New TMAU paper by Monell et al.
Conclusion (?) : TMAU might not just be because of FMO3 enzyme.
Paper funded by NORD grant crowdfunded by TMAU community in 2011.
Around 2009-2011 a TMAU community group spearheaded a crowdfunding campaign to get the NORD TMAU grant past it's $25K trigger point so that researchers could put forward proposals for the grant. The grant was awarded in 2011 to a Monell Chemical Senses proposal. This month the paper has been published in a peer journal.
NORD grant TMAU paper : Genetic analysis of impaired trimethylamine metabolism using whole exome sequencing
Conclusions
Thus, variants in genes other than FMO3 may cause TMAU and the genetic variants identified here serve as a starting point for future studies of impaired TMA metabolism.
My interp of the paper
My interp is they are saying genetic TMAU may not just be just to FMO3 enzyme flaws. In particualr they mention PYROXD2 enzyme, which has been mentioned in TMAU circles before (can't recall why).
My own view on the paper (bad analogy ... suspects and safehouses)
If you think of 'volatiles' as the suspects, and FMO3 as the safe-house, they are saying the suspect (TMA) stays at various safehouses, TMA is to blame for all the smells, and only TMA should be followed about even when it leaves FMO3 'house' to other safehouses.
My own current view is the only safehouse to watch is FMO3, and note all the 'volatiles' that stay there. In fact I reckon TMA is a 'small player' and other FMO3 'safehouse' suspects are more likley to blame for smells. Probably the likes of dimethylsulfide.
So this new paper has went in a direction that doesn't fit with my current thinking, but it is 'new' in that they are suggesting TMA might be metabolized by enzymes other than FMO3 (?).
Paper view
Current Safehouse : FMO3
Suspect : TMA is only suspect.
Paper : TMA might have other safehouses.
My View
Safehouse : FMO3
Suspect : many. TMA a small player
My view : No need to follow TMA. FMO3 is only safehouse that matters, Keep an eye on the all suspects at FMO3 house.
Overall, I think so little research has gone into FMO3 and TMA that we may be at 'chapter 1' of understanding them. As this was a small one-off study, I don't expect much more 'TMAU' research on it. But since TMA has been suggested as having a connection with cardiovascular disease, perhaps TMAU people will be able to read on such research from this aspect in future.
Other comments on the paper :
None of the 10 people seem to report fishy smell. Most report 'sulfury'/fecal smells
My impression is that Monell feel TMA causes a fishy smell, but through influence have broadened this to saying TMA might cause smells more broader than that. Personally I think the smells are not due to TMA, but to other volatiles (e.g. sulfides), and in a way TMA is probably a 'small player' but a good biomarker of FMO3 function (? not even sure about that).
Only one has FMO3 mutations that would be regarded by clinicians as TMAU1
In academia and the clinical world, the teaching is that genetic TMAU is caused by serious FMO3 mutations. But in this paper only one has taught 'serious' mutations (at codon 148). Or at least, I think faults at 148 are bad. I note that they are not the worst TMAU result in the paper (at about 56%).
All the other FMO3 faults listed are carriers of common 'benign' FMO3 faults
Common FMO3 variants carried by whites by % :
codon 158 : 20-50% ?
codon 308 - up to 20% ?
codon 257 - up to 15% ?
As can be seen, many people carry common FMO3 variants. Currently they are taught as being 'benign'. But in the paper, of the 10 tested, many of them only carry one of these FMO3 faults (mainly 158). Obviously 50% of whites don't have metabolic smells, so it's still an unknown full picture to understand.
The worst TMAU urine result seemed to only carry a PYROXD2 DNA fault.
In this paper, the worst result was #52 who only carried a fault in PYROXD2 enzyme.
Worst result in paper : #52 ... TMAO% output 13% ... FMO3 faults : none ... PYROXD2 faults : carries one
The worst TMAU result had no FMO3 faults and only carried 1 PYROXD2 fault. This throws up more questions than answers. 5 carried PYROXD2 faults (3 were homozygous, 2 heterozygous).
PYROXD2 faults listed : Not in coding part of PYROXD2
To make a PYROXD2 protein, you need an amino acid code. These are the codons on the exons.
Genes also have introns, which are generally regarded as 'junk' or unknown.
In this paper, the PYROXD2 faults listed are in the intronic region (not the exons). So they are not even in the coding part of the enzyme gene.
example of how gene makes a protein.
FMO3 has 532 amino acid code to make the FMO3 protein
this means 532 codons.
Genes also have intron part.
Introns not needed to form the protein, but faults there seem to be able to disable the protein.
PYROXD2
This enzyme has been listed before in one TMAU paper. I can't recall at the moment.
Final thoughts
The paper is certainly interesting in that it raises questions about current TMAU teaching. How much impact it will have ... possibly not much due to lack on interest in TMAU.
I will be looking around at PYROXD2 again in a mild way. My mind is currently too set on FMO3 and all it's sulfide/amine volatiles, rather than TMA.
I have no expertise and my interp and thoughts could be wildly wrong.
My impression is Monell can be sensitive about opinions.
My own current theory on systemic body odor/halitosis
Most people identify with 'fecal body odor'. I think this is due to sulfides, maybe some amines. I think it is due to problems with the FMO3 enzyme. Probably often a combo of FMO3 slight weakness and 'FMO3 substrate gut dysbiosis'.
Campaign.
2012 paper suggests bacteroidetes phyla are poor at degrading choline to trimethylamine.
