The 12th Invest in ME Conference, Part 1
OverTheHills presents the first article in a series of three about the recent 12th Invest In ME international Conference (IIMEC12) in London.
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Can Adeno B12 convert to Methyl B12?

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by NC360, Jul 26, 2016.

  1. NC360

    NC360

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    I know that some amount of Methyl B12 converts to Adeno B12, but can the reverse happen also? You don't have to get into too many of the details, as a simply yes or no would suffice, providing you know what you're talking about. I would also like people to stick to the topic (not get into the importance of each, etc.), thanks.
     
  2. ahmo

    ahmo Senior Member

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    no. 2 separate things.
     
  3. alicec

    alicec Senior Member

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    Yes. The adenosyl form is used for storage in the liver. It is converted to the methyl form as needed.
     
  4. NC360

    NC360

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    Two different answers? Which is correct? :(
     
  5. alicec

    alicec Senior Member

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    Here is a recent review which covers some of the issues.

    Here are some quotes

    I thought I had another reference but can't find it at the moment.

    If you need more detail you'll have to search for it yourself.
     
  6. Mor

    Mor

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    Does anyone know if Hydroxy B12 converts better to Methyl B12 when compared to Adeno B12?
     
  7. alicec

    alicec Senior Member

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    There is no reason to think it would be though I haven't seen any figures. The study I referenced above showed that that there was rapid interconversion of cyano, methyl and adenosyl forms (hydroxyl wasn't mentioned).

    Since the adenosyl form is the major storage form and methyl is the major form in blood, the most common interconversion in the body would be between these forms.
     
  8. Valentijn

    Valentijn Senior Member

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    I'm pretty sure hydroxoB12 is the storage form. And wikipedia says that adenosylB12 and methylB12 can't convert to each other:
     
  9. alicec

    alicec Senior Member

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    I'm quoting the paper I referenced above and I read several other sources saying that adenosyl is the major storage form.

    I've tried to find more info on interconversion previously but without much success. In the study cited, cyano, methyl and adenosyl interconverted readily.

    Most of the literature on this seems to be very old and not readily available so I've not been able to find a lot of info.
     
  10. Valentijn

    Valentijn Senior Member

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    Is there any info on which enzymes do the converting? That would help us figure it out :p
     
  11. alicec

    alicec Senior Member

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    The review talks about this a bit but I get the impression it is complicated and not fully understood. They make the statement

    Delving a bit more into the Cbl letter diseases might give a bit more info (they produce a table about this).

    I'll search again tomorrow and try to follow some of the references from the review but I'm too tired now.

    I bought a new car today - very satisfying but also exhausting.

    This is something I have been meaning to track down for some time - I should just go to the local medical school library - maybe later.
     
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  12. Eastman

    Eastman Senior Member

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    Many sites claim that the two forms can be converted to each other but don't give details.

    Ben Lynch said here: "Maybe they have a genetic defect or some enzymatic co-factor problem that converts methylcobalamin to adenosylcobalamin. That conversion occurs in the mitochondria, because adenosylcobalamin is a mitochondrial form of B12."

    VeganHealth cited a report as follows:

    Donaldson (2000, USA) studied 3 vegans with elevated urinary MMA levels who were treated with 1/2 to 1 sublingual MeCbl tablet, 2 times/day for 3 weeks. Correspondence with the author (March 21, 2002) verified that these tablets contained 1,000 µg MeCbl each.

    Two of the subjects' urinary MMA normalized while the remaining subject's stayed slightly elevated at 4.1 µg/mg creatinine (normal is < 4.0 µg/mg creatinine). Thus, at a rate of 1,000-2,000 µg/day, MeCbl appears to be absorbed at a high enough rate to improve B12 status in some vegans. Additionally, this indicates that the MeCbl was converted to AdoCbl for use in the MMA pathway.​
     
  13. Eastman

    Eastman Senior Member

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    I just remembered this paper:
    Processing of alkylcobalamins in mammalian cells: a role for the MMACHC (cblC) gene product


     
  14. Mor

    Mor

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    That's been my experience as well.

    In some vegans? Or rather those vegans may have gotten it elsewhere somehow? As of now—without good evidence—I will assume they (MeCbl and AdoCbl) don't covert to each other, or rather just AdoCbl converts to MeCbl?
     
    Last edited: Sep 20, 2016
  15. PeterPositive

    PeterPositive Senior Member

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    I think you may be right as I was able to deal with high homocysteine with folate + AdoCbl. If it did not convert to methyl-B12 it would have done nothing.

    On the other hand when I added MethylCbl the homocysteine level went down further, which suggests only a part of the AdoCbl had been converted... ?
     
