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March20 podcast Dr Hazen
anti-TMA pill in a year or 2 ? (scroll 12 mins)

Additional info: https://youtu.be/811v7RLXP9M
MEBO Karen
at UK Findacure conf 2020

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MEBO TMAU TESTING DISCONTINUED
(2012-2017)

MEBO Map Testing & Meetups


Full details : https://goo.gl/TMw8xu
want listed ? contact info@meboresearch.org

MEBO - UBIOME study 2018

'PRESS RELEASE'

NCT03582826
ClinicalTrials.gov

MEBO Gut Microbiome Study
"Microbial Basis of Systemic Malodor and PATM Conditions (PATM)"
Funded by uBiome Research Grant

"Microbial Basis of Systemic Malodor and PATM Conditions (PATM)"

Dynamics of the Gut Microbiota in
Idiopathic Malodor Production
& PATM

Started May 2018 - Ongoing

Current people sent kits : 100/100
3 kits per person

NO LONGER RECRUITING

Participation info : LINK English

MEBO Private Facebook Group
to join : go to
or contact
Join/Watch the weekly
BO Sufferers Podcasts

MEBO TMAU Videos

Petitions

TMAU Petition world
TMAU UK end total:262
TMAU UK ends 23/01/20
TMAU Petition USA end total 204
USA : Moveon open
TMAU (Dominican)
Metabolomic Profiling Study
NCT02683876

Start : Aug 2016
Stage 1 : 27 Canadian volunteers to test
Latest click here (26 oct) :
17 samples returned


Note : Stage 1 is Canada only.
Return cut-off date : passed
Analysis can take 6/8 weeks
Analysis start in/before Nov
MEBO Research is a
EURORDIS and
NORD Member Organization
See RareConnect

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MEBO Metabolic Malodor Survey (international) for Dr Hazen click here
click to Read more/less

survey for ANYONE who identifies with METABOLIC MALODOR

begun : Oct20
end : no ending for now

Regular readers will know that Dr Stan Hazen et al at Cleveland Clinic are developing a TMA-blocker pill, as they proposed in a 2011 paper that TMAO is a factor in CVD. Recently Dr Hazen and colleagues contacted MEBO as they have always thought they could also help with TMAU. This survey is to give them an idea of the 'state of the community'. It is a "version 1". They may not even look (though they have access permission), but it could be useful to give them an overview of the community

MEBO had a zoom call with Dr Hazen and his team in October. Another zoom call is planned when they have time

This is a GOOGLE FORMS survey

short url for survey :
https://forms.gle/vem2TjepKobYZPBu8

current participants : 113 (update 18dec20)

Wednesday, March 3, 2021

2019 FMO breakthrough : Scientists contruct FMO structure

Probably all living things have at least 1 FMO (Flavin mono-oxygenase enzyme).

Humans have 5 (and a number of pseudogenes), with FMO3 deemed the main 'worker' in humans.
Although FMOs were hypothesized in the 60s, and proven around 1980, it has been impossible to construct FMO in a lab until 2019.
A group led by a Dutch lab managed to do so and publish a paper in Dec 2019.


They have also updated the paper.

While it is a breakthrough, it's not currently known how this will help with 'FMO3 Malodor' 
1. Will it mean more interest and research ? 
2. Does it help in a practical way ?


While it might help pharma companies to make drugs (that are worse for sub-FMO3 people), it's not clear if any benefit will come to sub-FMO3 people.
Keeping in mind that probably the majority of people probably carry at least 1 FMO3 variant (currently taught as benign).   


Dec 2019 paper :
Ancestral-sequence reconstruction unveils the structural basis of function in mammalian FMOs
Lead Researcher : Marco W. Fraaije 
Fraaije Lab, Groningen Uni

Quotes from paper
Flavin-containing monooxygenases (FMOs) are ubiquitous in all domains of life and metabolize a myriad of xenobiotics, including toxins, pesticides and drugs. However, despite their pharmacological importance, structural information remains bereft. To further our understanding behind their biochemistry and diversity, we used ancestral-sequence reconstruction, kinetic and crystallographic techniques to scrutinize three ancient mammalian FMOs: AncFMO2, AncFMO3-6 and AncFMO5. Remarkably, all AncFMOs could be crystallized and were structurally resolved between 2.7- and 3.2-Å resolution. These crystal structures depict the unprecedented topology of mammalian FMOs. Each employs extensive membrane-binding features and intricate substrate-profiling tunnel networks through a conspicuous membrane-adhering insertion. Furthermore, a glutamate–histidine switch is speculated to induce the distinctive Baeyer–Villiger oxidation activity of FMO5. The AncFMOs exhibited catalysis akin to human FMOs and, with sequence identities between 82% and 92%, represent excellent models. Our study demonstrates the power of ancestral-sequence reconstruction as a strategy for the crystallization of proteins.
 
