Rich,
What is the role of hydrogen sulfide in the transsulfuration pathway?
Do you believe that it plays a role in CFS?
Were you part of the group credited in your report who became very excited about my hypothesis paper?
I look forward to your reply.
Marian Lemle
Why has hydrogen sulfide disappeared from your slides?
Hi, Marian.
It's good to see you here!
Yes, I still do believe that hydrogen sulfide plays a role in at least quite a few cases of CFS.
At this point, Kenny and his group probably have quite a bit of data from their urine test, but I don't know how it has been running. A few people have posted their results here in a poll:
http://www.forums.aboutmecfs.org/poll.php?do=showresults&pollid=4
As you can see, most were positive for hydrogen sulfide. Because they were self-selected, we can't say what the actual percentage of positive cases is among the entire CFS population, but it does seem to be a significant fraction.
I think Kenny is planning to publish about this, so I don't want to steal his thunder, but I think he has some good evidence for the importance of gut bacteria-generated H2S in at least a significant fraction of cases. I'd better not say more than that, but maybe you have communicated with him about his results.
As you know, there are two potential sources of excess H2S in the body: the human metabolism and the metabolism of bacteria in the gut. Amy Yasko has suggested that, especially in people who have upregulating polymorphisms in the CBS enzyme, hydrogen sulfide can be produced by the enzyme homocysteine desulfhydrase. She has quoted Devlin's biochemistry text, which says, "When the need is for energy, and not for cysteine, homocysteine is metabolized by homocysteine desulfhydrase to alpha-ketobutyrate [though Amy has actually misquoted this as alpha-ketoglutarate], NH3, and H2S."
This enzyme apparently is not present in humans, but as you know, both CBS and CTH (aka CGL) are capable of producing H2S under appropriate circumstances. In an earlier statement of the mechanism for what I've called the "Glutathione Depletion--Methylation Cycle Block" hypothesis, I suggested that because of the oxidative stress that is well-established to be present in CFS, cysteine will tend to oxidize to form cystine. Then, based on research in mice, I suggested that CTH will decompose cystine and introduce a pathway in which H2S is produced. You can see a slide showing this in my OHM talk in 2008 (at
www.cfsresearch.org). I also included this in my poster paper at the 2009 IACFS/ME conference, where I had the pleasure of meeting you!
Among others, after the conference I sent this paper to Ruma Banerjee, who is perhaps the foremost researcher on this part of the metabolism. She wrote back to me that this reaction does not occur in humans, based on her research. Accordingly, I took this part out of my hypothesis for the talk I gave in July, 2010 at the Yasko Protocol Conference.
At this point, I still think there must be a reaction that diverts some sulfur to form H2S, at least in some of the CFS patients. Perhaps the reaction I suggested actually does occur in humans under conditions of oxidative stress, while it doesn't occur under normal conditions. Or perhaps CBS or CTH uses a different substrate, such as homocysteine or cysteine. Ruma and her group have published a couple of papers recently discussing the various reactions that could be involved. The problem for me is that I'm not sure if the favored reactions would be different under conditions of oxidative stress. Tapan Audhya told me that he has found elevated thiosulfate in the urine in autism and CFS patients, and that could be produced in the reaction I suggested originally, together with H2S. So I think there is more that needs to be nailed down here, but in view of what Ruma wrote to me, I thought it best to pull that part out for now. This, however, is a working hypothesis, not an established theory, and if I get more evidence supporting this reaction or another that will produce H2S, I will put it back in!
As I think you know, Kenny believes that the H2S elevation he sees in his urine test is coming from gut bacteria. I think he bases this on the observation that when he is able to correct the dysbiosis, the H2S level in the urine drops down. As I wrote above, I think he plans to publish on this.
I started looking into the literature on production of H2S by gut bacteria, but then got waylaid by the retroviral developments, which have been pretty exciting lately. I hope to get back to that when I can. But I did manage to find out that there are two categories of bacteria that can be in the gut and can produce H2S. The first is the sulfate-reducing bacteria, which use sulfate as their terminal electron acceptor, reducing it to H2S. The second is the bacteria that are able to metabolize sulfur-containing amino acids, such as cysteine. If I understood correctly, this second group is usually the main H2S producing group under normal conditions. However, as we know, the gut is not operating normally in CFS, so I think it's possible that the SRBs could be the main producers in CFS. I just don't know. Maybe Kenny does.
Well anyway, I haven't finished trying to understand the role of H2S in CFS, and I would like to get a better grip on it. I do believe it is important, but I don't know the relative importance of the human and bacterial metabolisms in producing H2S, and for the bacteria, I don't know which category is the main producer in CFS. For the human metabolism, I also don't know which reaction is dominant. So as you can see, there is a whole lot that I don't know! I still do believe that H2S plays an important role in at least a significant fraction of the PWCs, and I still believe that you did a great job. Hopefully I will get time to study all of this some more, and hopefully also, Kenny will shed some light on what he has been finding.
If you have some more insight into these issues, I would love to read it. And don't worry about hijacking my thread. If the moderators don't object to discussing these things here, I certainly don't!
Best regards,
Rich
-)
