Zn(II) coordination influences the secondary structure, but not antimicrobial activity of the N-terminal histatin 3 hydrolysis product.

The relationship between the coordination chemistry and antimicrobial activity of Zn(II) and Cu(II)-bound histatins, salivary antimicrobial peptides, remains enigmatic. We focus on metal complexes of histatin 3 and its two products of hydrolysis: histatin 4 and its N-terminal fragment (histatin 3-4). The thermodynamic stability of these complexes is quite expected - the binding of Cu(II) the ATCUN motif results in the formation of very stable complexes.

Positively charged residues play a significant role in enhancing the antibacterial activity of calcitermin.

A systematic study on the human antimicrobial peptide calcitermin (VAIALKAAHYHTHKE) and its carefully designed derivatives was undertaken to verify the impact of divalent copper and zinc ions on the stability, coordination and antimicrobial activity of the formed complexes. In this work we investigate the calcitermin mutants where the alanine in position 7 and 8 is substituted with an arginine residue, with the aim of enhancing the antibacterial activity. Additionally, the analogue where alanine in position 7 is replaced with a histidine is considered, to obtain a chelating sequence with four histidines in alternate position; the aim of this change was to increase the cationic properties of the peptide under acidic conditions and possibly enhance its binding ability towards the metal ions.

Metal coordination governs the antimicrobial efficacy of calcitermin derivatives.

Antimicrobial peptides are promising alternatives to classical antibiotics. Their microbicidal activity can arise from different mechanisms, one of which is known as nutritional immunity and has metal micronutrients and metal-binding biomolecules as its main players. Calcitermin is an antimicrobial peptide and an effective metal chelator.

Zn(II) and Cu(II) Coordination Enhances the Antimicrobial Activity of Piscidin 3, but Not That of Piscidins 1 and 2.

Piscidins, antimicrobial peptides isolated from fish, are potent against a variety of human pathogens; they show minimum inhibitory concentration values comparable to those of commercially used antimicrobials. Piscidins 1 and 2 are generally more effective than piscidin 3 when applied alone; the contrary is observed for their metal complexes: Zn(II) and Cu(II) coordination does not enhance the efficacy of piscidins 1 and 2, while a moderate enhancement is observed for piscidin 3. All three piscidins bind Cu(II) in a so-called albumin-like binding mode, while for Zn(II) complexes, two coordination modes are observed: piscidins 1 and 2 bind Zn(II) by imidazole nitrogens from His4, His11, and His17 side chains; piscidin 3 coordinates Zn(II) by His3, His4, and His11 imidazole nitrogens and additionally supports the interaction, formed by carbonyl oxygen from His4.

Characterization of four peptides from milk fermented with kombucha cultures and their metal complexes-in search of new biotherapeutics.

The most common skin diseases include eczema, psoriasis, acne, and fungal infections. There is often no effective cure for them. Increasing antimicrobial drug resistance prompts us to search for new, safe, and effective therapeutics.

Impact of metal coordination and pH on the antimicrobial activity of histatin 5 and the products of its hydrolysis.

This work focuses on the relationship between the coordination chemistry and antimicrobial activity of Zn(II) and Cu(II) complexes of histatin 5 and the products of its hydrolysis: its N-terminal fragment (histatin 5-8) and C-terminal fragment (histatin 8). Cu(II) coordinates in an albumin-like binding mode and Zn(II) binds to up to 3 His imidazoles. The antimicrobial activity of histatins and their metal complexes (i) strongly depends on pH - they are more active at pH 5.

ZrfC Zn(II) transporter scavengers zincophore-bound Zn(II).

is an opportunistic pathogen that is able to invade and grow in the lungs of immunosuppressed patients and cause invasive pulmonary aspergillosis. The concentration of free Zn(II) in living tissues is much lower than that required for optimal fungal growth; thus, to obtain Zn(II) from the host, uses highly specified Zn(II) transporters: ZrfA, ZrfB and ZrfC. The ZrfC transporter plays the main role in Zn(II) acquisition from the host in neutral and mildly alkaline environment interacting with the secreted Aspf2 zincophore.

Bioinorganic chemistry of shepherin II complexes helps to fight Candida albicans?

The fungal cell wall and cell membrane are an important target for antifungal therapies, and a needle-like cell wall or membrane disruption may be an entirely novel antifungal mode of action. In this work, we show how the coordination of Zn(II) triggers the antifungal properties of shepherin II, a glycine- and histidine-rich antimicrobial peptide from the root of Capsella bursa-pastoris. We analyze Cu(II) and Zn(II) complexes of this peptide using experimental and theoretical methods, such as: mass spectrometry, potentiometry, UV-Vis and CD spectroscopies, AFM imaging, biological activity tests and DFT calculations in order to understand the correlation between their metal binding mode, structure, morphology and biological activity.

-HH and -HAAAH motifs act as fishing nets for biologically relevant metal ions in metallopeptides.

