Why don't dideoxypyrimidine kill E. coli?

Andre Sobolewski Andre_Sobolewski at MINDLINK.BC.CA
Wed Nov 2 01:59:14 EST 1994

Taken from MIND LINK! on Tue Nov  1 22:31:52 1994

Tue Nov  1 20:56:32 1994
Letter  : 2654209    From: Stephen_W._Mamber_at_~PRIWFB05 at ccmail.bms.com
Subject : Why don't dideoxypyrimidines kill E. coli?
Bytes   : 401

To: microbiology at net.bio.net

     The dideoxypurines I work with (ddA, ddG and ddI) all kill/inhibit E.
     coli in agar diffusion assays.  However, the dideoxypurines (ddT and
     especially ddC) have little/no effect.  Is this the result of a)
     metabolic inactivation/modification, b) transport/uptake phenomena, c)
     a combination of the two, or d) some other explanation?  Thanks, SWM

> I did an undergraduate thesis in 1978 on the effects of
> dideoxythymidylate on the yeast Saccharomyces cereviciae. First, we found
> that ddT would not be phosphorylated when taken up by cells, and so could
> not exert any biological effect. When we used mutants defective in
> certain aspects of transport and uptake of solutes (my memory fails me
> now: were they TUP mutants?), we could get the thymydilyate-derivative
> taken up, and it evidently was phosphorylated to ddTTP.
> The study findings (never published) were that growth was not affected,
> but that ddTTP induced the formation of "petite" cells. The
> interpretation was that nuclear DNA synthesis was unaffected (either
> sufficient discrimination by the DNA polymerase, or it was removed as
> quickly as it was inserted at the growing end), but that mitochondrial
> DNA synthesis was impaired. I even had preliminary data indicating that
> chromosomal DNA remained intact (by potassium iodide centrifugation
> gradients) in cells exposed to ddTTP, but that the mitochondrial DNA was
> being fragmented.
> Pity I could not move my supervisor to published these data: the
> experiment offered me the first thrill of making a scientific finding
> (such as it was). I felt that it could have helped in interpreting the
> effects of drugs such as methotrexate (sp.?) on cells.
Andre Sobolewski                      Microbial Technologies
andre_sobolewski at mindlink.bc.ca       Phone & Fax: (604) 222-4632

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