# A flow equilibrium model controlling cytoplasmic transition metal cation pools and preventing mis-metalation as exemplified for zinc homeostasis

## TL;DR

The paper explains how cells maintain proper metal cation balance to prevent incorrect enzyme metalation, using zinc homeostasis as an example.

## Contribution

A theoretical model is introduced to explain how metal cation discrimination and homeostasis are regulated in cells.

## Key findings

- Cytoplasmic metal cation pools are maintained through a flow equilibrium of uptake and export systems.
- Regulators control gene expression for import and export pumps to calibrate metal cation pools.
- The model provides insight into how correct metalation is achieved despite competing cations.

## Abstract

The metal cations of the first transition period fill up their 3d orbitals from 3d5 for Mn(II) to 3d10 for Zn(II). Enzymes use these cations as cofactors and exploit their individual chemical features for important catalytic reactions. A prerequisite for this process is metalation of the respective enzyme with the correct cation to form metal complexes, despite the presence of other competing transition metal cations. The first step to avoid mis-metalation requires maintenance of cytoplasmic cation homeostasis, which adjusts not only the concentration of an individual cation but also that of the overall metal-ion pools. This is achieved via a flow equilibrium of metal cation uptake by importers with broad substrate specificity combined with export of unwanted cations by efflux systems. A third group of cation importers with high substrate affinity contributes under metal starvation conditions. Experimental evidence for the existence of such a flow equilibrium comes from studies using the metal-resistant beta-proteobacterium Cupriavidus metallidurans. Central to the calibration of the pool of an individual metal cation are the regulators that control expression of the genes for the import and export pumps. A theoretical model that deduces how metal-cation discrimination may be performed by the respective regulator and the pathway from uptake of an external cation to correct metalation provides new insight into these processes.