Team:TPHS San Diego/Model

Breakdown of Trimethylamine via Trimethylamine Dehydrogenase to Minimize Heart Disease Caused by Red Meat Consumption


1. Predict the time it takes for TMADH to significantly reduce TMA to a negligible concentration
2. Use the results to determine whether it is a viable solution for TMADH to prevent the risk of heart disease associated with TMAO

Overview of the Model

We implemented the model that was created and published by the 2018 TAS Taipei team. We chose this model because it predicts the concentrations of an enzyme needed to degrade another molecule in the human body with parameters that are common to our project. The model treats the metabolism of TMA in a two-step approach. First, TMADH will break down the compound TMA into formaldehyde, which is broken down by formaldehyde dehydrogenase into formate and formic acid.

The four factors we modified are the concentration of TMA, the rate at which TMA converts to formaldehyde, the concentration of formaldehyde produced as a byproduct, and the rate at which formaldehyde dehydrogenase will degrade formaldehyde.
The model utilizes the Michaelis-Menten Equation, which describes the kinetics of enzymatic reactions. The equation above utilizes the variables of Vmax (maximal velocity), the Michaelis-Menten constant (substrate concentration at which the reaction rate is half of Vmax), and S(substrate concentration).
We obtained the Michaelis-Menten constant of FDH from the paper by Sanghani et. al and the maximal velocity of FDH from the paper by Uotila and Koivusalo. The maximal velocity and Michaelis-Menten constant were both from Basran et. al. We chose these values because of the common strains of enzymes and conditions of 37 °C and a pH of 7.6.

Modeling Results

Using the TAS Taipei open source code and values we found through experimental and literary research, we created model above. The graph demonstrates the concentration of Trimethylamine and Formaldehyde over time, we restricted the window to only about 60 seconds because that shows where the greatest differences occur. For reference, we also created a TMA in absence of TMADH to show the the magnitude of the enzymatic activity. Both the TMA and formaldehyde concentrations begin to diminish immediately in the presence of TMADH and FDH, respectively. It is clear that TMADH will effectively reduce a significant amount of TMA within the first minute of digestion. The resulting formaldehyde will also be broken down to minimize any harmful effects that may result from an excess amount in the body.

Does TMADH degrade TMA effectively to reduce risks of heart disease?

In a paper published by BioMed Central exploring Metabolic Retrocnversion of Trimethylamine N -Oxide and the Gut Microbiota, TMA is converted to TMAO within the first two hours of consumption. As previously stated, excess of TMAO is linked to atherosclerosis and other heart related diseases due to a buildup of cholesterol in the bloodstream. If TMADH and FDH act as predicted by our model, we believe our engineered solution is a viable method to reduce the risk of heart disease caused by consuming foods with high levels of choline and l-carnitine. The enzymatic activity of TMADH acts much quicker than TMA can convert to TMAO as it degrades within a minute, and formaldehyde can also be degraded by FDH before it causes any further toxicity in the body.