Hi, all.
I have been puzzled about Freddd's body's response to glutathione ever since he reported it. I think I now may have an explanation. A recently published paper from Korea looks as though it explains it. I've pasted the abstract of the paper below. The full text is available free from PubMed.
This is the story: In the cells of a person who has normally operating B12 processing enzymes, there is an enzyme called cblC. Relatively recent research by Ruma Banerjee's group in Michigan had shown that this enzyme removes ligands (cyano-, methyl-, and adenosyl-) from the corresponding forms of B12 that come into the cell via the normal transcobalamin transport pathway, and it uses glutathione to do so, acting as a glutathione transferase, and binding glutathione to the ligands. Other research has indicated that glutathione plays a role in protecting cobalamin from reactions with xenobiotics.
Based on this new paper, it appears that cblC also then protects cobalamin from reacting with glutathione (which is normally inside cells) and forming glutathionylcobalamin. In addition, if some cobalalamin does react with glutathione to form glutathionylcobalamin, normal cblC has the capability of taking it back and passing it on to be used to make methylcobalamin and adenosylcobalamin for use by the cell.
When you put these together, it looks as though glutathione is not only used in the removal of these ligands if they come in bound to cobalamin, but glutathione also acts as a protector of cobalamin from reactions with toxins until it is picked up by cblC and used to make the right amounts of the two coenzyme B12 forms needed by the cells.
I have suggested in the past that Freddd might have a mutation in cblC, and I think this paper makes that explanation more likely. It would explain not only why taking glutathione was so devastating to Freddd, but also why low dosages of other forms of B12, such as cyanocobalamin, are not helpful to him. Either of these would result in formation of glutathionylcobalamin, and I suggest that his mutated version of cblC is not able to retrieve the cobalamin once this has happened. The only thing he has found to work for him is very high dosages of both methyl- and adenosylcobalamin. I suggest that the reasons are that he needs to bypass his mutated cblC enzyme and also he needs to overcome any losses of the coenzyme forms of cobalamin by reaction with intracellular glutathione. To accomplish this, he takes large enough dosages of the final coenzyme forms of B12 and diffuses enough of them directly into the cells so that he can satisfy the need of his cells for these coenzymes.
I maintain that in contrast, in most people who have ME/CFS, there is a normally functioning version of cblC. The problem these people have is that glutathione has gone too low, i.e., it has become depleted. Therefore, not only is there not enough glutathione to help remove the ligands, but also there is not enough to protect cobalamin from reactions with toxins. That would explain why large dosages of hydroxocobalamin work for most of these people, and also why people who have nebulized hydroxocobalamin together with glutathione have received benefit. They receive both B12 and glutathione in this way, the B12 is protected from loss by reactions with toxins and their normal cblC is able to take cobalamin from glutathione and use it. I think all of this fits together well. It will be interesting to see what Freddd thinks about this when he comes back. Word on another thread is that he's planning to come back soon.
Best regards,
BMB Rep. 2011 Mar;44(3):170-5.
Protection of aquo/hydroxocobalamin from reduced glutathione by a B12 trafficking chaperone.
Jeong J, Ha TS, Kim J.
Source
School of Biotechnology, Yeungnam University, Gyeongsan, Korea.
Abstract
We identified a bovine B(12) trafficking chaperone bCblC in Bos taurus that showed 88% amino acid sequence identity with a human homologue. The protein bCblC was purified from E. coli by over-expression of the encoding gene. bCblC bound cyanocobalamin (CNCbl), methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) in the base-off states and eliminated the upper axial ligands forming aquo/hydroxocobalamin (OH(2)/OHCbl) under aerobic conditions. A transition of OH(2)/OHCbl was induced upon binding to bCblC. Interestingly, bCblC-bound OH(2)/OHCbl did not react with reduced glutathione (GSH), while the reaction of free OH(2)/OHCbl with GSH resulted in the formation of glutathionylcobalamin (GSCbl) and glutathione disulfide (GSSG). Furthermore we found that bCblC eliminates the GSH ligand of GSCbl forming OH(2)/ OHCbl. The results demonstrated that bCblC is a B(12) trafficking chaperone that binds cobalamins and protects OH(2)/OHCbl from GSH, which could be oxidized to GSSG by free OH(2)/OHCbl.
PMID:
21429294
Rich
