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5. Beskrive virkningen af speciffike inhibitorer på transkriptionsprocesserne
Stryer, s.791, 793-4
Devlin, s.210-1, cc. 5.1

RNA polymerase is an essential enzyme for life since transcription is the first step to gene expression. No RNA polymerase means no other enzymes.

α-amantin – binds very tightly to RNA polymerase II and thereby blocks the elongation phase of RNA synthesis. (RNA polymerase III gets affected at higher levels of α-amantin)

α-amantin is produced by the poisonous mushroom Amanita Phalloides; the poisoning starts with relatively mild gastrointestinal symptoms, followed 48 hours later by massive liver failure as essential mRNAs and their proteins are degraded but not replaced by newly synthesized molecules. The only therapy is supportive including liver transplantation.  More then 100 deaths result worldwide per year from the indigestion of this mushroom.

Rifampicin – an antibiotic that inhibits the transcription in prokaryotic cells, fx. in bacteria. Rifampicin specifically inhibits the initiation of RNA synthesis. Rifampicin does not block the binding of RNA polymerase to the DNA template; rather, it interferes with the formation of the first few phosphodiester bonds on the RNA chain.

Rifampicin blocks the channel in RNA polymerase through which the DNA-RNA hybrid just generated by the enzyme must pass for the first time.

Rifampicin does not hinder chain elongation one initiated, because the DNA-RNA hybrid has already passed though the channel and prevents the antibiotic from binding.

Rifampicin is used in the treatment of tuberculosis.  

Since mammalian RNA polymerase differs from the prokaryotic, inhibition of RNA polymerase in prokaryotes by Rifampicin is possible without great toxicity to the host. Rifampicin is 1000 times more toxic on bacteria then on human cells. This implies a good therapeutic index for the drug, that is, the ability to treat a disease without causing undue harm to the patient.

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