The survival and reproduction of bacteria is heavily dependent on the absorption of transition metal elements such as iron, manganese, copper, zinc, etc., because they can stabilize the folded conformation of metal proteins while participating in important biochemical reactions. Studies have shown that such metalloproteins account for the total One third of the protein. Among them, zinc-binding proteins are involved in a variety of important biochemical reactions, including DNA replication, transcription, translation, cell division, glycolysis, pH regulation, and the like. There are two reasons why zinc can be widely present in various types of proteins. First, zinc can be used as a structural component of protein. For example, zinc can chelate in the amino acid chain to form a zinc finger structure. Second, zinc can act as a catalytic cofactor and act as a Lewis acid to catalyze biochemical reactions as electron acceptors. To counter the survival and reproduction of invading bacteria, the host has evolved a number of mechanisms to limit the concentration of zinc ions that can be utilized. At the same time, bacteria must produce high-affinity zinc ion transport systems (such as ZnuABC) to get enough zinc to survive. Therefore, understanding the regulation mechanism of zinc ion homeostasis and its relationship with infection is very important for controlling bacterial infection.
The important role of zinc in bacteria
Zinc is widely present in various types of proteins, and the transport and regulation of zinc ions is essential for the survival and reproduction of bacteria. Bioinformatics studies have shown that approximately 5% of bacterial proteins contain identifiable zinc binding sites. About one in six proteins in the Escherichia coli proteome can bind to zinc. Zinc can be involved in the function of various enzymes and proteins of bacteria as a structural component or a catalytic cofactor. First, zinc is associated with a number of basal metabolic enzymes, including RNA and DNA polymerases, alcohol dehydrogenases, isomerases, and the like. In E. coli, zinc is indispensable for the function of isoprene pyrophosphate isomerase (IPP isomerase), which catalyzes isoprene pyrophosphate (IPP) in the mevalonate pathway. It is dimethylallyl pyrophosphate (DMAPP), which is a synthetic precursor of biomolecules such as steroids and terpenoids. Second, zinc is associated with a number of key mechanisms, including DNA repair, production of toxicity-related proteins, antibiotic resistance, and response to oxidative stress. For example, metal β-lactamase is a zinc-binding protein that facilitates bacterial invasion and colonization. The carbapenemase in such enzymes can passivate β-lactam antibiotics, allowing bacteria to produce such antibiotics. Resistance. Zinc is an essential component of CuZn SOD, which is the first line of defense against reactive oxygen species (ROS). In addition, zinc-binding proteins include ribosomal proteins, major antigens, and exotoxins. It can be seen that zinc has a peculiar effect on the bacterial proteome.
Although zinc plays an important role in bacteria, high concentrations of zinc can have toxic effects on bacteria. First, excess zinc ions compete with protein binding sites of other metal ions to inactivate the protein. Second, zinc can also form hydroxyl radicals, causing damage to DNA, proteins, and lipids. In addition, high concentrations of zinc Ions directly inhibit electron transport in the electron transport chain, affecting respiration and causing damage to living organisms. Therefore, zinc ions in bacteria must be strictly regulated.
Transport and regulation of zinc ions in bacteria
Bacterial zinc ion transport
There are non-specific and specific zinc ion transport systems in bacteria that take up zinc primarily through some low-affinity, non-specific ion channels when the bacteria grow in a zinc-rich environment. At the same time, a specific high-affinity zinc ion transport system in a suppressed state can also transport a portion of the zinc ions. For example, in Gram-negative bacteria such as Escherichia coli, zinc ions are absorbed by the constitutively expressed transporter ZupT (which belongs to the ZIP family). The ZIP family of proteins is the first transporter found in eukaryotes and is capable of transporting various metal ions such as zinc, iron, manganese and cadmium. The E. coli ZupT transporter is the first ZIP family of proteins identified in bacteria. The ZupT transporter of Escherichia coli has a wide range of substrates and can transport zinc ions, ferrous ions, manganese ions, cadmium ions and cobalt ions, but has a clear preference for zinc ions than other divalent metal ions. Studies have shown that ZIP family proteins have the same topology, ie, these proteins have eight transmembrane domains, and the amino and carboxy termini are located outside the cell membrane. There is a histidine-rich hypervariable region between the third and fourth transmembrane domains, such as the sequence of the hypervariable region in ZIP1 is HAGHVHIHTHAS HGHTH. This region has been shown to have potential for binding metal ions, suggesting that this region is likely to be involved in zinc ion binding, regulation and transporter antibody functions, but the mechanism by which zinc transports zinc ions is not well understood. Through the study of ZupT structure, its structure is similar to that of the cation diffusion facilitator (CDF family), and the CDF family transport driving force comes from the proton dynamic potential. It is speculated that the ZIP family transport driving force may also come from the proton dynamic potential.
