We know that AZT attacks DNA synthesis
DNA directed DNA polymerase activity d While AZT will inhibit DNA synthesis from BIO 7.014 at MIT
Zidovudine (ZDV), also known as ..
As an alternative to the AZT-MP-mediated toxicity (discussed above) and the DNA polymerase γ hypothesis, we demonstrate in this paper that AZT itself is a potent inhibitor of thymidine phosphorylation in isolated heart mitochondria. Because the heart does not express TK1, and TMP is not transported across the inner membrane, mitochondrial synthesis of TTP is the only route available to the cell. We have recently confirmed this point by demonstrating that AZT also inhibits thymidine phosphorylation in the intact perfused rat heart (McKee, E.E., Bentley, A., and Susan-Resiga, D., personal observations) and is thus observed in the presence of all cellular enzymes. The importance of a balanced deoxynucleotide pool in mitochondrial replication has recently been strongly supported by three inherited enzyme deficiencies in the deoxynucleoside anabolic and catabolic pathways. Individuals with mutations in TK2 have a severe myopathy associated with marked mitochondrial DNA depletion (,). Mutations in the mitochondrial dGK are associated with marked hepatocerebral mitochondrial DNA depletion (). Lastly, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP), leading to an overabundance of thymidine and mitochondrial DNA deletions as well as depletion ().
Later, independent studies found that AZT isa *nonselective* terminator of DNA synthesis -- as much as 1000times more toxic to human cells as had been estimated by theBW-connected researchers.
AZT is proposed to interfere with the transcription of proviral DNA
The early studies, by research-ers employed by or close to Burroughs Wellcome, claimed to findthat AZT strongly preferred to terminate viral DNA synthesis asopposed to human cellular DNA synthesis.
It is thought that the triphosphorylated form of AZT can enter the mitochondrial matrix, the inner core of the mitochondrion, and disrupt the replication of mitochondrial DNA by prematurely terminating DNA synthesis.Samuels added: "We're just starting our work.
Why AZT is selective towards HIV and doesn't impair …
In clinical practice, apart from acyclovir which is a similar drug, but in a special category, such analogues were used systemically in malignancies and some viral infections – such as herpes encephalitis or neonatal herpes, but only for short periods. Acyclovir is in a different category as it can only be used by the herpes virus enzymes, and has no effect in cells not infected with herpes viruses. The idea of a possibly lifelong exposure to a DNA chain terminating compound – or even an analogue that is incorporated into DNA that continues to be synthesized, was I believe a novel concept at that time. To emphasize, what was novel was not the use of such compounds, but a life time exposure to them. . So, I was somewhat concerned at the very idea of this approach, and also found it strange that colleagues were mostly silent on this issue. These analogues need to undergo changes in the cell, and are added to the growing DNA chain by enzymes, either those that belong to the cell, or enzymes that are specific to the virus, such as the reverse transcriptase of HIV. It was hoped that AZT, which is turned into its active form by cellular enzymes, would be preferentially used by the viral rather than the cell enzymes that synthesize DNA, and therefore not terminate cellular DNA synthesis; there was some evidence to support this. HIV’s reverse transcriptase adds AZT to the viral DNA chain, while cellular enzymes add it to cellular DNA. Cell DNA is found in two different sites. In the nucleus it is the DNA that constitutes our genome – that is all the information that determines our inherited characteristics. DNA is also found in cellular structures called mitochondria which are the source of the energy needed by the cell. Two different enzymes are needed to make DNA in each situation. While there was comforting evidence that AZT much preferred the viral reverse transcriptase to the enzyme that makes our genomic DNA, this preference was less evident in the case of the enzyme that makes mitochondrial DNA. In fact much of the toxicity of AZT is a result of its effect on mitochondrial DNA synthesis.
No, it's true in the sense that viral DNA synthesis can bestopped before cell DNA synthesis, because the viral RT enzyme >is less finicky about putting AZT into the DNA chain than arecellular enzymes.
14/12/2014 · Zidovudine (AZT, Retrovir) ..
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01/12/2008 · Journal of the Brazilian Chemical Society ..
Healing AIDS and HIV Naturally with a Drug-free …
AZT was originally developed as a chemotherapeutic agent and was later found to be useful in AIDS treatment. As such, AZT is not a natural substrate for the salvage pathway enzymes, and because the mitochondrial pathway appears to be required for TTP synthesis in the heart, we have developed an alternative hypothesis of AZT toxicity. We will demonstrate that AZT is a potent inhibitor of the thymidine salvage pathway, disrupting the synthesis of TTP that supplies mitochondrial DNA replication. Recent work has shown that an inherited deficiency in TK2 leads to a severe myopathic mitochondrial deletion disease, clearly illustrating the importance of this enzyme in TTP synthesis and DNA replication (). The present study offers direct evidence that impaired mitochondrial pyrimidine metabolism is also a player in the complex process of mitochondrial toxicity associated with AZT.
Healing AIDS and HIV Naturally with a Drug-free Approach
This hands-on activity is part of a series of activities and demonstrations focusing on various aspects of the human immunodeficiency virus (HIV) life cycle. Students will first model reverse transcription, the process that results in the production of a double-stranded DNA copy of the HIV single-stranded RNA genome. Using an actual HIV RNA sequence as a template, students will model the synthesis of a complementary strand of DNA by attaching nucleotides to one another. Then, students will substitute AZT in place of thymidine. When AZT is incorporated in a growing DNA sequence it prevents further nucleotides from being added, thereby blocking the production of HIV DNA.
What Is Erythropoietin (EPO)? Test, Definition, Side Effects
As noted in the Introduction, AZT toxicity is complex and a variety of affects of AZT that occur more rapidly than can be accounted for by mt-DNA depletion have been reported in in vitro studies (,). Lewis et. al. () have reported a 40% decrease in mitochondrial protein synthesis secondary to mitochondrial DNA depletion associated with long-term AZT treatment (). This led to our initial experiments aimed at determining whether AZT or its phosphorylated intermediates had direct effects on mitochondrial protein synthesis in isolated intact rat heart mitochondria. The results shown in demonstrate that AZT and AZT-MP had little effect on translation in isolated heart mitochondria. In contrast, AZT-TP inhibited translation with an IC50 of 0.72 mM. Levels of AZT-TP have not been reported in the heart, but typical treatment levels in other cells are 5–20 μM (,,). Thus the inhibition of translation would not appear to be relevant to the mitochondrial toxicity of AZT. However, the differential effect of AZT vs AZT-TP in these experiments suggests that isolated mitochondria were not particularly adept at converting AZT to AZT-TP. Consequently, the mechanism of cardiotoxicity of AZT by AZT-TP inhibition of mitochondrial DNA polymerase γ needed to be further examined. We therefore began studies to directly investigate the phosphorylation of AZT in isolated heart mitochondria and to compare AZT phosphorylation to that of the naturally occurring substrate thymidine.
05/12/2014 · What is erythropoietin (EPO)
Nonmitotic tissues such as the heart do not express a de novo synthesis pathway or cytosolic TK1. As a result, mitochondrial DNA replication would appear to depend solely on the mitochondrial pathway that is inhibited by AZT. Thus it is possible that mitochondrial DNA replication might be affected by limiting levels of TTP. This hypothesis is supported by recent work showing that individuals with inherited deficiencies in TK2 suffer from a severe myopathy associated with marked mitochondrial DNA depletion (,).
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