Press Release quotes :

To disarm toxic substances, many organisms – including humans – possess enzymes called flavin-containing monooxygenases (FMOs). Despite their importance, the structure of the enzymes has not been resolved, as the protein is too unstable to study in detail. University of Groningen enzyme engineer Marco Fraaije and colleagues from Italy and Argentina reconstructed the ancestral genetic sequences for three FMO genes and subsequently studied the enzymes. The ancestral enzymes proved to be stable enough to study and revealed how FMOs metabolize toxic substances. The results were published on 23 December in Nature Structural & Molecular Biology...

FMOs are present in animals, plants and bacteria. In humans, our five different FMOs are not only involved in metabolizing toxic substances but also in drug activation, while mutations in FMO genes may cause illnesses. ‘These enzymes are studied in detail by pharmaceutical companies but we still had no detailed structure available,’ says Fraaije. Human FMOs are membrane-bound proteins, which proved to be impossible to crystallize for standard structural analysis by X-ray diffraction. ‘My group published the structure of a bacterial FMO, some fifteen years ago, but this was not a membrane-bound protein.’...

...‘The results are fascinating,’ says Fraaije. ‘The membrane-bound part of the enzyme forms a kind of tunnel through which substances can be transported to the active site.’ Many toxic compounds are fatty substances that will accumulate in the fatty cell membrane. ‘The FMO enzymes can take them from the membrane and oxidize them.’ This makes the toxins more hydrophilic, which makes it easier for the cell to excrete them. Whereas the active site is the same in the three FMOs, they have slightly different tunnels, probably suited to different classes of toxic compounds. ‘We knew that different FMOs metabolize different substances and now we can explain why this is so.’...

...Scientists and pharmaceutical companies are now finally able to see how the FMOs work. ‘This could help in the design of drugs that are activated by these enzymes. And the observation that the ancestral protein is more stable is also of interest...

... Finally, it is now possible to reconstruct the effect of disease-causing mutations in FMO genes. One of those mutations causes fish odour syndrome, where a mutation in FMO3 results in the inability to metabolize the substance trimethylamine. This substance, which has a strong fish odour, consequently builds up in the body and is released in sweat, urine and breath, among other things . Fraaije: ‘This was a high-risk project, as we didn’t know if the ancestral protein would be stable enough. But it has paid off.’

press release links :

Prof Elizabeth Shephard and Prof Ian Phillips comment on breakthrough (quotes)

FMOs catalyze the oxidative metabolism of a range of chemicals, including drugs, pesticides and compounds derived from the diet by the action of gut bacteria1,2,3,4. The enzymes act at the interface between an organism and its chemical environment to protect against potentially harmful foreign chemicals. Some FMOs are also involved in endogenous metabolic processes: in the regulation of energy balance5, metabolic aging6 and glucose homeostasis7. In vertebrates, FMOs are located in the membranes of the endoplasmic reticulum and have proved, to date, impossible to crystallize. Now, based on the reconstruction of ancestral mammalian FMO sequences, Nicoll et al.8 report the crystallization and structures of three membrane-bound FMOs. This major advance provides a structural basis for the catalytic mechanism of FMOs and gives insights into how the enzymes bind to membranes and control access to their catalytic site.

Early during the evolution of tetrapods, duplications of a single FMO gene gave rise to a family of genes. In humans, the FMO gene family consists of five functional genes (FMO1, 2, 3, 4 and 5) and six pseudogenes9, one of which is FMO6. FMO3 and FMO6 arose from a more recent duplication that took place early during mammalian evolution9. Based on a phylogenetic analysis, Nicoll et al. reconstructed ancestral sequences for three mammalian FMOs: FMO2, FMO5 and the precursor of FMO3 and 6. The ancestral FMOs, which have 83–92% amino acid sequence identity with the corresponding extant human FMO, were expressed in Escherichia coli as holoenzymes bound to their prosthetic group FAD. The ancestral FMOs were catalytically active, with kinetic parameters similar to those of the corresponding human FMO, and ancestral FMOs 2 and 3/6 reacted rapidly with oxygen to form a stable C4a hydroperoxyflavin intermediate, a key feature of the catalytic mechanism

Remarkably, despite numerous unsuccessful attempts to crystallize human FMO3 and FMO5, all three of the ancestral proteins crystallized, possibly because of their higher melting temperatures. The crystal structures of the ancestral FMOs provide valuable insights into how FMOs bind to membranes, interact with FAD and the cofactor NADP+, and control access to their catalytic sites...

