Term
prokaryotes = 70s ribosomes with 2 subunits: 50s (large subunit) and 30s (small subunit)
eukaryotes = 80s ribosomes with 2 subunits: 60s (large subunit) and 40s (small subunit)
the size is different, but the process is the same.
difference in size leads to selective toxicity |
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Definition
| differences in the ribosomes of prokaryotes and eukaryotes |
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Term
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Definition
| the synthesis of proteins is the process of ( ) translation |
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Term
initiation
elongation
termination
in each stage a different set of protein factors is utilized by the ribosome. these factors cycle on and off the ribosome and allow the ribosome to interact with them sequentially at a single site |
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Definition
| protein synthesis is divided into what 3 stages? |
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Term
involves formation of an initiation complex
in bacteria, the first amino acid is formylmethionine
formylmethionine and its appropriate tRNA are first united under the direction of an aminoacyl-tRNA-synthetase to form the aminoacyl-tRNA
[image]
1st amino acid will bind to the initiation codon (on tRNA) and then the small subunit will bind to the complex which will be recognized by the large subunit. once this is formed, the ribosome is ready to start protein synthesis |
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Definition
| process of initiation of protein synthesis |
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Term
at the end of initiation the ribosome is ready to translate the reading frame associated with the initiation codon
elongation is accomplished by the sequential repetition of three reactions with each amino acid
[image] |
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Definition
| process of elongation of protein synthesis |
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Term
the elongation process continues until a termination sequence containing code triplets UAA, UGA, or UAG in the mRNA signals that the protein chain is complete
the terminal codon is not an aminoacyl-tRNA (as the elongation codons are)
the ribosome binds a protein called "terminal release factor" which recognizes the terminal codon in the A site
the peptidyl transferase works now as an esterase that releases the peptide
the ribosome dissociates (the small and large subunits go in different directions to take part in another protein synthesis) |
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Definition
| process of termination of protein synthesis |
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Term
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Definition
| are aminoglycosides considered bactericidal or bacteriostatic? |
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Term
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Definition
| what is the spectrum of aminoglycosides? |
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Term
[image]
multifunctional hydrophilic carbohydrates
aminocyclitol nucleus (3 nuclei)
polycationic compound
[image] |
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Definition
| general structure of aminoglycosides |
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Term
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Definition
| chemistry of streptidine derivatives |
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Term
strictly not an aminoglycoside
[image]
rings are fused instead of linked by a bridge |
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Definition
| chemistry of strepiniomycin |
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Term
neomycin = 4,5 disubstituted
[image]
gentamicin = 4,6 disubstituted
[image] |
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Definition
| chemistry of deoxystreptamine derivatives |
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Term
bactericidal and the killing effect DEPENDS ON THE CONCENTRATION OF THE DRUG
bind to the 30s ribosomal subunit (small subunit)
charge interactions with one edge
hydrophobic or stacking interactions with the other edge
transport through membranes: aminoglycosides diffuse through aqueous channels (porins in Gram -); electron transport (active transport) is needed to further transport the aminoglycosides across the cytoplasmic or inner membrane
residual effect
the killing effect: metabolic changes (cell permeability and transport), inhibition of protein synthesis, misreading the genetic code (this is why aminoglycosides are bactericidal as compared to other protein synthesis inhibitors)
[image]
[image]
aminoglycosides block the initiation of translation and causes misreading of mRNA |
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Definition
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Term
streptomycin interacts specifically with the 30s subunit that induces a conformational change in the ribosome
at low concentrations 70s subunits bind one molecule of streptomycin (other aminoglycosides do not bind the 70s subunit)
streptomycin's binding to the 30s subunit alone is weak
the binding site of streptomycin may be near the interface
its effect can be seen as an increased incorporation of "wrong" amino acids
in vivo can be seen as a "phenotypic suppression"
may be due to stabilization of the aminoacyl-tRNA binding to the A site of the ribosome
the distortion of codon recognition result in frequent insertion of the "wrong" amino acid |
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Definition
| how does the binding of streptomycin differ from other aminoglycosides and what is the effect of this binding? |
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Term
ribosomal resistance:
from mutations in genes coding for ribosomal proteins
Str A confer a high resistance to streptomycin
ribosomal resistance is not found in other aminoglycosides and is not relevant in most bacterial infections, relevant in mycobacteria
if there is bacterial resistance to streptomycin, you can still use other aminoglycosides
bacterial uptake:
it is by an active process
occurs in 3 phases: the 1st step is energy independent binding of the drug to cation binding sites; 2nd an energy dependent stage by which drug traverses the membrane (this phase is related to the low rate of accumulation); an energy dependent stage II starts after the aminoglycoside has bound to the ribosome
the bacteria can change any of these stages to decrease the uptake of aminoglycosides
decreased drug uptake:
anaerobic bacteria are intrinsically resistant to aminoglycosides: may be due to altered components of the membrane transport system
resistance due to decrease drug uptake if frequent in Pseudomonas aeruginosa
aminoglycoside modifying enzymes:
blocking drug uptake
inactivation of the drug so that it can no longer affect the ribosome
it is associated with bacterial cell membrane (enzymes no longer help in the movement of aminoglycosides to the active site)
several enzymes have been identified: O-phosphotransferase, O-nucleotidyltransferase, N-acetyltransferase
[image] |
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Definition
| bacterial resistance to aminoglycosides |
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Term
potent gram - activity
broad spectrum
kanamycin and streptomycin have limited spectrum compared with other aminoglycosides
synergistic activity with penicillins (penicillins weaken the cell wall which helps aminoglycosides get into the cell)
all the inhibitors of the cell wall are synergistic with aminoglycosides |
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Definition
| antibacterial activity of aminoglycosides |
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Term
absorption: highly polar compounds (1% is absorbed orally); oral administration is done to kill the bowel flora (local administration of the drug); they are absorbed well from IM administration; also found in topical therapy and wound irrigation
distribution: poorly distributed; excluded from the CNS (cannot pass BBB) and eyes; little or no binding to plasma proteins; they accumulate in high levels in the kidneys; poor penetration of the CSF; they pass across the placenta
metabolism: aminoglycosides are not metabolized
excretion: excreted by glomerular filtration; some tubular reabsorption occurs. |
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Definition
| pharmacology of aminoglycosides |
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Term
all the aminoglycosides are toxic to the kidneys
neuromuscular blockade: aminoglycosides compete for the binding sites of Ca on the presynaptic membrane, they reduce the amount of acetyl choline released from the motor nerve terminal; at high concentrations they can produce nondepolarizing type of neuromuscular blockade; respiratory paralysis may occur, but is completely reversible
ototoxicity: hearing and balance functions of the inner ear can be affected; predisposing factors = renal impairment, therapy longer than 10 days
nephrotoxicity: acute tubular necrosis, reduction in glomerular filtration, is a result of accumulation and retention of aminoglycosides in the kidneys, usually reversible |
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Definition
| adverse effects of aminoglycosides |
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