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  16. alicec

    alicec Senior Member

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    Just to clarify, there is not direct interconversion of adenosyl and methyl forms, rather all forms of cobalamin transported into the cell have the upper axial ligand removed (ie the methyl, adenosyl, hydroxyl or cyano residue). The cobalamin moiety is then directed to formation of methyl or adenosyl forms as required.

    Studies with labelled forms with different upper axial ligands taken up by the cell show that the different forms interconvert readily.

    The reverse process in the liver whereby adenosyl is removed from stores and converted to methyl is not understood, but is presumed to take place in several steps.
     
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  17. Eastman

    Eastman Senior Member

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    The book Comprehensive B12: Chemistry, Biochemistry, Nutrition, Ecology, Medicine has graphs sourced from the Quadros et al, 1979 paper showing the formation of AdoCbl from MeCbl and vice versa by human lymphocytes in vitro.
     
  18. alicec

    alicec Senior Member

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    I have reread the Quadros review of cobalamin assimilation and metabolism plus a two reviews on the cobalamin letter diseases (inborn errors of metabolism) which help to define the steps in intracellular cobalamin processing.

    I was reminded all over again of my original frustration in trying to understand the detail better - every interesting reference in the Quadros review is behind a significant pay wall.

    I found out though that Quadros is very active in cobalamin research and has made significant contributions to understanding. So until evidence is produced to the contrary, I'll accept the statements made in the review even if I can't read the detail behind them.

    The reviews of the letter diseases (described as cblA - cblG) support what he says.

    To summarise :-

    Cobalamin is stored in liver and kidney. The storage form is not specifically addressed in the review but a more general statement is made that the predominant form of cobalamin in tissues is adenosyl with a small amount of hydroxyl; the form in blood is predominantly methyl. I have seen other studies stating that the storage form is adenosyl. So it seems that adenosyl is the storage form but I would like more direct evidence for this. In any case, the details of storage and release from storage are not understood.

    Cobalamin in blood (predominantly the methyl form) is taken into cells bound to the carrier protein transcobalamin 2 (TCN2), via a specific receptor (Quadros was involved in isolation and characterisation of both the carrier protein and the receptor).

    The 3-component complex is processed inside the cell with the receptor recycled to the cell surface and cobalamin/TCN2 sent to lysozomes to release the cobalamin from the binding protein.

    This is when the first of the errors occurs - (cblF) - cobalamin largely remains stuck in the lysozome.

    Normally though free cobalamin with its upper axial ligand attached (ie methyl, adenosyl etc) is released from the lysozome and two steps follow.

    The first removes the ligand (the dealkylation reaction described in the reference linked by @Eastman, which is performed by the gene product of MMACHC, defined by cblC.

    The second, the product of MMADHC definied by cblD, changes the oxidation state of the cobalt, a cobalamin reductase.

    From here, cobalamin is shepherded either to the enzyme complex MTR/MTRR where cobalt is further reduced and a methyl group added, or into the mitochondrion. cblE and G define defects in MTRR and MTR respectively.

    Two different variants defined by cblD (variant 1 and 2) appear to act as chaperones in this process, protecting and stabilising cobalamin (ie the cobalamin is never left naked). Variant 1 is involved with MTR/MTRR and variant 2 with MUT.

    In the mitochondrion, the product of MMMA, defined by cblA, of uncertain function, but presumably a cobalamin reductase, further reduces the cobalt atom. Then an adenosyltransferase, the product of MMMB, defined by cblB, adds an adenosyl group (in an ATP dependant reaction) before the cofactor binds to its enzyme MUT (methyl malonylcoA mutase).

    A defect in MUT is described as MUT rather than a cbl letter.

    I have uploaded a diagram.

    The other relevant studies were also performed by Quadros. In these, various labelled forms of cobalamin were added to cells and the products analysed. These showed that the three forms studied, viz cyano, adenosyl and methyl, were readily interconverted.

    That's all I have the energy for now.

    Intracellular processing of cobalamin is very complex and is not fully understood.

    Initially though the upper axial ligand is removed from all forms once they are inside the cell. From there, cobalamin can be converted to either of the active forms.

    Labelling studies show that the forms can interconvert readily.

    Probably adenosyl is the storage form but storage mechanisms are understood even less well.
     

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    Last edited: Sep 20, 2016
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  19. alicec

    alicec Senior Member

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    I thought afterwards that we should consider that cobalamin can also get into cells from blood by passive diffusion - ie independent of the receptor mechanism described above.

    This might be particularly relevant when supplementing relatively large amounts of the vitamin.

    I haven't seen any studies describing what happens inside the cell to cobalamin which enters by this mechanism.
     
    Last edited: Sep 21, 2016
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  20. Creachur

    Creachur

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    That sounds like an interesting book. Is it open-access or free-access, so I can browse through a copy?
     
    Last edited: Oct 12, 2017

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