...The availability of structures of ancestral mammalian FMOs will enable more accurate modeling of structures of extant human FMOs. For instance, a structure of human FMO3 would contribute to understanding the effect on enzyme activity of known causative mutations of trimethylaminuria and help predict the likely consequences of novel mutations. Such structures would also provide a basis for structure-based design of drugs that are substrates of FMOs. 

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Monday, February 15, 2021

Messina lab has TMAU - brain chemistry theory (paper)

Messina genetics lab new TMAU paper on TMAU affecting brain chemistry.

Seem to be a theory whereby TMA might affect the brain negatively (physiology, not psychologically).
This is a new theory it seems, put forward by only this lab currently. 

Messina genetics lab in Italy has a long interest in TMAU, and seems to do TMAU research.
It's the Italian lab mentioned in the previous post.

The full paper is here : link to paper
Gut-Brain Axis Cross-Talk and Limbic Disorders as Biological Basis of Secondary TMAU
by Luigi Donato, Simona Alibrandi, Concetta Scimone, Andrea Castagnetti, Giacomo Rao, Antonina Sidoti and Rosalia D’Angelo

Some quotes :

Background: Trimethylaminuria (TMAU) is a rare metabolic syndrome characterized by the accumulation and the excretion of trimethylamine (TMA), a volatile diet compound produced by gut microbiota. Gut microbiota alterations are mainly involved in the secondary TMAU, whose patients show also different psychiatric conditions. We hypothesized that the biological activity of several molecules acting as intermediate in TMA metabolic reaction might be at the basis of TMAU psychiatric comorbidities. Methods: To corroborate this hypothesis, we performed the analysis of microbiota of both psychiatric suffering secondary TMAU patients and TMAU “mentally ill” controls, comparing the alteration of metabolites produced by their gut bacteria possibly involved in neurotransmission and, in the same time, belonging to biochemical pathways leading to TMA accumulation. Results: Microbiota analyses showed that Clostridiaceae, Lachnospiraceae and Coriobacteriaceae alterations represented the bacterial families with highest variations. This results in an excessive release of serotonin and an hyperactivation of the vagus nerve that might determine the widest spectrum of psychiatric disorders shown by affected patients. These metabolites, as short chain fatty acids, lactate and neurotransmitter precursors, are also related to TMA accumulation. Conclusions: Knowledge of microbiota-gut-brain axis may become a potential new strategy for improving metabolic diseases and to treat linked psychiatric disorders.


Conclusion

The relationship between gut microbiota and psychiatric disturbs is one of the most challenging topics involving researchers. The vagal nerve is the anatomical structure which permits the communication between the central nervous system (CNS) and enteric nervous system (ENS). Vagal afferent neurons express receptors for gut microbiota metabolites, such as serotonin, that can modulate nutrient metabolism. Furthermore, SCFAs, catecholamines, acetylcholine, the intermediates of mixed acid fermentation and TMAO are able to regulate metabolism through a microbiota-gut-liver axis. However, very little is known about the direct connection between metabolic diseases and mental disorders, involving common pathway in which the considered metabolites play an orchestral role. In our retrospective comparison, we laid the bases for further investigation about biochemical and biological link between secondary trimethylaminuria and psychiatric behaviors. We suppose that the mental disturbs affecting TMAU patients are probably not only related to social consequence of their metabolic disease but also to a physiopathological effect determined by TMA accumulation. The knowledge of this aspects might allow us to personally modulate each gut microbiota. Thus, the related microbiota-gut-brain axis may become a potential new strategy for improving prognosis of metabolic diseases and treat linked psychiatric disorders.
  

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Wednesday, February 10, 2021

TMAU Test in Italy : Messina

TMAU Test lab in MESSINA Italy


Medical Genetics Clinic
Pavilion F - Ground floor (Entrance F2)
Polyclinic “G. Martino ”of Messina
Via Consolare Valeria 1, Gazzi, Messina

Italy Messina TMAU test lab

Comment on the lab
It looks to be a University Genetics lab. Says 'Medical'. Possibly interested in TMAU mostly due to some research interest.  
They do seem to require any 'patient' to have a Dr referral.

