Zinc ions (Zn²⁺), an essential trace element in bacteria, fungi, plants, and animals, including humans [1], serve as a key component in many signal transduction processes and act as an essential cofactor for many proteins and enzymes [2,3]. Zinc deficiency causes several human diseases [4,5,6,7,8,9,10,11,12,13]; indeed, zinc supplements have beneficial effects on human health [8,14,15,16,17,18,19]. However, excessive adsorption of Zn²⁺ leads to disruption of the gastrointestinal flora balance, deficiency of other essential heavy metals, including iron, copper, and manganese, and reduction in immune function [20,21,22,23]. Zn²⁺ also plays an important role in the physiology of organisms such as plants and bacteria [24,25]. In plants, zinc deficiency is linked to growth defects and inhibition of flowering [26,27]. Additionally, Zn²⁺ is responsible for the virulence of some bacteria [28]. Since Zn²⁺ is involved in numerous biological events, humans, plants, yeasts, and bacteria have evolved elaborate Zn²⁺ transport systems that respond to Zn²⁺ perturbation.

Failure of the Zn²⁺ transport systems plays a role in diseases such as cancer [29,30], Alzheimer’s [31,32], and Parkinson’s [33,34], as well as temporary zinc deficiency in newborns [35], perinatal fatal cardiomyopathy [36], risk of febrile seizures [37], Lowe’s syndrome [38], disorders of muscle tone with polycythemia [39,40], and chronic liver disease [40]. Therefore, human zinc transporters (ZnTs) are potential targets of drugs and preclinical diagnostic tests. Owing to the important physiological roles, and pharmacological and preclinical diagnostic significance of Zn²⁺ transport systems, a variety of biochemical, structural, physiological, and genetic experiments have been carried out over the past several decades to better understand their functions and mechanisms. The most comprehensively studied bacterial zinc transporter is YiiP, which works in Escherichia coli and Shewanella oneidensis (EcYiiP and SoYiiP, respectively) [41,42,43,44,45,46,47,48,49]. These transporters are a convenient model to study the general mechanisms underlying Zn²⁺ transport. The most intensively studied mammalian ZnTs are SLC30A7/ZnT7 [50] and SLC30A8/ZnT8 [51,52]. Our interests in ZnT family members stem mainly from their roles in maintaining Zn²⁺ homeostasis in cellular organelles throughout the body and the fact that their dysfunction causes serious diseases.

As is the case for other membrane transporters, ZnTs undergo conformational conversion to transport Zn²⁺ across biological membranes. To fully understand the mechanism underlying Zn²⁺ transport, high-resolution structures of the transporters have been captured in different states. The first X-ray crystal structure of a zinc transporter (Table 1) was reported for EcYiiP [41,42], followed by the EM structure of SoYiiP [43,44,45,46]. More recently, cryo-EM structures of vertebrate ZnTs have been reported (Table 1); these include Homo sapiens ZnT7 (HsZnT7) [50], Homo sapiens ZnT8 (HsZnT8) [51], and Xenopus tropicalis ZnT8 (XtZnT8) [52]. These structures allow us to propose an updated model of ZnTs-mediated Zn²⁺ transport. Of note, our recent structural and biochemical studies on HsZnT7 revealed the role of its cytosolic histidine-rich loop (His-loop) in efficient Zn²⁺ uptake [50]. Thus, researchers have built on the structural and mechanistic foundations of ZnTs in the biological kingdom, while making significant progress regarding research into other members with Zn²⁺ transport functions.

Prokaryotes and eukaryotes have developed a variety of Zn²⁺ transport systems to promote the uptake or efflux of Zn²⁺ across biological membranes. ZnTs can be divided into three major groups depending on the mode of transport: Uniporters that transport Zn²⁺ alone; symporters that transport Zn²⁺ in the same direction as other ions, such as protons; and antiporters that transport Zn²⁺ and another ion in opposite directions, such that the binding of one is concomitant with the release of the other. In general, uniporters require no external energy input and transport specific molecules along their concentration gradients; they are therefore passive transporters. However, it can also act as an active transporter if the transport process is against the concentration gradient. By contrast, symporters and antiporters use the energy stored in the concentration gradient of another ion, in many cases, a proton, to transport specific molecules against their concentration gradients. In this regard, symporters and antiporters can be regarded as active transporters. In addition, some P-ATPases and ABC transporters transport Zn²⁺ using ATP as an external energy source to overcome the Zn²⁺ concentration gradient.

Zinc transporters (ZnTs) and ZRT- and IRT-related proteins (ZIPs) are the two major Zn²⁺ transport families found universally in bacteria, yeasts, plants, and animals, including humans. ZnTs and ZIPs selectively transport Zn²⁺, but in opposite directions: ZnTs export Zn²⁺ from the cytoplasm, whereas ZIPs import Zn²⁺ into the cytoplasm. Thus, ZnTs and ZIPs play important roles in maintaining homeostasis of intracellular and intra-organelle Zn²⁺ levels.

While ZntB from Escherichia coli (EcZntB) acts as a Zn²⁺/H⁺ symporter [53], many ZnTs function as proton-driven antiporters, exchanging H⁺ in the extracellular space or organelle lumens for Zn²⁺ in the cytoplasm [41,42,43,44,45,46,47,48,49,50,51,52,53,54,55]. By contrast, there is no clear evidence that ZIPs use proton energy flux to transport Zn²⁺ across the membranes. However, recent biochemical studies suggest that, like ZnTs, Bordetella bronchiseptica ZIP (BbZIP) may function as a Zn²⁺/H⁺ antiporter [56].

3. ZnTs

3.1. Mammalian ZnTs

3.2. Plant ZnTs

3.3. Yeast ZnTs

3.4. Bacterial ZnTs