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Misconceptions Surrounding DNA Methylation

Discussion in 'Breaking News' started by Travis, Nov 16, 2017.

  1. robknob

    robknob Member

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    So here's my shot in the dark; you found reasons to draw a new distinction between C-linked and N-linked, one that is previously unrecognized by the mainstream, which describes their relationship as follows: C-linked being upstream from N-linked and more genetically conserved...?
     
  2. OP
    Travis

    Travis Member

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    The difference is well recognized among chemists; you can see indication of this on any published table of bond energies. Carbon–carbon bonds are formed with more difficulty than carbon–nitrogen bonds, and enzymes which are capable of doing this—like tryptophan-2-methyltransferase—rely on the electrical potential of a transition metal. The enzyme in question has no such thing; it is simply an S-adenosylmethionine-dependent enzyme.

    The nitrogen-linked methylations are admittedly easier to form, and are rather common. You can find them in the adrenals, as norepinephrine becomes epinephrine; you can also find them after the ingestion of niacin, as it's N-methylated and excreted. The formation of O-linked methylations also have a lower energy requirement, and are likewise ubiquitous—melatonin perhaps the most well-known example, followed by the products of catechol-O-methyltransferase methoxytyramine and methoxyestradiol.

    What seems to be the problem is not any lack of recognition by biochemists, but simply the inertia of ideas—almost as if updating textbooks would cause too much discord, as students across the nation would be taught different things. All simple textbooks mirror eachother—to such a degree as to almost suggest a circle of inter-plagiarism. Things proven false can persist in textbooks for years, as evidenced by Na⁺/K⁺-ATPase and photoconduction; this is more of a sociological problem than a scientific one, but Thomas Kuhn and Karl Popper do talk about this.


    If you're curious as to the ability of this enzyme to do as claimed, you can have a look at the assays. There's been a small handful of studies where they add this enzyme to solution of DNA and S-adenosylmethionine, with the S-linked methyl group of such consisting of radioactive ¹⁴Carbon so it can be easily tracked and counted later. Besides showing about one transfer per hour, not one study actually demonstrates the nature of the new methyl bond. This can be done, and studies of such a nature are done all the time. This would simply require either using a strong reducing agent, to see if the methyl group becomes unattached (impossible with a C–C bond), or by using DNA depolymerizing enzymes (deoxyribonucleases) followed by liquid chromatography—characterized by either mass spectrometry, infrared spectroscopy, and/or nuclear magnetic resonance. If this enzyme can do as supposed, someone needs to actually prove it.
     
  3. Terma

    Terma Member

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    Hey there that's an impressive write-up, incredible attention to detail.

    I might have walked right by it, but I didn't quite catch this: why would the methylation be throttled by a ratio of glutamate/aspartate (or any of the others you mentioned), rather than absolute levels of glutamate?
     
  4. OP
    Travis

    Travis Member

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    Since β-methylaspartate is formed from glutamate through the action of glutamyl mutase, I use the two terms almost interchangeably for brevity. We have a system of aspartate vs β-methylaspartate (~glutamate).

    The aspartate concentration matters because they're both here assumed to be substrates for the same enzyme: aspartate transcarbamoylase—responsible for the formation of cytosine from aspartate. A two carbon unit is added to aspartate to form orotate, which eventually becomes cytosine. I think the evidence suggests that β-methylaspartate can also serve as substrate forming 5-methylorotate, precursor to 5-methycytosine.

    When two species are in competition for the same enzyme the concentrations of their products depend on the concentration of the respective substrates. The rate of formation of the enzyme–substrate complex, in this case the enzyme–aspartate complex, can be viewed as proportional to the concentration of ororate produced. Even if—for instance—the affinity in which β-methylaspartate complexes with the enzyme is only ¹⁄₄ that of aspartate, the concentrations all three species would still matter—enzyme [E], aspartate [A], and β-methylaspartate [A
    -CH₃]—as well as the rate constants (Kᵢ, Km):

    [EA] = (Kᵢ[A][E]) ÷ (Km+Kᵢ+Kᵢ[A]+Km[ A-CH₃])

    The concentration of 5-methylcytosine formed can be lowered simply by raising the concentration of, or diluting the solution with, its competitor—aspartate.
     
