*1.1. Fungal–Metal Interactions*

Metals can exist in various forms such as salts, oxides, sulfates, and nanoparticles. Fungi are able to utilize metal ions from these compounds after dissociation, which leaves unbound ions available for uptake and transport. For example, in the presence of water, copper sulfate (CuSO4) hydrates to copper (II) sulfate pentahydrate (CuSO<sup>4</sup> 5H2O) and then dissociates into Cu2+ + SO<sup>4</sup> <sup>2</sup>−. Upon dissociation, Cu2+ can then be reduced by fungal proteins for uptake. More recently, metals in the form of nanoparticles have gained interest for use as antifungals, which has fueled the escalation of nanoparticle production [8–10].

**Citation:** Robinson, J.R.; Isikhuemhen, O.S.; Anike, F.N. Fungal–Metal Interactions: A Review of Toxicity and Homeostasis. *J. Fungi* **2021**, *7*, 225. https://doi.org/ 10.3390/jof7030225

Received: 5 March 2021 Accepted: 17 March 2021 Published: 18 March 2021

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Nanoparticles are particles that range from 1 to 100 nm in size and vary in shape, physiochemical, optical, and biological properties [11]. Ions dissociate from nanoparticles at a much lower rate, but are also available to interact with homeostatic systems [12,13].

In general, most ions have dedicated homeostatic systems to control import, export, storage, and transport within the cell (Table 1). Metal ion import and export often occurs through transmembrane channels, which are proteins that span the entirety of the membrane and protrude from both sides (e.g., transmembrane proteins Fet4, Zrt1, and Zrt2 in Figure 1) [14,15]. In some species, chelators, such as siderophores, also play a role in uptake. These organic, low molecular weight compounds have a binding capacity for certain metal ions, such as iron, and are imported into the cell through transmembrane channels [16,17]. As a mechanism of ion storage or detoxification, metallothioneins (MTs), cysteine-rich proteins that use metal ions as cofactors, bind free cytosolic ions which may be released back into the cellular environment in metal deficient conditions [18,19]. For the movement of ions to organelles for storage or as cofactors for protein functioning, intracellular transporters, such as Zrc1 (Figure 1) or Pic2 (Figure 2), are utilized [20,21]. If these systems are interfered with, homeostatic imbalance can cause toxicity.

**Figure 1.** *S. cerevisiae* zinc homeostatic systems.

**Figure 2.** Yeast copper transport systems. In *S. cerevisiae*, cupric reductase, Fre1 reduces extracellular cupric oxide for transport across high and low-affinity copper membrane transports Ctr1 and Fet4. From the cytoplasm, Ccc2 shuttles Cu<sup>+</sup> to Golgi bodies, and Pic2 shuttles Cu<sup>+</sup> to the mitochondrial matrix. During meiosis in *S. pombe*, Mfc1 transports Cu<sup>+</sup> across the forespore membrane.

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**Table 1.** Fungal proteins involved in metal transport.
