsequent translation mechanisms taking place at the ribosome incorporation. This has been observed with ethionine, level. norleucine [ 17,21,22], alloisoleucine, azetidine- carboxylic acid, canavanine, N-ethylglycine and O-methyl threonine [ 131. On the other hand, a num- 2. Inhibitors of steps taking place prior to translation ber of competitive inhibitors of amino acid activation block the formation of a specific aminoacyl-tRNA. 2.1. Inhibitors of aminoacyl-tRNA formation This is so with the antibiotics borrelidin, which has been shown to prevent threonyl-tRNA formation in a The synthesis of aminoacyl-tRNA, catalysed by number of bacterial species [23,27], and furano- North-Holland Publishing Company - Amsterdam S63 Volume 40, Supplement FEBSLETTERS 23 March 1974 mycin, which inhibits isoleucyl-tRNA formation in tion can take place by blocking either N”-formyl-H4 bacterial and mammalian cells [25,26], whereas folate formation or the transformylase. minosine likewise blocks phenylalanyl-tRNA synthe- N” -Formyl-H4 folate synthesis is inhibited by a sis [27]. Similarly, ten aminoalkyl-adenylates have number of dihydrofolate analogues such as amino- been synthesized and shown to compete specifically pterin, amethopterin (synonym methotrexate) and with their corresponding amino acids and with ATP pteroylaspartic acid. Aminopterin has indeed been in the activation step, whereas their amino alcohols shown to block the f-Met-tRNAF required for initia- are, by themselves, inert competitive inhibitors of tion of protein synthesis in mitochondria without both amino acid activation and the transfer step affecting cytoplasmic protein synthesis in mammalian [28,29]. cells [31]. Because of the permeability barriers for An increasing number of oligonucleotides and these drugs in a number of organisms, simpler com- polynucleotides have been used as analogues of some pounds have been synthesized, including pyrimeth- parts of the tRNA molecule to inhibit aminoacyl- amine and trimethoprim [32]. Indeed, in E. coli tRNA formation since Hayashi and Miura [30] ob- trimethoprim blocks the synthesis of &galactosidase served that some rRNA-derived oligonucleotides and phage Tq proteins. inhibit valyl-tRNA formation. There are abundant Furthermore, extracts of trimethoprim-treated data in this field reporting competitive inhibition of bacteria require the addition of f-Met-tRNAP to specific aminoacyl-tRNA formation by certain poly- initiate protein synthesis [33,34] . 6-Chloro-8-aza-9- nucleotides. However, there are many contradictory cyclopentylpurine and a number of related com- reports, probably owing to uncertainty about the pounds are also inhibitors of N” -formyl-H4 folate purity of nucleotides and aminoacyl-tRNA synthetases formation, and therefore block DNA, RNA and pro- used, a point which is discussed elsewhere [ 131. tein synthesis in E. coli [35,36]. From the data presented above it is obvious that The catalytic action of the N” -formyl-H4 folate- some of the known inhibitors of aminoacyl-tRNA methionyl-tRNAF transformylase can be inhibited by formation may useful for studying individual reac- either N” -formyl-H4 folate analogues, of Met-tRNA, tions in some purified cell-free systems, but in most analogues, or compounds which deplete the pool of cases they have neither a specific effect on this step the substrates of the reaction. Indeed, a number of nor a selective action on certain types of cells, nor pteridine derivatives have been shown to block the can they even be used with intact cells. Therefore formylation reaction by competing with Ni”-formyl- their importance as protein synthesis inhibitors is not H4 folate [37,38]. very great, with the possible exception of some amino Hydroxylamine is known to block DNA, RNA and acid analogues, minosine [27] and the antibiotics protein synthesis, but when added at low concentra- borrelidin [23,24] and furanomycin [25,26]. tions to growing bacterial cultures, it specifically blocks the initiation phase of protein synthesis [34]. 2.2. Inhibitors of f-Met-tRNAF formation This is due to the reaction of hydroxylamine with the formyl residue of 5,1 0-methylene-H4 folate, leading Biosynthesis of the initiator fV-formyl-Met-tRNAF to the formation of a folmaldoxine and depleting the takes place according to the reaction: pool of N” -formyl-H4 folate which is the precursor of 5,1 0-methylene-H4 folate [40] . Met-tRNAF+N”-formyl-H4 folateZJV-formyl-Met- Inhibitors of f-Met-tRNAF formation inhibit the tRNAF+H4 folate initiation of translation in bacteria, blue green algae, mitochondria and chloroplasts, but not in eukaryotic in which the o-NH2 group of the methionine of Met- systems, since f-Met-tRNAF is not an initiator in tRNAF is the acceptor group, the donor is Ni” - these systems. In any case, care has to be taken in the formyl-H4 folate and the enzyme catalysing the reac- use of inhibitors of dihydrofolate reductase and iV” - tion is N” -formyl-H4 folate-methionyl-tRNAF trans- formyl-H4 folate transformylase in intact bacteria as formylase. Hence, inhibition of f-Met-tRNAF forma- specific inhibitors of protein synthesis, since they can also block many other cell processes. S64 Volume 40, Supplement FEBS LETTERS 23 March 1974 3. Inhibitors of translation protein (figs. 1 and 2). There is evidence for only a single entry site in the small subunit, and therefore 3.1. Translation of mRNA for the codon-anticodon interaction of the incoming aminoacyl-tRNA (step (d)), the anticodon interaction The translation of mRNA into protein, which of either f-Met-tRNAF or peptidyl-tRNA in the small takes place at the ribosome level, can be divided into subunit has to be interrupted. The specific step of three phases: initiation, elongation and termination. peptide bond formation (step (e)) is catalysed by the The overall reactions taking place in the process of peptidyl transferase centre, which is an integral part translation by bacterial and eukaryotic ribosomes are of the larger ribosomal subunit. The translocation shown schematically in figs. 1 and 2, according to the step requires one of the elongation factors and in- translocation mode with one single entry site on the volves movement of the peptidyl-tRNA from the small subunit. A-site to the P-site, coupled with GTP hydrolysis and A single entry site on the small ribosome subunit is release of the uncharged tRNA. favoured in studies with a number of protein synthe- The termination phase takes place when a chain- sis inhibitors, since all these compounds preventing terminating codon (nonsense codon) (either UAA or mRNA-directed f-Met-tRNAF binding to the small UAG or UGA) is recognized and cleavage of the bond ribosome subunit (step (b)) are equally active in between the peptidyl and tRNA moieties takes place preventing aminoacyl-tRNA binding (step (d)). For in a reaction catalysed by the ribosomal peptidyl the purpose of understanding the whole process, it transferase centre requiring the release factors (g). can be divided into three phases: initiation, elonga- tion and termination (figs. 1 and 2). 3.2. Selectivity of protein synthesis inhibitors In the initiation phase we have to distinguish three steps: (a) recognition of initiation factors and mRNA Early studies on [14 Clchloramphenicol binding by the small subunit, (b) binding of the initiator and showed that this antibiotic binds to all classes of (c)joining to the complex of the larger subunit ribosomes of the 70 S type which were tested, but (fig. 1). does not bind to any of the 80 S type ribosomes This step (c) involves two reactions; in the first, studied [43].
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