Histidine are one of the most common residues involved in transition metal ion binding in the active sites of metalloenzymes. In order to mimic enzymatic metal binding sites, it is crucial to understand the basic coordination modes of histidine residues, distributed at different positions in the peptide sequence. We show that: (i) the separation of two histidines has a large effect on complex stability - a sequence with adjusting histidine residues forms more stable complexes with Zn(II) than the one in which the residues are separated, while the contrary is observed for Cu(II) complexes, in which amide nitrogens participate in metal binding.

Zn(II) Induces Fibril Formation and Antifungal Activity in Shepherin I, An Antimicrobial Peptide from .

Shepherin I is a glycine- and histidine-rich antimicrobial peptide from the root of a shepherd's purse, whose antimicrobial activity was suggested to be enhanced by the presence of Zn(II) ions. We describe Zn(II) and Cu(II) complexes of this peptide, aiming to understand the correlation between their metal binding mode, structure, morphology, and biological activity. We observe a logical sequence of phenomena, each of which is the result of the previous one: (i) Zn(II) coordinates to shepherin I, (ii) causes a structural change, which, in turn, (iii) results in fibril formation.

Impact of C- and N-terminal protection on the stability, metal chelation and antimicrobial properties of calcitermin.

The main limitation to the use of antimicrobial peptides (AMPs) as regular drugs, against antibiotic and antifungal resistance, mainly relates to their rapid degradation by proteolytic enzymes. The introduction of suitable structural changes in the peptide chain can make the peptide less susceptible to the action of proteases, thus overcoming this problem. To improve the plasma stability of calcitermin, a metal-chelating AMP present in the human respiratory tract and investigated in the present study, C- and/or N- terminal modifications have been introduced in the native sequence.

Metal coordination to solute binding proteins - exciting chemistry with potential biological meaning.

Zn(II) is essential for bacterial survival and virulence. In host cells, its abundance is extremely limited, thus, bacteria have evolved transport mechanisms that enable them to take up this essential metal nutrient. encodes two solute binding proteins (SBPs) - ZnuA and AztC, which are responsible for zinc acquisition from the host cells.

Semenogelins Armed in Zn(II) and Cu(II): May Bioinorganic Chemistry Help Nature to Cope with ?

Proteolytic degradation of semenogelins, the most abundant proteins from human semen, results in the formation of 26- and 29-amino acid peptides (SgIIA and SgI-29, respectively), which share a common 15 amino acid fragment (Sg-15). All three ligands are effective Zn(II) and Cu(II) binders; in solution, a variety of differently metalated species exist in equilibrium, with the [NH, 3N] donor set prevailing at physiological pH in the case of both metals. For the first time, the Cu(II)-induced antimicrobial activity of Sg-15 against is shown.

CH vs. HC-Promiscuous Metal Sponges in Antimicrobial Peptides and Metallophores.

Histidine and cysteine residues, with their imidazole and thiol moieties that deprotonate at approximately physiological pH values, are primary binding sites for Zn(II), Ni(II) and Fe(II) ions and are thus ubiquitous both in peptidic metallophores and in antimicrobial peptides that may use nutritional immunity as a way to limit pathogenicity during infection. We focus on metal complex solution equilibria of model sequences encompassing Cys-His and His-Cys motifs, showing that the position of histidine and cysteine residues in the sequence has a crucial impact on its coordination properties. CH and HC motifs occur as many as 411 times in the antimicrobial peptide database, while similar CC and HH regions are found 348 and 94 times, respectively.

Spectroscopic Characterization and Biological Activity of Hesperetin Schiff Bases and Their Cu(II) Complexes.

The three Schiff base ligands, derivatives of hesperetin, HHSB (-[2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-ylidene]isonicotinohydrazide), HIN (-[2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-ylidene]benzhydrazide) and HTSC (-[2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-ylidene]thiosemicarbazide) and their copper complexes, CuHHSB, CuHIN, and CuHTSC were designed, synthesized and analyzed in terms of their spectral characterization and the genotoxic activity. Their structures were established using several methods: elemental analysis, FT-IR, UV-Vis, EPR, and ESI-MS. Spectral data showed that in the acetate complexes the tested Schiff bases act as neutral tridentate ligand coordinating to the copper ion through two oxygen (or oxygen and sulphur) donor atoms and a nitrogen donor atom.

Zn(II) binding to pramlintide results in a structural kink, fibril formation and antifungal activity.

The antimicrobial properties of amylin, a 37-amino acid peptide hormone, co-secreted with insulin from the pancreas, are far less known than its antidiabetic function. We provide insight into the bioinorganic chemistry of amylin analogues, showing that the coordination of zinc(II) enhances the antifungal properties of pramlintide, a non-fibrillating therapeutic analogue of amylin. Zinc binds to the N-terminal amino group and His18 imidazole, inducing a kink in the peptide structure, which, in turn, triggers a fibrillization process of the complex, resulting in an amyloid structure most likely responsible for the disruption of the fungal cell.

Poly-Gly Region Regulates the Accessibility of Metal Binding Sites in Snake Venom Peptides.

