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Table 9 Effect of long-chain fatty acids (LCFA) oxidization in the triacarboxylic acid (TCA) cycle over model analysis

From: Exploring metabolism flexibility in complex organisms through quantitative study of precursor sets for system outputs

Main properties of the simplex vertices, assuming constant ATP-production,
with different ratios of LCFA oxidized in TCA
  Dataset % of FA Model Example of Combinatorics   Validation  
   oxidated name maximized of pathways     
   in TCA   function         
      R 19 R 15 R 14 R 8 R 64 R 63 R 13  
      NADPH OAA →G3P OAA →PYR G3P →G6P Peptide Peptide Pyr OAA  
      oxidation     hydrolysis synthesis   
  (Ctrl) 0%     1831     125 1835 Non relevant flux values for R 13, R 64
  10%     2451     2455
  (CN) 0% B v 15- v 19 0 795 0 0 0 150 803
  10% 1489 1497
  20% 2357 2365
  25% 2878 2886
  (HB) 10%     6173     150 6145
  20%     7115     7086  
   25%     7675     7646  
  (Ctrl) 0%      1831    125 1835 Non relevant flux values for R 13, R 64
  10%      2451    2455
  (CN) 0% F v 14- v 19 0 0 795 0 0 150 803
  10% 1489 1497
  20% 2357 2365
   25% 2878 2886
  (HB) 10%      6173    150 6145
  20%      7115    7086  
   25%      7675     7646  
  (Ctrl) 0%       3662   125 4 Non relevant flux values for R 8, R 64
  10%       4902  
  (CN) 0% D v 8- v 19 0 0 0 1590 0 150 8
  10% 2978
  20%      4714  
   25%       5756   
  (HB) 10%       12289     
  20% D1 v 8- v 19- v 14   29 0 14172     
  25%    0    15292 0 150 0  
  10%       12289     
  20% D2 v 8- v 19- v 15   0 29 14172     
   25%       15292     
  (Ctrl) 0%        305 430 4 Glucose is the unique precursor of lactose synthesis (AIO)
   10%        409 533
  (CN) 0% H v 64- v 19 0 0 0 0 133 283 8
   10% 248 398
   20%        393 543  
   25%        480 630   
  (HB) 10% H1 v 64- v 19- v 14 0 29 0 0 1024 1174 0 Non relevant flux values for R 63
   20% 1181 1331   
   25% 1274 1424   
   10% H2 v 64- v 19- v 15   0 29   1024 1174   
   20%    1181 1331   
   25%    1274 1424   
  (Ctrl) 0%    669 1714     125 1718 Non relevant flux values for R 13, R 64
   10%    694 2330     2334
  (CN) 0% A v 15 + v 19   791 0 0 0 150 799
   10% 22 1485 1493
   20%    2353      2361
  (HB) 10%    1216 5961     150 5932
   20%    6902     6873
Extreme flux distributions within the set of plausible solutions   25%    7462     7433  
  (Ctrl) 0%    694   1714    125 1718  
   10%      2330     2334  
  (CN) 0% E v 14 + v 19 22 0 791 0 0 150 799  
   10% 1485 1493  
   20%     2353    2361  
   25%     2874    2882 Non relevant flux values for R 13, R 64
  (HB) 10% E1 v 14 + v 19 1216 32 5929 0 0 150 5932  
   20% 1216 32 6902   6873  
   25%    1216 32 7462   6920  
   10%      6008     5979  
   20% E2 v 14 + v 19- 50v 15 946 0 6949     6920  
   25%      7509     7481  
  (Ctrl) 0%    694    3428   125 4  
   10%      4659    
  (CN) 0% C v 8 + v 19 22 0 0 1583 0 150 8  
   10% 2971  
   15%      4706    
   20%      5749     
  (HB) 10% C1 v 8 + v 19 1216 32 0 11858    3  
   20%       13840     
   25%       14961 0 150   
   10% C2 v 8 + v 19- 50v 15 946 0 29 11958    0 Non relevant flux values for R 8, R 64
   20%       13840     
   25%       14961     
  (Ctrl) 0%    694     286 410 4 Glucose is the unique precursor of lactose synthesis (AIO)
   10%       388 513
  (CN) 0% G v 64 + v 19 22 0 0 0 132 282 8
   10% 248 398
   20%       392 542  
   25%       479 629  
  (HB) 10% G1 v 64 + v 19 1216 32 0 0 989 1139 3 Non relevant flux values for R 63, R 64
   20%   1145 1295
   25%        1238 1388  
   10% G2 v 64 + v 19- 50v 15 946 0 29   996 1146 0
   20%    1146 1296  
   25%        1247 1397   
Litterature-based upperbounds for fluxes      ≤ 591 Non-zero Lower than ≤ 266 mmol/h/half  
        mmol/ [28, 31] whole body udder [33]   
        h/half udder [33]   protein synthesis [29]    
  1. To study the impact of the variability of FA oxidation, a ratio of long-chain FA (10%, 20%, 25%) was introduced in the TCA cycle. For datasets (CN), (Ctrl) and (HB) which were compatible with a given ratio of LCFA oxidation, extreme flux distributions and AIO coefficients variability were studied. Our main conclusions are robust to the introduction of LCFA oxidation (Table 8). Interestingly, as shown in (Table 9), the structure of the simplex generated by the (HB) diet is more complicated than the (Ctrl) and (CN) treatments, with 13 vertices for all hypotheses. This is due to the fact that R 15 is highly constrained by measurements, so that this flux cannot vanish when R 14 is optimized or when R 19 is maximized. All the vertices for the (HB)-simplex contradict knowledge-based literature.