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ATP, ADP and oxalates

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by GreyOwl, Jun 4, 2016.

  1. GreyOwl

    GreyOwl Dx: strong belief system, avoidance, hypervigilant

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    I'm really, really trying to understand biochemistry, I really am. But the cycles and components are so complicated and I'm overwhelmed.

    So I'm going to just ask my question, because I'm not able to figure it out for myself, and hopefully someone will be able to shed some light for me.

    In the event that a person ingested a substance that led to blockage of active sites of mitochondrial translocator proteins and resulted in poor ADP to ATP re-conversion, would this create acute oxalate crystals in the urine (hyperoxaluria)?

    (I'm sorry if my question is completely non-sensical or conflates different biochemical processes, I really am trying...)
     
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  2. shannah

    shannah Senior Member

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  3. Gondwanaland

    Gondwanaland Senior Member

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  4. GreyOwl

    GreyOwl Dx: strong belief system, avoidance, hypervigilant

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    Thanks @Gondwanaland, that's the thread that's so overwhelming :)

    I'll ask my question there.
     
  5. alicec

    alicec Senior Member

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    I can probably answer your question if I understand exactly what you want to know.

    I don't quite follow why you link blockage of mitochondrial translocator proteins to poor ADP to ATP re-conversion. Do you have a particular transporter in mind, is there some study you have come across that provokes this question? Maybe I can help you interpret it if you give me a bit more detail.
     
  6. GreyOwl

    GreyOwl Dx: strong belief system, avoidance, hypervigilant

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    Thanks so much @alicec.

    I'm wondering where, in a situation where benzoate was shown to have an adverse effect on mitochondria (http://forums.phoenixrising.me/inde...ice-experience-with-avoiding-benzoates.44987/), would this be an error in the Krebs cycle, and if this resulted in acute hyperoxaluria, what would be the likely cause of the oxalate crystals (as in what metabolic cog might have slipped)?

    Sorry again if I'm asking a ridiculous question.
     
  7. alicec

    alicec Senior Member

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    I have looked at the thread you linked. I don't have any particular knowledge of this test, just what I read on the Myhill website.

    The 26% blockage of active sites refers to blockage of active sites in the electron transport chain, according to the test, by benzoate and nickel. The enzyme complexes in this chain transfer electrons produced from oxidation of NADH and succinate from the Kreb's cycle, to oxygen, through a series of redox reactions. The energy released is transferred to ATP synthetase and ATP is generated. This is the main, but not only, source of ATP to power the cell.

    So the blockage is not in the Kreb's cycle as such, but downstream in linked oxidative phosphorylation reactions. The effect is to reduce production of ATP.

    The second part of your question relates to a possible link between benzoate as the blocking agent and acute hyperoxaluria. I think you are asking would benzoate ingestion cause acute hyperoxaluria and if so, would blocking of ATP production be the mechanism?

    Please correct me if I have misunderstood you.

    I can't think of a way that this could happen and in fact, googling benzoate and hyperoxaluria shows that benzoate administration has been used to try to reduce hyperoxaluria. The reasoning was that benzoate traps glycine (forming hippurate) and since there is some evidence that glycine is transformed into oxalate, this might be a way of reducing it.

    The treatment was only slightly successful for a short time, presumably because we now know that glycine makes only a small contribution to oxalate formation. Personally I think this shows poor understanding of the central role of AGxT (alanine glyoxylate aminotransferase) in controlling oxalate formation, though these seem to be very old studies and maybe less was known about the enzyme then.

    Setting benzoate aside, I can't see either how reduction in ATP production would precipitate acute hyperoxaluria. I can think of how the opposite could happen, ie hyperoxaluria could reduce ATP production.

    The only other link that I can think of, though this is sheer speculation on my part and I don't know exactly how it would work, is through sulfation pathways. Benzoate is a phenolic compound, of the type that causes salicylate sensitivity. This is thought to reflect problems in the phenol-sulfur transferase pathway, possibly a shortage of usable sulfate ions.

    Salicylate accumulation can overwhelm the pathway, in effect paralysing it. Possibly a decent dose of benzoate could do this.

    Oxalate is transported out of the body in exchange for sulfate, so shortage of sulfate can also be a problem here, but maybe if sulfate use elsewhere were paralysed, an increase in sulfate availability might stimulate the transporter to dump oxalate.
     
