The peculiar glycolytic pathway in hyperthermophylic archaea: Understanding its whims by experimentation in silico

Yanfei Zhang, Theresa Kouril, Jacky L. Snoep, Bettina Siebers, Matteo Barberis, Hans V. Westerhoff*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


Mathematical models are key to systems biology where they typically describe the topology and dynamics of biological networks, listing biochemical entities and their relationships with one another. Some (hyper)thermophilic Archaea contain an enzyme, called non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase (GAPN), which catalyzes the direct oxidation of glyceraldehyde-3-phosphate to 3-phosphoglycerate omitting adenosine 5′-triphosphate (ATP) formation by substrate-level-phosphorylation via phosphoglycerate kinase. In this study we formulate three hypotheses that could explain functionally why GAPN exists in these Archaea, and then construct and use mathematical models to test these three hypotheses. We used kinetic parameters of enzymes of Sulfolobus solfataricus (S. solfataricus) which is a thermo-acidophilic archaeon that grows optimally between 60 and 90 °C and between pH 2 and 4. For comparison, we used a model of Saccharomyces cerevisiae (S. cerevisiae), an organism that can live at moderate temperatures. We find that both the first hypothesis, i.e., that the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) plus phosphoglycerate kinase (PGK) route (the alternative to GAPN) is thermodynamically too much uphill and the third hypothesis, i.e., that GAPDH plus PGK are required to carry the flux in the gluconeogenic direction, are correct. The second hypothesis, i.e., that the GAPDH plus PGK route delivers less than the 1 ATP per pyruvate that is delivered by the GAPN route, is only correct when GAPDH reaction has a high rate and 1,3-bis-phosphoglycerate (BPG) spontaneously degrades to 3PG at a high rate.

Original languageEnglish
Article number876
JournalInternational Journal of Molecular Sciences
Issue number4
Publication statusPublished - 20 Apr 2017


The modeling was used the Infrastructure Systems Biology Europe M4 modeling service (www.ISBE.NL) and was supported by the University of Amsterdam RPS Systems Biology as well as by various systems biology grants, zoals Synpol: EU-FP7 (KBBE.2012.3.4-02 #311815), Corbel: EU-H2020 (NFRADEV-4-2014-2015 #654248), Epipredict: EU-H2020 MSCA-ITN-2014-ETN: Marie Skłodowska-Curie Innovative Training Networks (ITN-ETN) #642691, BBSRC China: BB/J020060/1. Yanfei Zhang thanks the China Scholarship Council for a PhD fellowship. Matteo Barberis thanks the SILS Starting Grant of the University of Amsterdam (UvA). No funds were received to publish open access. This work was performed within the e:Bio initiative of the Federal Ministry of Education and Research (BMBF), Germany. Theresa Kouril and Bettina Siebers acknowledge the BMBF for financial support (SulfoSYSBIOTEC 0316188A, HotSysAPP 031L0078A). The authors acknowledge Thierry Mondeel who helps Yanfei Zhang to construct the models and Stefania Astrologo who helps in preparing the figure that summarizes the manuscript.

FundersFunder number
Horizon 2020 Framework Programme642691, 654248
Biotechnology and Biological Sciences Research CouncilBB/J020060/1
Universiteit van Amsterdam
Bundesministerium für Bildung und ForschungHotSysAPP 031L0078A, 0316188A
China Scholarship Council
Seventh Framework Programme311815


    • Archaea
    • Flux
    • Flux control coefficient
    • GAPN
    • Mathematical models
    • Non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase


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