Wyjaśnienie elementów homeostazy niklu(II) i cynku(II) u bakterii i grzybów

In the last 30 years, no new class of antibiotic was developed, and resistance to these already existing has increased dramatically. It seems reasonable to search for new classes therapeutics, targeting metabolic pathways, which standard therapies do not aim at. One of the biggest obstacles in finding effective and specific antibacterial and antifungal agents, which do not cause serious side effects in patients, is due to the fact that micro-organisms share many basic metabolic pathways with their human hosts. One of the significant differences may be the transport system and homeostasis of Zn²⁺ and Ni²⁺. The review sheds new light on the homeostasis of the two metals in bacteria and fungi. The main points are: (i) determination of Zn²⁺ binding sites on the C. albicans Pra1 zincophore and in the N-terminal domain of the C. albicans Zrt1 zinc transporter; description of the geometry and thermodynamics of such binding (Fig. 5 and 6); (ii) understanding of the bioinorganic chemistry of zincophore based Zn²⁺ transport (understanding Pra1-Zrt1 interactions); suggesting how Zn²⁺ is delivered from the zincophore to the zinc transporter (Fig. 7); (iii) defining the specificity of zincophore-based transport; showing that they can also transport Ni²⁺ ions; (iv) pointing out Zn²⁺ binding sites on amylin_1-19 and pramlintide – amylin’s non-aggregating analogue; describing the thermodynamics of the process (Fig. 10) and suggesting the potential effect of Zn²⁺ coordination on the antimicrobial effectiveness of amylin (Fig. 11 and 12); (v) defining how the non-coordinating poly- Gln region affect the structure and how it increases the thermodynamic stability of nickel complexes of the N-terminal region Hpn-like, a microbial Ni²⁺ storage protein (Fig. 13); (vi) indicating the specific regions of proteins with polyHis and polyGln regions, which are most likely to bind Ni²⁺ and Zn²⁺; (vii) explaining the effect of pH and Ni²⁺ binding to the N-terminal domain of HypA, a bacterial protein involved in the maturation of hydrogenase (Fig. 14 and 15); (viii) explaining the average efficiency and selectivity of HupE, a bacterial Ni²⁺ transporter (Fig. 16 and 17). This new piece of knowledge is an interesting contribution to the beautiful, basic bioinorganic chemistry, which allows for a better understanding of basic mechanisms in biology and can be the basis in the design of effective, specific and selective drugs to be used in anti-microbial therapy, e.g. of traditional drugs combined with a part of a zincophore, which is specifically recognized by the fungus. First biological studies, which show that Candida albicans recognizes the C-terminal region Pra1, have already been carried out (see Figure 8 and its description).