Potential allosteric sites captured in glycolytic enzymes via residue-based network models: Phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase and pyruvate kinase

Metehan Celebi, Tugce Inan, Ozge Kurkcuoglu, Ebru Demet Akten*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Likelihood of new allosteric sites for glycolytic enzymes, phosphofructokinase (PFK), glyceraldehyde-3-phosphate dehydrogenase (GADPH) and pyruvate kinase (PK) was evaluated for bacterial, parasitic and human species. Allosteric effect of a ligand binding at a site was revealed on the basis of low-frequency normal modes via Cα-harmonic residue network model. In bacterial PFK, perturbation of the proposed allosteric site outperformed the known allosteric one, producing a high amount of stabilization or reduced dynamics, on all catalytic regions. Another proposed allosteric spot at the dimer interface in parasitic PFK exhibited major stabilization effect on catalytic regions. In parasitic GADPH, the most desired allosteric response was observed upon perturbation of its tunnel region which incorporated key residues for functional regulation. Proposed allosteric site in bacterial PK produced a satisfactory allosteric response on all catalytic regions, whereas in human and parasitic PKs, a partial inhibition was observed. Residue network model based solely on contact topology identified the ‘hub residues’ with high betweenness tracing plausible allosteric communication pathways between distant functional sites. For both bacterial PFK and PK, proposed sites accommodated hub residues twice as much as the known allosteric site. Tunnel region in parasitic GADPH with the strongest allosteric effect among species, incorporated the highest number of hub residues. These results clearly suggest a one-to-one correspondence between the degree of allosteric effect and the number of hub residues in that perturbation site, which increases the likelihood of its allosteric nature.

Original languageEnglish
Article number106701
JournalBiophysical Chemistry
Volume280
DOIs
Publication statusPublished - Jan 2022

Bibliographical note

Publisher Copyright:
© 2021 Elsevier B.V.

Funding

This work has been partially supported by The Scientific and Technological Research Council of Turkey (TÜBİTAK Project # 218 M320).

FundersFunder number
TÜBİTAK
Türkiye Bilimsel ve Teknolojik Araştirma Kurumu218 M320

    Keywords

    • Allostery
    • Communication pathway
    • Glycolytic
    • Hub residues
    • Low-frequency normal mode
    • Residue network model

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