It is supposed that the presence of poly-His regions in close proximity to poly-Gly domains in snake venoms is related to their biological activity; poly-His/poly-Gly (pHpG) peptides inhibit the activity of metalloproteinases during venom storage via the chelation metal ions, necessary for their proper functioning. This work shows that only the histidyl residues from the N-terminal VDHDHDH motif (but not from the poly-His tag) were the primary Zn(II) binding sites and that the poly-Gly domain situated in the proximity of a central proline residue may play a regulatory role in venom gland protection. The proline induces a kink of the peptide, resulting in steric hindrance, which may modulate the accessibility of potential metal binding sites in the poly-His domain and may, in turn, be one of the regulators of Zn(II) accessibility in the venom gland and therefore a modulator of metalloproteinase activity during venom storage.

Specific Zn(II)-binding site in the C-terminus of Aspf2, a zincophore from Aspergillus fumigatus.

Aspergillus fumigatus, one of the most widespread opportunistic human fungal pathogens, adapts to zinc limitation by secreting a 310 amino acid Aspf2 zincophore, able to specifically bind Zn(II) and deliver it to a transmembrane zinc transporter, ZrfC. In this work, we focus on the thermodynamics of Zn(II) complexes with unstructured regions of Aspf2; basing on a variety of spectrometric and potentiometric data, we show that the C-terminal part has the highest Zn(II)-binding affinity among the potential binding sites, and Ni(II) does not compete with Zn(II) binding to this region. The 14 amino acid Aspf2 C-terminus coordinates Zn(II) via two Cys thiolates and two His imidazoles and it could be considered as a promising A.

Correction: Novel insights into the metal binding ability of ZinT periplasmic protein from and .

Correction for 'Novel insights into the metal binding ability of ZinT periplasmic protein from and ' by Denise Bellotti , , 2020, , 9393-9403, DOI: 10.1039/D0DT01626H.

Zn and Cu Binding to the Extramembrane Loop of Zrt2, a Zinc Transporter of .

Zrt2 is a zinc transporter of the ZIP family. It is predicted to be located in the plasma membrane and it is essential for zinc uptake and growth at acidic pH. Zrt2 from is composed of 370 amino acids and contains eight putative transmembrane domains and an extra-membrane disordered loop, corresponding to the amino acid sequence 126-215.

Thermodynamic surprises of Cu(II)-amylin analogue complexes in membrane mimicking solutions.

Membrane environment often has an important effect on the structure, and therefore also on the coordination mode of biologically relevant metal ions. This is also true in the case of Cu(II) coordination to amylin analogues-rat amylin, amylin, pramlintide and Ac-pramlintide, which offer N-terminal amine groups and/or histidine imidazoles as copper(II) anchoring sites. Complex stabilities are comparable, with the exception of the very stable Cu(II)-amylin, which proves that the presence of the amylin C-terminus lowers its affinity for copper(II); although not directly involved, its appropriate arrangement sterically prevents early metal binding.

A Comparative Study on Nickel Binding to Hpn-like Polypeptides from Two Strains.

Combined potentiometric titration and isothermal titration calorimetry (ITC) methods were used to study the interactions of nickel(II) ions with the N-terminal fragments and histidine-rich fragments of Hpn-like protein from two strains (11637 and 26695). The ITC measurements were performed at various temperatures and buffers in order to extract proton-independent reaction enthalpies of nickel binding to each of the studied protein fragments. We bring up the problem of ITC results of nickel binding to the Hpn-like protein being not always compatible with those from potentiometry and MS regarding the stoichiometry and affinity.

Metal specificity of the Ni(II) and Zn(II) binding sites of the N-terminal and G-domain of HypB.

HypB is one of the chaperones required for proper nickel insertion into [NiFe]-hydrogenase. HypB has two potential Ni(II) and Zn(II) binding sites-the N-terminal one and the so-called GTPase one. The metal-loaded HypB-SlyD metallochaperone complex activates nickel release from the N-terminal HypB site.

Chemical "Butterfly Effect" Explaining the Coordination Chemistry and Antimicrobial Properties of Clavanin Complexes.

Can a minor difference in the nonmetal binding sequence of antimicrobial clavanins explain the drastic change in the coordination environment and antimicrobial efficiency? This study answers the question with a definite "yes", showing the details of the bioinorganic chemistry of Zn(II) and Cu(II) complexes with clavanins, histidine-rich, antimicrobial peptides from hemocytes of the tunicate .

Zn-Enhanced Asp-Rich Antimicrobial Peptides: N-Terminal Coordination by Zn(II) and Cu(II), Which Distinguishes Cu(II) Binding to Different Peptides.

The antimicrobial activity of surfactant-associated anionic peptides (SAAPs), which are isolated from the ovine pulmonary surfactant and are selective against the ovine pathogen , is strongly enhanced in the presence of Zn(II) ions. Both calorimetry and ITC measurements show that the unique Asp-only peptide SAAP3 (DDDDDDD) and its analogs SAAP2 (GDDDDDD) and SAAP6 (GADDDDD) have a similar micromolar affinity for Zn(II), which binds to the N-terminal amine and Asp carboxylates in a net entropically-driven process. All three peptides also bind Cu(II) with a net entropically-driven process but with higher affinity than they bind Zn(II) and coordination that involves the N-terminal amine and deprotonated amides as the pH increases.