UK lab blocks TMA formation from CARNITINE

The 2 main sources of Trimethylamine in humans (via diet) seem to be (not much research) bacterial enzyme degradation of diet CHOLINE and CARNITINE. 

Choline degradation seems to be the main source, say 80-90% ?? (pure guess).

The upcoming Cleveland / Procter & Gamble tma-blocker pill looks to mainly block the choline path (though we don't know really. Maybe it blocks both?).

Now a (small) UK Uni lab (University of Warwick) which looks at bacterial enzymes has blocked bacterial degradation of Carnitine to TMA.

Bacterial enzymes :

Bacteria (and archeae etc) have enzymes that can break things down.

In relation to TMA formation in the human gut, there seems to be 2 enzymes that can break down TMA precursors :

cut-C enzyme for Choline to TMA ?

and now this lab says CntA enzyme for Carnitine to TMA.

So the lab seems to have blocked CntA enzymes from breaking down Carnitine.

It seems they are at the first stage, and a long way from producing a carnitine-TMA blocker pill (if ever). Including the need for funding (not got money on tap like Cleveland Clinic).

It's also unknown how big an impact a carnitine-tma blocker pill would have, as most of the TMA seems to be from choline pathway.

The lead researchers write in an email :

"Thank you for your email regarding our recent work on the Carnitine to TMA formation pathway.

Yes, this work complements the Choline pathway in that we have a crystal structure model of the carnitine degrading “CntA” enzyme with a better understanding of how carnitine is recognised by the enzyme. And yes, the inhibitors we report are the first of their kind against CntA.  

We envisage, this work establishes a strong platform to progress the research to improve the inhibitors. We are eagerly awaiting to hear if we have been successful in securing follow up funding to progress this work. We’d be looking to test the inhibitors against a wider range of bacteria representative of the gut microbiome and demonstrate that we can indeed inhibit carnitine breakdown with such inhibitors in the gut microbiome. We’d also like to further develop the inhibitors for potency and improved efficacy against the bacteria responsible. Ideally, a combo Carnitine + Choline blocker therapeutic would be the ultimate realisation to treat TMAU in the long run.  

Thank you once again for reaching out, it is a pleasure to know our work is noticed and appreciated; reinforcing our research motivations."

Full Paper

Structural basis of carnitine monooxygenase CntA substrate specificity, inhibition and inter-subunit electron transfer

Mussa Quareshy1, Muralidharan Shanmugam2, Eleanor Townsend3, Eleanor Jameson3, Timothy D.H. Bugg4, Alexander D Cameron3 and Yin Chen3

1School of Life Sciences, University of Warwick, United Kingdom

2University of Manchester, United Kingdom

3University of Warwick, United Kingdom

4Department of Chemistry, University of Warwick, United Kingdom

Science Daily article on study

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