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  8. GreyOwl

    GreyOwl Dx: strong belief system, avoidance, hypervigilant

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    Thank you @alicec. I'm going to re-read what you've read a few times, so I'm sorry that I can't give you feedback now.
     
  9. GreyOwl

    GreyOwl Dx: strong belief system, avoidance, hypervigilant

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    @alicec
    It's taken me a while and a few readings of your response to be able to post something, so here goes.
    You were absolutely correct, that was my question.
    Would a problem with the phenol-sulfur transferase pathway also be reflected by aspirin and ibuprofen intolerance? Because this does not seem to be a problem.
     
  10. alicec

    alicec Senior Member

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    I looked to see which pathways are used to process these drugs. Aspirin uses glycination and glucuronidation, ibuprofen uses glucuronidation, so no, no link to PST. There could be an indirect link with aspirin which after all is a salicylate. If its normal processing pathways were not working it could accumulate and inhibit the PST pathway.
     
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  11. GreyOwl

    GreyOwl Dx: strong belief system, avoidance, hypervigilant

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    Thank you again @alicec.

    So if I've got this right, your theory is that a large enough dose of benzoate could paralyse the PST pathway and in this case hyperoxaluria could result from the sudden availability of sulfate once the pathway was moving again? Is that right?

    A paralysed PST pathway would result in an inability to metabolise paracetamol, wouldn't it.

    (Amazingly there is no wikipedia page for phenol-sulfur transferase).
     
  12. alicec

    alicec Senior Member

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    The sudden availability of sulfate would be because the pathway wasn't working. The pathway consumes sulfate.

    What I was thinking about was that problems with the PST pathway are often because of a limited supply of sulfate. If the total pool of sulfate was indeed limited, then stopping a significant drain on it - namely detox via sulfation - would mean more would be available for other uses.

    One of these would be in exchange for oxalate. More sulfate to fuel the exchanger would allow more oxalate to be transported out of cells and into the urine (among other places). If sulfate was limiting, this mechanism might not be working well but a sudden increase in sulfate could boost the mechanism with resulting hyperoxaluria.

    Paracetemol is processed by glucuronidation and by sulfation, so yes, paralysing the PST pathway could affect paracetamol if glucuronidation capacity was exceeded.
     
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  13. GreyOwl

    GreyOwl Dx: strong belief system, avoidance, hypervigilant

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    @alicec, I think your theory is actually really remarkable and relevant.

    The question that remains for me is a link between benzoate and a shutdown of the PST pathway. You thought that a large enough dose of benzoate could paralyse the PST pathway, but what about an exaggerated response to a "normal" dose of benzoate, say as a food additive, if the person was sensitised to it?

    (I understand this would be theory now, but I really think you're onto something.)
     
  14. alicec

    alicec Senior Member

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    I think that is exactly what happens in salicylate sensitivity. I don't know a lot about the mechanism, but problems with the PST pathway seem to be behind it.

    Salicylates are also cumulative and there is a threshold of response that varies with individuals. In other words, the thing that appears to trigger a response is just the endpoint of an additive process that took the person over his/her threshold of tolerance. On another occasion when there hasn't been an accumulation of other salicylates and so total salicylates are well below the threshold, the same dose will not trigger a response.

    This can make it very difficult to work out what is going on.
     
  15. GreyOwl

    GreyOwl Dx: strong belief system, avoidance, hypervigilant

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    I'm going to do some research so that hopefully I can give you some interesting information! From what I've read (briefly) on SS, it seems that ibuprofen intolerance can be an indicator of SS. So, if there is no ibuprofen intolerance, but there is benzoate intolerance/hypersensitivity, does that mean there are multiple places in the PST pathway where things can get messed up? I'll come back with some ideas...
     
  16. Gondwanaland

    Gondwanaland Senior Member

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  17. GreyOwl

    GreyOwl Dx: strong belief system, avoidance, hypervigilant

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  18. GreyOwl

    GreyOwl Dx: strong belief system, avoidance, hypervigilant

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    @alicec, @Gondwanaland (and anyone else) - here is a strange question:

    is there a biochemical relationship between cocaine and methyl hydroxy benzoate?
     
  19. alicec

    alicec Senior Member

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    They both contain a benzene ring but have different side chains in different positions.
     
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