Cui, Kaandorp, Lloyd, 2008

Model Status

This CellML model runs in both PCEnv and COR to recreate the published results. The units have been checked in COR and they are consistent. In this particular version of the model the zinc-buffering effects of TPEN are NOT considered.

ValidateCellML verifies this model as valid CellML with full unit consistency.

Model Structure

Zinc plays an essential role in a large number of biological processes; including a structural role in RNA polymerase and zinc finger proteins, and a signalling role in cell proliferation and apoptosis. However, at high concentrations, zinc is toxic, and therefore intracellular zinc levels must be carefully regulated. Escherichia coli achieves intracellular zinc homeostasis by balancing the uptake and efflux of zinc across the plasma membrane. As shown in the figure below, zinc ions are transported into the cell via ZnuABC (an ABC-type transporter) and ZupT (a zinc permease), and they are removed from the cell via ZntA (a P-type ATPase) and ZitB (a cation diffusion facilitator). Zinc uptake via ZnuABC is regulated by Zur, a dimer protein which binds at least 2 zinc ions to become a repressor of znuABC gene expression. By contrast, zinc efflux through ZntA is accomplished by ZntR, a dimer protein which can bind one or two zinc ions per monomer. In its active form, ZntR binds to the promoter of the zntA gene and enhances its transcription.

In 1999-2001, Outten et al. published a series of papers presenting data from several in vitro transcription and metal-binding competition experiments in E. coli. These studies provide a detailed data set on which a mathematical model can be based. In the study described here, Cui and Kaandorp have developed such a mathematical model, and they use it to simulate the in vitro transcriptional response of zinc homeostasis system in E. coli. Cellerator, an open source software, was used to automatically generate the equations, and the model was subsequently translated into CellML to facilitate future model exchange, reuse and implementation.

A schematic diagram of the reactions described in the model of zinc homeostasis system in Escherichia coli. Extracellular zinc enters the cytoplasm through ZnuABC and ZupT, where its presence can cause Zur to bind to the znu operator and repress the transcription of the znuACB gene cluster. Excess intracellular zinc ions are exported by ZntA and ZitB, and cytosolic zinc can bind with protein ZntR to form a strong transcriptional activator of the zntA gene. Cytoplasmic zinc trafficking may involve chaperone-like proteins. Abbreviations: Zur* : active Zur; ZntR* : active ZntR; C? : (a possible zinc chaperone protein whose existence is still under debate).

The complete original paper reference is cited below:

Jiangjun Cui, Jaap A. Kaandorp and Catherine M. Lloyd 2008, BMC Systems Biology , 2:89. PubMed ID: PUBMEDID