But, as with any many-cooked project, some errors slipped through. The biggest issue I encountered involves unbalanced reactions and generic metabolites. Here are three reactions from the model:
- generic fatty acid R-group transfer from CoA (C21) to DHAP (C3)
This reaction provides a template to be followed by all fatty acid side groups. However, to function as a model, there need to be connections between these generic molecules and their specific counterparts:
- specific to generic reaction, converting C14–CoA to R–CoA
- generic-to-specific reaction, converting R–CoA to C16–CoA
Taken together, reactions 2 and 3 are elementally-unbalanced, providing a mechanism for generating two carbons for free, and meaning any analyses with Recon 2 examining carbon flux will be unreliable.
We can, however, modify the network to ensure that all reactions are elementally-balanced. Generic molecules must be replaced by their specific counterparts, creating a new reaction for each possible R-group, and removing any specific-to-generic interconversions:
Given n possible R-groups, there are n3 possible triglycerides. Replacing all generic metabolites as above thus leads to a much larger network, “Recon 2.1”.
|Recon 2||Recon 2.1|
The number of unique metabolites still falls well short of the forty thousand defined in HMDB, but is a step in the right direction.
- Thiele I, Swainston N, Fleming RM, Hoppe A, Sahoo S, Aurich MK, Haraldsdottir H, Mo ML, Rolfsson O, Stobbe MD, Thorleifsson SG, Agren R, Bölling C, Bordel S, Chavali AK, Dobson P, Dunn WB, Endler L, Hala D, Hucka M, Hull D, Jameson D, Jamshidi N, Jonsson JJ, Juty N, Keating S, Nookaew I, Le Novère N, Malys N, Mazein A, Papin JA, Price ND, Selkov E Sr, Sigurdsson MI, Simeonidis E, Sonnenschein N, Smallbone K, Sorokin A, van Beek JH, Weichart D, Goryanin I, Nielsen J, Westerhoff HV, Kell DB, Mendes P, Every Man, His Dog, Palsson BØ (2013) “A community-driven global reconstruction of human metabolism” Nature Biotechnology 31:419-425.
- Smallbone K (2013) “Striking a balance with Recon 2.1” arXiv:1311.5696