Year: 2025
Type: article
Abstract: Rather than inhibiting copper entry when grown on high Cu, yeast cells import excessive Cu while simultaneously increasing expression of metallothionein CUP1 which then sequesters excess Cu. An ordinary-differential-equations-based kinetic model was developed to investigate this unusual behavior. The assumed reaction network included 25 reactions and 10 components in the cytosol of yeast cells growing in media supplemented with a series of increasing nutrient COPPER concentrations. Published concentrations of copper proteins and coordination complexes that constitutes the low-molecular-mass (or labile) Cu pool were assumed. Other components included transcription factors MAC1 and ACE1, the MAC1-dependent copper importer CTR1, and other copper proteins considered collectively. A second MAC1-independent importer was required for sufficient Cu to enter the cell under Cu-excess conditions. The mathematical system was initially solved at steady state for each condition in the series. The null-space of the stoichiometric matrix was evaluated using the basic pathways approach. Steady-state rates and rate-constants were calculated for each reaction and each condition of the series. Twenty-one rate-constants remained relatively constant across the series, while 4 trended higher, indicating that cells regulate those latter reactions in ways that were not included in their assumed rate-law expressions. This behavior was simulated by augmenting those expressions with logistical functions that sensed labile Cu and/or nutrient COPPER. The resulting integrated dynamical system approximately generated observed component concentrations over the series and was stable to both intracellular and extracellular perturbations. The MAC1-independent importer is predicted to be FET4, a nonspecific importer of both Cu and Fe. Cells may tolerate excessive Cu import to import sufficient iron.
Source: Journal of Biological Chemistry
Authors: Cade Dulaney, Jay R. Walton, Paul A. Lindahl
Institution: Texas A&M University
Language: English
Topic: Trace Elements in Health
Subfield: Nutrition and Dietetics
Field: Nursing
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,430
OpenAlex ID: W4411334750