Regulation of zinc ion transport in bacteria
Bacteria can respond to different concentrations of zinc ion by regulating the amount of zinc ions in their cells. The transport of zinc ions is tightly regulated by the transcriptional regulator Zur. Zur can bind two or more zinc ion antibody, one of which acts as a structural component to stabilize the protein conformation, while the other zinc ions help Zur bind to the promoter region of the gene, thereby inhibiting the expression of the gene encoding the zinc ion transport system. When the intracellular zinc content is reduced, Zur lacking zinc can no longer stably bind to DNA, and thus the transcription of these genes is no longer inhibited. The de-suppressed gene expresses a high-affinity zinc ion transport system that acquires zinc ions from a low-zinc environment. Zur is sensitive to fly-molar levels of zinc present in the cell. We found that in P. aeruginosa PAO1, Zur is encoded by PA4599, which is located in the same operon as the forward gene znuBC, and is only 68 bp apart from the reverse gene znuA. By detecting the LUX luminescent reporter (pKD-znuA), it was found that the expression of the znuA gene was significantly increased in the Zur mutant, which also indicated that Zur can inhibit the expression of the znuA gene as a suppressor in Pseudomonas aeruginosa. From the positional relationship between zur, znuBC and znuA in the P. aeruginosa genome, we hypothesized that Zur protein can bind to the operon zur-znuBC and the gene znuA, and regulate the expression of both.
Relationship between bacterial zinc ion regulation and infection
During the process of establishing infection, bacteria must accurately sense changes in the concentration of zinc ions in the host and respond in a timely manner. Bacteria respond to changes in zinc ions in the host by regulating the amount of zinc ions in their cells. Therefore, the regulation of bacterial zinc ions is closely related to its ability to infect.
Studies have shown that for invading bacteria, the concentration of zinc ions that can be utilized in the host is very low. When Salmonella typhimurium was cultured in a synthetic medium with a zinc ion concentration as low as 1 μmol/L, the expression of znuABC was still inhibited. In contrast, when the bacteria were cultured in epithelial cells or macrophages, the expression of znuABC was strongly induced. It can be seen that the concentration of zinc ions in the host is much lower than 1 μmol/L. In order to control bacterial infection, the host limits the concentration of zinc ions that can be utilized by means of transport, binding, storage, etc., and the bacteria must rapidly acquire zinc in a "free state" by highly expressing ZnuABC.
Zinc is an important trace element in life metabolism and is widely involved in physiological activities such as glycolysis, nucleic acid and protein metabolism. Lack and excess of zinc ions can affect the survival of bacteria and the establishment of infection. Therefore, infection can be controlled to some extent by affecting the homeostasis of zinc ions in bacteria. So far, although extensive research has been conducted on the important role of zinc ions in the competition between bacteria and host zinc, there are still many problems that require further study. For example, how macrophages decide when to choose zinc deficiency or zinc poisoning to kill bacteria; and the detailed mechanisms of zinc ion transport, storage, regulation and other metabolic activities remain to be further studied. It is believed that an in-depth study of the steady-state regulation mechanism of zinc ions will help prevent and treat bacterial infections.
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