A protein synthesis inhibitor is a substance which stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins.[1]
While a broad interpretation of this definition could be used to describe nearly any antibiotic, in practice it usually refers to substances that act at the ribosome level (either the ribosome itself or the translation factor),[2] taking advantages of the major differences between prokaryotic and eukaryotic ribosome structure.
Toxins such as ricin also function via protein synthesis inhibition.[3] Ricin acts at the eukaryotic 60S.[4]
Examples:
- Neomycin
- Geneticin, also called G418
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Mechanism
Protein synthesis inhibitors generally work at different stages of prokaryotic mRNA translation into proteins, like initiation, elongation (including aminoacyl tRNA entry, proofreading, peptidyl transfer and ribosomal translocation) and termination:
Earlier stages
- Rifampicin inhibits prokaryotic DNA transcription into mRNA by inhibiting DNA-dependent RNA polymerase by binding its beta-subunit.
Initiation
- Linezolid acts at the initiation stage,[5] probably by preventing the formation of the initiation complex, although the mechanism is not fully understood.[6]
Aminoacyl tRNA entry
- Tetracyclines and Tigecycline[7] (a glycylcycline related to tetracyclines) block the A site on the ribosome, preventing the binding of aminoacyl tRNAs.
Proofreading
- Aminoglycosides, among other potential mechanisms of action, interfere with the proofreading process, causing increased rate of error in synthesis with premature termination.[8]
Peptidyl transfer
- Chloramphenicol blocks the peptidyl transfer step of elongation on the 50s ribosomal subunit in both bacteria and mitochondria.
- Macrolides (as well as inhibiting ribosomal translocation[9] and other potential mechanisms) bind to the 50s ribosomal subunits, inhibiting peptidyl transfer.
- Quinupristin/dalfopristin act synergistically, with dalfopristin enhancing the binding of quinupristin, as well as inhibiting peptidyl transfer.[10] Quinupristin binds to binds to a nearby site on the 50S ribosomal subunit and prevents elongation of the polypeptide,[10] as well as causing incomplete chains to be released.[10]
Ribosomal translocation
- Clindamycin,[11] among other potential mechanisms.[12]
- Aminoglycosides[8] and macrolides[9] among other potential mechanisms of action, have evidence of inhibition of ribosomal translocation.
- Fusidic acid prevents the turnover of elongation factor G (EF-G) from the ribosome.
Termination
- Puromycin has a structure similar to the tyrosinyl aminoacyl-tRNA. Thus, it binds to the ribosomal A site and participates in peptide bond formation, producing peptidyl-puromycin. However, it does not engage in translocation and quickly dissociates from the ribosome causing a premature termination of polypeptide synthesis.
- Macrolides[13][14] and clindamycin[13][14] (both also having other potential mechanisms) cause premature dissociation of the peptidyl-tRNA from the ribosome.
See also
References
- ^ "Definition: protein synthesis inhibitor from Online Medical Dictionary". http://cancerweb.ncl.ac.uk/cgi-bin/omd?protein+synthesis+inhibitor.
- ^ "MIT OpenCourseWare". http://ocw.mit.edu/OcwWeb/Biology/7-344Spring-2007/LectureNotes/index.htm.
- ^ Leonard JE, Grothaus CD, Taetle R (October 1988). "Ricin binding and protein synthesis inhibition in human hematopoietic cell lines". Blood 72 (4): 1357–63. PMID 3167211. http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=3167211.
- ^ Terao K, Uchiumi T, Endo Y, Ogata K (June 1988). "Ricin and alpha-sarcin alter the conformation of 60S ribosomal subunits at neighboring but different sites". Eur. J. Biochem. 174 (3): 459–63. doi:. PMID 3391162. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0014-2956&date=1988&volume=174&issue=3&spage=459.
- ^ Swaney SM, Aoki H, Ganoza MC, Shinabarger DL (December 1998). "The oxazolidinone linezolid inhibits initiation of protein synthesis in bacteria". Antimicrob. Agents Chemother. 42 (12): 3251–5. PMID 9835522. PMC 106030. http://aac.asm.org/cgi/pmidlookup?view=long&pmid=9835522.
- ^ Skripkin E, McConnell TS, DeVito J, et al. (October 2008). "Rχ-01, a new family of oxazolidinones that overcome ribosome-based linezolid resistance". Antimicrobial Agents and Chemotherapy 52 (10): 3550–7. doi:. PMID 18663023.
- ^ Slover CM, Rodvold KA, Danziger LH (June 2007). "Tigecycline: a novel broad-spectrum antimicrobial". Ann Pharmacother 41 (6): 965–72. doi:. PMID 17519296. http://www.medscape.com/viewarticle/557981_2. Retrieved 2009-12-19.
- ^ a b Pharmamotion --> Protein synthesis inhibitors: aminoglycosides mechanism of action animation. Classification of agents Posted by Flavio Guzmán on 12/08/08
- ^ a b Protein synthesis inhibitors: macrolides mechanism of action animation. Classification of agents Pharmamotion. Author: Gary Kaiser. The Community College of Baltimore County. Retrieved on July 31, 2009
- ^ a b c Page 212 in: Title: Hugo and Russell's pharmaceutical microbiology Authors: William Barry Hugo, Stephen P. Denyer, Norman A. Hodges, Sean P. Gorman Edition: 7, illustrated Publisher: Wiley-Blackwell, 2004 ISBN 0632064676 Length: 481 pages
- ^ Wisteria Lane cases --> CLINDAMYCIN University of Michigan. Retrieved on July 31, 2009
- ^ "Lincosamides, oxazolidinones, and streptogramins". Merck Manual of Diagnosis and Therapy. Merck & Co.. July 2009. http://www.merck.com/mmpe/print/sec14/ch170/ch170g.html. Retrieved 2009-12-19.
- ^ a b Menninger JR (1995). "Mechanism of inhibition of protein synthesis by macrolide and lincosamide antibiotics". J Basic Clin Physiol Pharmacol 6 (3-4): 229–50. PMID 8852269.
- ^ a b Tenson T, Lovmar M, Ehrenberg M (July 2003). "The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome". J. Mol. Biol. 330 (5): 1005–14. doi:. PMID 12860123.
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