Metabolic sensitivity analysis

Motivation

From several experiments that investigated the role of nutrient availability in cancer metabolism, we know that changing the availability of nutrient sources (such as glucose) affects tumor fitness. However, the complex landscape of varying nutrients and cellular objectives makes it difficult to determine how a single nutrient affects the metabolic landscape.

In this study, we are interested in modeling the effects of nutrient availability and its impact on several metabolic reactions that influence post-translational modifications such as acetylation and methylation.

Metabolic sensitivity

The metabolic_sensitivity.m is a MATLAB function that determines which nutrient components highly contribute to the production of specific metabolites in the context of the metabolic network. There are 3 experiments that this script performs:

1. Single reaction analysis (SRA): This analysis reveals the objective coefficient that best maximizes the dynamic range of a given reaction with respect to the metabolic reactions we're interested in.
2. Competitive flux balance analysis (cFBA): In cFBA, the objective coefficients for all the reactions of interest are simultaneously maximized. This is more indicative of what happens in a real cell, where there are multiple objectives optimized at any instantaneous moment.
3. Flux variability analysis (FVA): In FVA, the maximum and minimum metabolic flux values are determined with respect to optimizing a specific cellular objective with a given percentage. This allows us to determine the maximum metabolic flux going through given reactions of interest while maximizing biomass production.

The pseudocode for this function is as follows:

for all 20 reactions:
  for excess and depletion of medium components:
    Set the weight kappa to be 10 for excess and 0.01 for depletion
  for every medium component
    Set the substrate uptake rates to be scaled with respect to kappa for specific components
    Specifically set the substrate uptake rate for methionine to be non-limiting
    First, calculate the growth rate and associated parameters
    Second, calculate the metabolic fluxes for the reaction of interest and associated parameters 
  end
  end
end

Notes:

• Need to get experimentally validated substrate uptake rates from literature