  5. Dhair

    Dhair Member

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    Do you have any book recommendations that are somewhere along the lines of "Biochemistry for the Mentally Handicapped?" I would one day like to be able to actually follow these discussions.
     
  6. Terma

    Terma Member

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    @Travis Do you have any idea if this glutamate hypothesis of methylation could influence in any way the methylation of specific promoters, such as the 5-alpha-reductase promoter? how generic can this be taken?

    Here's a cool study I saw awhile ago regarding 5-ar: https://sci-hub.la/http://www.sciencedirect.com/science/article/pii/S0303720716300946?via=ihub (Pregnancy and lactation differentially modify the transcriptional regulation of steroidogenic enzymes through DNA methylation mechanisms in the hippocampus of aged rats - ScienceDirect)

    It's something I wanted to look into but I don't have time and one of the threads disappeared (forums!).

    I'm not expert on the DNA methylation of the methylation of things, and all I am aware of as far as mechanisms are what you've posted, and also the demethylation enzyme LSD1 (closely tied to folate). I couldn't look for long but doubted the necessary research exists. I wanted to try to find out the exact mechanism that causes the methylation of 5-a-reductase, and which if any demethylation mechanisms could apply to it.
     
  7. Terma

    Terma Member

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    @Travis this is getting hard to write but I think I shoud write this. I think you have a gift for this stuff. Not a lot of users I see in forums can do this, the last one I saw was 2 years ago (a user name Kimsie on the pheonix rising forum, hence the LSD1 thing, disappeared). pellagra is neat but kind of old, if you look into the real hard issues like 5-ar / finasteride syndrome / ME/CFS I think you could do incredible things.
     
  8. OP
    Travis

    Travis Member

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    I am essentially done reading about hair loss; I have explained, to my own satisfaction, nearly everything surrounding it.

    Pellagra is old, and that is why it's not understood properly. Most people simply take no interest in it; and thus, forty year‐old explanations persist. Niacin is stressed more than anything, but this seems secondary. I think it should be seen primarily as a tryptophan deficiency, exacerbated by leucine (via mTORC1 pathway). If there were more tryptophan in corn, there would be more niacin; but more importantly there would be more picolinate, necessary for chelating zinc. There are striking parallels between the skin changes seen in zinc deficiency and those seen in pellagra. I think pellagra is best understood as a zinc deficiency caused by low tryptophan⟶picolinate. The administration of niacin of course negates the necessity of its own synthesis, sparing tryptophan and creating more picolinate—the endogenous zinc‐chelator and real issue behind the skin changes. I looked into pellagra because I though the corn protein could be immunogenic; it it not. The corn protein is totally safe—like rice—and any symptoms from eating corn, rice, or potatoes likely come from the insulin release (starch). After reading studies and coming across something interesting, like how leucine is incorporated into cholesterol directly, I like to write about it. This helps me consolidate the information that I've just read, as well as reading angles from other people. Although you can rightly view pellagra in a few different ways, since there are six or seven important molecules involved, just considering how zinc and picolinate interact—irregardless of ancient diseases of questionable importance—is interesting in itself.

    One interesting thing about DNA‐5‐cytosine methylation that I had come across yesterday is that stretches of it, or CpG islands, more easily adopt the Z‐configuration—the left‐handed DNA helix. This is induced by the polyamine spermine in low micromole concentrations, and spermine has been demonstrated to increase the velocity of DNA synthesis via PCR and in vitro cell studies. This adds another wrinkle to 'DNA methylation' mythology, since 'methylated' DNA stretches are generally thought to be more resistant to replication. Perhaps the O‐linked and N‐linked methyl groups act to inhibit, this would indeed make sense, but the C‐linked methylcytosine–guanosine stretches have actually been proven to accelerate it (in the presence of spermine). This is another reason why its naïve view O‐, N‐, and C‐linked methylation under one paradigm; these represent radically different concepts with different origins and functions.
     
  9. Terma

    Terma Member

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    Ok thanks travis it's just that I don't care about hair loss. I mean the 5-ar methylation that lead to terrible brain disease. I don't care about my hair, I can lose my hair that is ok. the pellagra old I understand too. anyway, it is so late, sorry if this not make sense.
     
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