Striking a balance with Recon 2.1

In 2013, after years of work, a comprehensive reconstruction of human metabolism, called “Recon 2“, was released to much fanfare [1].

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:

1. 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:

2. specific to generic reaction, converting C₁₄–CoA to R–CoA
3. 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
reactions	7440	71159
variables	5463	13940

.

The number of unique metabolites still falls well short of the forty thousand defined in HMDB, but is a step in the right direction.

The new model is available in SBML format from BioModels.net (MODEL1311110001). A more detailed description (and further tinkerings) can be found on arXiv [2].

References

1. 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.
   doi:10.1038/nbt.2488
2. Smallbone K (2013) “Striking a balance with Recon 2.1” arXiv:1311.5696

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