Structural Requirements for Puromycin Inhibition of Protein Synthesis

Nathans, Daniel; Neidle, Amos

doi:10.1038/1971076a0

Cited by 197 publications

(79 citation statements)

References 13 publications

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“…I n their pioneering work, Nathans and Neidle [6] and later Symons, Harris, Clarke, Wheldrake and Elliot [28] observed that protein synthesis is inhibited only by those derivatives of puromycin which contain a p-methoxyphenylalanine or a phenylalanine residue while derivatives with a different amino acid were practically inactive. A similar conclusion was reached by Waller et al [9].…”

Section: Products Of the L'ransfer Reactimmentioning

confidence: 99%

Substrate Specificity of Ribosomal Peptidyl Transferase

Rychlík

Černá

Chládek

et al. 1970

European Journal of Biochemistry

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The effect of the nature of the amino acid residue on the acceptor activity of substrates of ribosomal peptidyl transferase was investigated. We tested 2′(3′)‐O‐aminoacyladenosines containing the following amino acid residues: l‐alanine, l‐glutamine, glycine, l‐3‐(1‐benzyl‐4‐imidazolyl)‐alanine, l‐leucine, l‐lysine, l‐methionine, l‐methionine S‐oxide, l‐phenylalanine, d‐phenylalanine, l‐proline, l‐serine and l‐valine as acceptors of the acylaminoacyl residue transferred from peptidyl‐tRNA. The acceptor activity of these compounds was dependent on the nature of the side chain of the amino acid residues bound to adenosine. The acceptor activity was also affected by the nature of the donor tRNA derivative. With l‐acetylphenylalanyl‐tRNA or l‐acetylleucine npetanucleotide fragments derived from l‐acetylleucyl‐tRNA donating the acetylphenylalanyl and the acetylleucyl residue, respectively, a high acceptor activity was shown by the basic 2′(3′)‐O‐l‐lysyladenosine or 2′(3′)‐O‐l‐3‐(1‐benzyl‐4‐imidazolyl)‐alanyladenosine which acted only as weak acceptors of lysine peptides from (Lys)n‐tRNA. The transfer reaction catalyzed by peptidyl transferase was stereospecific with respect to acceptor substrates. The acylaminoacyl residue was transferred from tRNA to 2′(3′)‐O‐l‐phenylalanyladenosine, whereas 2′(3′)‐O‐d‐phenylalanyladenosine, containing a d‐phenylalanine residue, was completely inactive as acceptor.

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Section: Products Of the L'ransfer Reactimmentioning

confidence: 99%

Substrate Specificity of Ribosomal Peptidyl Transferase

Rychlík

Černá

Chládek

et al. 1970

European Journal of Biochemistry

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“…Thus, it follows that the high affinity constant of C-d2'A-Phe (IIIa) is responsible for the efficient interaction of this compound with the peptidyltransferase center. High inhibitory activity of puromycin derivatives of aromatic amino acids in polypeptide synthesis or more specifically the high acceptor activity of 2'(3')-O-aminoacyladenosines with aromatic amino acids have been already noted [22,23]. As was first suggested by Rychlik et LIZ.…”

Section: Discussionmentioning

confidence: 53%

“…Thus, it has been observed that chloramphenicol inhibits poorly poly(U)- coded poly(Phe) synthesis, whereas copolymer-coded polypeptide synthesis is inhibited readily [24]. Likewise, puromycin inhibits most powerfully incorporation of proline and least powerfully that of phenylalanine [22]. These observations can be reasonably explained by different affinities of the aminoacyl termini of aa-tRNA for the peptidyltransferase A-site (but see also [25]).…”

Section: Discussionmentioning

confidence: 72%

Inhibition of Chloramphenicol Binding to Escherichia coli 70‐S Ribosomes by 2′(3′)‐O‐Aminoacyl‐dinucleoside Phosphates Derived from the Aminoacyl‐tRNA Acceptor Terminus

Goldberg

Ringer

Chládek

1977

European Journal of Biochemistry

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The effect of 2′ and 3′‐O‐aminoacyl‐dinucleoside phosphates cytidylyl(3′‐5′)‐2′(3′)‐O‐l‐phenylalanyladenosine (I), cytidylyl(3′‐5′)‐3′‐deoxy‐2′‐O‐l‐phenylalanyladenosine (IIa), cytidylyl(3′‐5′)‐2′‐deoxy‐3′‐O‐l‐phenylalanyladenosine (IIIa), cytidylyl(3′‐5′)‐3′‐deoxy‐2′‐O‐glycyladenosine (IIb), cytidylyl(3′‐5′)‐2′‐deoxy‐3′‐O‐glycyladenosine (IIIb), cytidylyl(3′‐5′)‐3′‐deoxy‐2′‐O‐l‐leucyladenosine (IIc), cytidylyl(3′‐5′)‐2′‐deoxy‐3′‐O‐l‐leucyladenosine (IIIc), cytidylyl(3′‐5′)‐3′‐O‐methyl‐2′‐O‐l‐phenylalanyladenosine (IId) and cytidylyl(3′‐5′)‐2′‐O‐methyl‐3′‐O‐l‐phenylalanyladenosine (IIId) as analogs of the 2′(3′)‐aminoacyl‐tRNA termini, on chloramphenicol binding to 70‐S Escherichia coli ribosomes was investigated. The association constants (Kb) of the investigated compounds were determined by the equilibrium dialysis method. Based on the constancy of Kb over the range of inhibitor concentration, it was determined that the binding site of the 2′ isomers IIa–IIc overlaps with the chloramphenicol site, whereas the variability of Kb for the 3′ isomers IIIb, IIIc and especially IIIa seems to indicate that they do not achieve a complete fit. The consistently higher values of the Kb values for the 3′ isomers IIIa–IIIc relative to that of the 2′ isomers IIa–IIc also indicate a stabilization of the binding of the former due to a specific interaction between its amino acid portion and a ribosomal site.

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“…The analogs of aromatic amino acids, L-phenylalanine and L-tyrosine were most effective [6-81, and those with 0-benzyl+serine, S-benzyl-Lcysteine [7,8], L-homocitrulline [9] and L-lysine [lo] were moderately active, whereas the analogs of other amino acids were almost inactive. The optical configuration of the amino acids was also important since the D-phenylalanyl analog was far less active than the L-isomer [6].…”

Section: Introductionmentioning

confidence: 99%

Adaptability of nonnatural aromatic amino acids to the active center of the E. coli ribosomal A site

et al. 1993

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-Aminoacyl analogs of puromycin with nonnatural aromatic amino acids were synthesized and their inhibitory activity in E. coli in vitro protein synthesizing system was evaluated. The analogs with L-2-naphthylalanine, L-p-biphenylalanine, L-2-anthrylalanine and trans+p-phenylazophenylalanine were found to inhibit the protein synthesis with high efficiency. The inhibition suggests that these nonnatural amino acids are accepted by the active center of the E. coli ribosomal A site. A model for the adaptability of nonnatural aromatic amino acids to the active center is proposed.

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Structural Requirements for Puromycin Inhibition of Protein Synthesis

Cited by 197 publications

References 13 publications

Substrate Specificity of Ribosomal Peptidyl Transferase

Substrate Specificity of Ribosomal Peptidyl Transferase

Inhibition of Chloramphenicol Binding to Escherichia coli 70‐S Ribosomes by 2′(3′)‐O‐Aminoacyl‐dinucleoside Phosphates Derived from the Aminoacyl‐tRNA Acceptor Terminus

Adaptability of nonnatural aromatic amino acids to the active center of the E. coli ribosomal A site

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