Quotes from the site 

This site is managed by a group of researchers of the University of Messina who are involved in research, diagnosis, genetics and therapy of Trimethylaminuria ( TMAU ).

The operational core of our team consists of:

Prof.  Antonina SIDOTI , prof. associate of Biology and Genetics (BIO / 13) and head of the "Molecular Genetics" laboratory at the University of Messina, biologist executive of the "Medical Genetics" service of the Messina Polyclinic, deputy scientific director of the Euro Institute -Mediterraneo di Scienza e Tecnologia (IEMEST) of Palermo, of which he is also director of the department of “Biomolecular strategies, genetics and cutting-edge therapies”;

Dr.  Rosalia D'ANGELO , researcher at the “Molecular Genetics” laboratory of the University of Messina, biologist executive of the “Medical Genetics” service of the Messina Polyclinic Company;

Dr.  Carmela RINALDI , researcher at the "Molecular Genetics" laboratory of the University of Messina, biologist executive of the "Microbiology" service of the Messina Polyclinic Company;

Dr. Luigi DONATO , researcher at the Euro-Mediterranean Institute of Science and Technology (IEMEST) in Palermo, biologist and PhD in “Applied Biology and Experimental Medicine”; 

Dr.  Concetta SCIMONE , researcher at the Euro-Mediterranean Institute of Science and Technology (IEMEST) in Palermo, biotechnologist and PhD in “Biology and Cellular Biotechnology”, as well as specializing in “Medical Genetics”.

Dr.  Simona  ALIBRANDI , PhD Student in "Applied Biology and Experimental Medicine".

Prof.  Herbert Ryan MARINI , Aggregate Professor of Applied Dietetic Technical Sciences, SSD MED / 49, SC 06 / D2 - Endocrinology, Nephrology and Nutrition and Wellness Sciences, of the Department of Clinical and Experimental Medicine, at the University of Messina, and Equivalent Medical Director, UOC of Internal Medicine, DAI of Medical Sciences, AOU Policlinico “G. Martino ", Messina.

Prof.  Salvatore SETTINERI , associate professor of Clinical Psychology in the BIOMORF Department of the University of Messina.

Prof.  Maria Rosaria Anna MUSCATELLO , at the Clinical Psychology Unit of the Department of Biomedical, Dental and Morphological and Functional Imaging Sciences of the University of Messina, UOC of Psychiatry, AOU of G. Martino, Messina.

***

The diagnosis of TMAU is based on:

On the dosage of trimethylamine (TMA) and trimethylamine N-oxide (TMAO) in the urine . This analysis is carried out after the administration of 5g of choline dissolved in orange juice or by administering a fish-based meal (300g). This determination makes it possible to distinguish carriers of the condition from unaffected individuals. It is based on the determination of the ratio of TMAO to TMA with normal reference values ​​≥0.90.

On the genetic test , based on the search for specific variants in the FMO3 gene related to a more or less severe impairment of the enzymatic function. The FMO3 gene maps to chromosome 1q23-q25 and is made up of nine exons. However, some people with TMAU may not have variants in this gene. For this reason it cannot be ruled out that variants in other genes may contribute to the onset of TMAU. 

***

We inform you that starting from January 2020, in order to carry out the pre-test genetic counseling, it is necessary to obtain the prescription from the attending physician bearing the following wording "General visit code 897" and to book at the numbers of the CUP (Single Booking Center)  0902213976 or 0902213977 , from Monday to Friday , specifying that the genetic counseling will be conducted by Dr. Silvana Briuglia . 

Since genetic testing is not provided for the secondary form of TMAU, it is advisable to contact our working group through our contacts , before proceeding with the booking through CUP, in order to evaluate together if the conditions for the prescription of the genetic test.

We also inform you that for the prescription of the genetic test it is also possible to contact a medical geneticist in your region. In this case, for more information regarding the forms and sending the blood sample, you can contact our contacts.

***

For more information contact us at the following email address:

infotmau@unime.it

Or at the following telephone number (Italy) :

090-2213136

***
Email update from Messina Lab

Our lab performs the TMAU genetic test even for patients who do not live in Italy. The test is free because it is carried out with research fund money contributions, especially for patients who cannot pay or for any other reasons. Therefore we cannot release an official report, but we will be able to let you know if you have TMAU or not, in a mild o severe form

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