ArticleThe Journal of biological chemistry2014
A fundamental trade-off in covalent switching and its circumvention by enzyme bifunctionality in glucose homeostasis.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
17 citing papers in PubMed.
- Orchestrating glucose metabolism: PFKFB2 as a signal-integrating conductor in homeostasis and disease.The Journal of biological chemistry · 2026Review
- Algebraic formulas for first-passage times of Markov processes in the linear framework.Bulletin of mathematical biology · 2025Article
- Thermodynamic bounds on ultrasensitivity in covalent switching.Biophysical journal · 2023Article
- The linear framework II: using graph theory to analyse the transient regime of Markov processes.Frontiers in cell and developmental biology · 2023Article
- The linear framework: using graph theory to reveal the algebra and thermodynamics of biomolecular systems.Interface focus · 2022Review
- Emergence and Enhancement of Ultrasensitivity through Posttranslational Modulation of Protein Stability.Biomolecules · 2021Article
- Allosteric conformational ensembles have unlimited capacity for integrating information.eLife · 2021Article
- Robustness and parameter geography in post-translational modification systems.PLoS computational biology · 2020Article
- p53-TP53-Induced Glycolysis Regulator Mediated Glycolytic Suppression Attenuates DNA Damage and Genomic Instability in Fanconi Anemia Hematopoietic Stem Cells.Stem cells (Dayton, Ohio) · 2019Article
- Structural conditions on complex networks for the Michaelis-Menten input-output response.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Inositol Pyrophosphate Synthesis by Diphosphoinositol Pentakisphosphate Kinase-1 is Regulated by Phosphatidylinositol(4,5)bisphosphate.Bioscience reports · 2018Article
- Intimate connections: Inositol pyrophosphates at the interface of metabolic regulation and cell signaling.Journal of cellular physiology · 2018Review
- The Significance of the Bifunctional Kinase/Phosphatase Activities of Diphosphoinositol Pentakisphosphate Kinases (PPIP5Ks) for Coupling Inositol Pyrophosphate Cell Signaling to Cellular Phosphate Homeostasis.The Journal of biological chemistry · 2017Article
- The significance of the 1-kinase/1-phosphatase activities of the PPIP5K family.Advances in biological regulation · 2017Review
- Laplacian Dynamics with Synthesis and Degradation.Bulletin of mathematical biology · 2015Article
- Robust network structure of the Sln1-Ypd1-Ssk1 three-component phospho-relay prevents unintended activation of the HOG MAPK pathway in Saccharomyces cerevisiae.BMC systems biology · 2015Article
- Time-scale separation--Michaelis and Menten's old idea, still bearing fruit.The FEBS journal · 2014Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors.
Funding
Abstract
Covalent modification provides a mechanism for modulating molecular state and regulating physiology. A cycle of competing enzymes that add and remove a single modification can act as a molecular switch between "on" and "off" and has been widely studied as a core motif in systems biology. Here, we exploit the recently developed "linear framework" for time scale separation to determine the general principles of such switches. These methods are not limited to Michaelis-Menten assumptions, and our conclusions hold for enzymes whose mechanisms may be arbitrarily complicated. We show that switching efficiency improves with increasing irreversibility of the enzymes and that the on/off transition occurs when the ratio of enzyme levels reaches a value that depends only on the rate constants. Fluctuations in enzyme levels, which habitually occur due to cellular heterogeneity, can cause flipping back and forth between on and off, leading to incoherent mosaic behavior in tissues, that worsens as switching becomes sharper. This trade-off can be circumvented if enzyme levels are correlated. In particular, if the competing catalytic domains are on the same protein but do not influence each other, the resulting bifunctional enzyme can switch sharply while remaining coherent. In the mammalian liver, the switch between glycolysis and gluconeogenesis is regulated by the bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2). We suggest that bifunctionality of PFK-2/FBPase-2 complements the metabolic zonation of the liver by ensuring coherent switching in response to insulin and glucagon.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.