A. Antibodies to RF1 and RF2
VII. OTHER INHIBITORS
A. Colicin E3
Colicins are bacterial killing agents produced by certain strains of Enterobacteriaceae which carry extrachromosomal elements (218). These
bacteriocidal proteins are several in number and vary in their mechanism of cytotoxicity. For example, colicins K and El inhibit transport systems, RNA, DNA, and protein biosynthesis. Colicin E2 causes DNA degrada
tion and E3 specifically inhibits protein synthesis. Approximately 100 molecules of E3 are required for the kill of a sensitive bacterium.
The mechanism of inhibition of protein synthesis by colicin E3 has been the focus of interest of several laboratories. Early studies using radioactive colicin E2 and K indicated that 90 and 60%, respectively, of the colicin added was bound to the cell wall and membrane fraction
(219). Identical studies with E3 were not performed, but since trypsin treatment of cells did not reduce the action of E3 it was suspected that E3 either penetrated the membrane or became attached to the mem
brane in a protected form. Recent in vitro studies have clarified this situation (220).
Colicin E3 exerts its inhibitory effect on protein biosynthesis by inacti-vation of the 30 S ribosomal subunit (220, 221). Detailed study of the modified 30 S ribosomal subunit indicated that the 16 S RNA component of this particle had undergone a specific cleavage, which yielded a frag
ment of about 50 nucleotides in length (E3 fragment) and the E3 16 S RNA or remainder of the 16 S molecule. This identical cleavage has recently been achieved in vitro by purified E3 (222, 223). Furthermore, purified E3 was shown to directly inactivate purified 70 S ribosomal par
ticles with respect to polymerization of phenylalanine directed by poly U.
The cleavage was found to require the 50 S ribosomal subparticle although no detectable modification was apparent. Earlier studies of this type had indicated that colicin E3 had no in vitro effect on the 30 S ribosomal subparticle. These discrepancies are now adequately ex
plained by the finding of an inhibitor of E3 in the crude preparation used in the early studies. Purification of E3 removes the inhibitor and thus permits in vitro study. The inhibitor of E3 is found in extracts of colicinogenic cells with immunity to E3 and not in extracts of sensitive cells. On this basis it has been suggested that immunity factor" cor
responds to this substance (222, 223). The precise manner in which
"immunity factor" blocks the action of E3 is not known.
The precise intermediate step(s) in protein biosynthesis affected by E3-promoted cleavage of the 30 S ribosomal subunit RNA are not de
fined. Furthermore, an enzymic activity of E3 has not been demonstrated although the data strongly suggest that it is either an RNase or activator of a ribosomal RNase. The effect of E3 on eukaryotic cells has not been reported.
B. GDPCP
Protein biosynthesis requires GTP and its y-phosphate hydrolysis in a variety of intermediate steps. While the actual number of GTP residues hydrolyzed per peptide bond formed is an actively debated issue, it is clear that each intermediate reaction requiring GTP hydrolysis is inhibited by GDPCP, which cannot undergo hydrolysis (1). This in
hibition occurs with eukaryotic and prokaryotic protein biosynthesis only, since GDPCP apparently does not cross mammalian or bacterial cell walls.
The analog GDPCP can substitute for GTP for ribosomal binding of fMet-tRNA with IF factors in bacteria (26). The fMet-tRNA-AUG-ribosome complex formed with GDPCP differs from that formed with
GTP since it does not react with puromycin to yield fMet-puromycin.
In analogous studies using EFTu and EF1 and aminoacyl-tRNA, GDPCP can stimulate ribosomal binding with appropriate mRNA templates. The aminoacyl-tRNA-mRNA-ribosome-peptidyl-tRNA com
plexes formed with GDPCP differ from those formed with GTP (40, 63). Complexes formed with GTP result in peptide chain extension while those formed with GDPCP do not form peptide bonds. Mam
malian RF similarly binds to reticulocyte ribosomes with GDPCP but does not promote peptide chain termination (46). In each of these cases a ribosomal GTPase reaction is essential for completion of the particular partial event in protein biosynthesis. Two possibilities have been suggested to explain these observations, (a) The GTPase reaction
"accommodates" or alters the recognition molecule on the ribosomal com
plex such that it is an activated form, or (b) the GTPase reaction dis
places from the ribosome soluble protein factors, which, when ribosomal bound, actually inhibit chain initiation, elongation, and termination. The GTPase reaction of EF2 and EFG associated with translocation is also inhibited by GDPCP (1). There is considerable evidence to suggest that this reaction may be catalyzed on the ribosome at a site that is near or identical to that of GTPase of the EFTu site (137).
The GTP analog GDPCP is an inhibitor of protein biosynthesis at all intermediate steps requiring GTP hydrolysis and thus is not a specific inhibitor. It is effective in both prokaryotic and eukaryotic cellular ex
tracts but not in whole cells.
VIII. SUMMARY
Protein biosynthesis is susceptible to inhibition by a variety of agents, which range from small molecules such as NaF to immunoglobulin against soluble factors. Since many affect ribosomal function, absolute specificity for a given intermediate step in protein biosynthesis is rare.
The inhibitors most frequently affect one step predominantly and, in minor ways, other steps. Until we have an understanding of the topo
graphy and function of ribosomal proteins it will be difficult to predict antibiotic effects. Conversely, the observed effects of antibiotics on inter
mediate steps in protein biosynthesis, coupled with molecular altera
tions of resistant ribosomes and factors, should allow a potent method of probing this ribosomal topography and function. The inhibitors dis
cussed are summarized in Table II.
T A B L E I I
INHIBITORS OF PROTEIN BIOSYNTHESIS
Component Pro Eu
Process Inhibitor affected karyotic karyotic
Initiation Aurintricarboxylic acid
30 or 40 S Subunit
+ +
Pactamycin 30 or 40 S Subunit
+ +
Kasugamycin 30 S Subunit
+
0N a F 40 S Subunit 0
+
Elongation
A m i n o a c y l - t R N A
binding Streptomycin 30 S Subunit
+
0Tetracycline 30 or 40 S Subunit
+ +
Edeine 30 S Subunit
+
0Translocation Fusidic acid E F G or EF1
+ +
A n t i - E F G E F G
+
0Diphtheria toxin E F 1 0
+
Both Thiostrepton 50 S Subunit
+
0Cycloheximide 60 S Subunit 0
+
Peptidyltransferase Chloramphenicol 50 S Subunit
+
0Erythromycin 50 S Subunit
+
0Lincomycin 50 S Subunit
+
0Gougerotin 50 or 60 S Subunit
+ +
Sparsomycin 50 or 60 S Subunit
+ +
Anisomycin 60 S Subunit 0
+
Termination Streptomycin 30 S Subunit
+
0Tetracycline 30 or 40 S Subunit
+ +
Chloramphenicol 50 S Subunit
+
0Erythromycin 50 S Subunit
+
0Lincomycin 50 S Subunit
+
0Gougerotin 50 and 60 S Subunits
+ +
Sparsomycin 50 and 60 S Subunits
+ +
Anisomycin 60 S Subunit 0
+
Premature chain Puromycin 50 or 60 S Subunit
+ +
termination Aminooligo
nucleosides
50 or 60 S Subunit
+ +
Other Colicin E3 30 S Subunit
+
0G D P C P 50 and 60 S Subunit
+
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