AdcA lipoprotein involved in Zn(II) transport in - is it as metal-specific as expected?

, a Gram-positive pathogen, is a primary causative agent of dental caries. It modifies the oral biofilm architecture on tooth enamel and, like other bacteria, requires transition metal ions such as Zn(II), Cu(II), and Ni(II) for survival and virulence. Physiological salivary Zn(II) levels are insufficient for optimal bacterial growth, prompting to develop a specialized ABC transport system comprising AdcA, AdcB, and AdcC.

Thiol, His-His Motif, and the Battle over Cu(II) in the Relationship of CopM Metallophore and OprC Outer Membrane Protein.

The mechanisms of Cu import across the bacterial outer membrane have been investigated only in a few cases. One such mechanism involves the outer membrane OprC transporter with a unique CxxxM-HxM metal-binding site, discovered recently. This newly identified site in OprC is located outside the cell and is, therefore, most likely to bind Cu(II) through this domain.

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.

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.

-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.

Investigation of metal interactions with YrpE protein of Bacillus subtilis by a polyhistidine peptide model.

The use of model peptides that can simulate the behaviour of a protein domain is a very successful analytical method to study the metal coordination sites in biological systems. Here we study zinc and copper binding ability of the sequence HTHEHSHDHSHAH, which serves as model for the metal interactions with YrpE, a putative metal-binding protein of the ZinT family identified in Bacillus subtilis. Compared to other ZinT proteins secreted by Gram-negative bacteria, the metal-coordination properties of YrpE N-terminal histidine-rich domain have not been yet characterized.

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.

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.

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.

Zinc(II)-The Overlooked Éminence Grise of Chloroquine's Fight against COVID-19?

Zn(II) is an inhibitor of 's RNA-dependent RNA polymerase, and chloroquine and hydroxychloroquine are Zn(II) ionophores-this statement gives a curious mind a lot to think about. We show results of the first clinical trials on chloroquine (CQ) and hydroxychloroquine (HCQ) in the treatment of COVID-19, as well as earlier reports on the anticoronaviral properties of these two compounds and of Zn(II) itself. Other FDA-approved Zn(II) ionophores are given a decent amount of attention and are thought of as possible COVID-19 therapeutics.

Novel Perspective on Alzheimer's Disease Treatment: Rosmarinic Acid Molecular Interplay with Copper(II) and Amyloid β.

Alzheimer's disease is a severe disorder that affects millions of people worldwide. It is a very debilitating disease with no cure at the moment. The necessity of finding an effective treatment is very demanding, and the entire scientific community is putting in a lot of effort to address this issue.

Metal Complexes of Two Specific Regions of ZnuA, a Periplasmic Zinc(II) Transporter from .

The crystal structure of ZnZnuA from reveals two metal binding sites. (i) The primary binding site, His143, is located close the His-rich loop (residues 116-138) and plays a significant role in Zn(II) acquisition. (ii) The secondary binding site involves His224.

Zinc Binding Sites Conserved in Short Neuropeptides Containing a Diphenylalanine Motif.

A diphenylalanine motif in peptides plays a crucial role in supramolecular systems. The current work represents a novel strategy in which a diphenylalanine motif in the central domain of neuropeptides conserves the specific Zn binding site and prevents "hopping" of the Zn ion between alternative metal binding sites. Alternative metal binding sites may also include carboxylic atoms in the terminal domains of a peptide.

Copper(II)-Induced Restructuring of ZnuD, a Zinc(II) Transporter from Neisseria meningitidis.

Cluster 2 (HDDDNAHAHTH) from Neisseria meningitidis ZnuD is a flexible loop that captures zinc(II) ions, acting as a "fishing net". We describe its Zn(II) and Cu(II) binding capabilities, focusing on the thermodynamics of such interactions and comparing them with the complexes of the MAHHHHHHL-NH region. Copper(II) complexes with the studied ZnuD regions are thermodynamically more stable than the zinc(II) ones-Cu(II) complexes dominate in solution even in close to physiological ratios of the studied metal ions (a 10-fold excess of Zn(II) over Cu(II)).

Structural analysis of copper(I) interaction with amyloid β peptide.

The N-terminal fragment of Aβ (β = beta) peptide is able to bind essential transition metal ions like, copper, zinc and iron. Metal binding usually occurs via the imidazole nitrogens of the three His residues which play a key role in the coordination chemistry. Among all the investigated systems, the interaction between copper and Amyloid β assume a biological relevance because of the interplay between the two copper oxidation states, Cu(II) and Cu(I), and their involvement in redox reactions.

How copper ions and membrane environment influence the structure of the human and chicken tandem repeats domain?

Prion proteins (PrPs) from different species have the enormous ability to anchor copper ions. The N-terminal domain of human prion protein (hPrP) contains four tandem repeats of the -PHGGGWGQ- octapeptide sequence. This octarepeat domain can bind up to four Cu ions.

Histidine tracts in human transcription factors: insight into metal ion coordination ability.

Consecutive histidine repeats are chosen both by nature and by molecular biologists due to their high affinity towards metal ions. Screening of the human genome showed that transcription factors are extremely rich in His tracts. In this work, we examine two of such His-rich regions from forkhead box and MAFA proteins-MB3 (contains 18 His) and MB6 (with 21 His residues), focusing on the affinity and binding modes of Cu and Zn towards the two His-rich regions.

Ag+ Complexes as Potential Therapeutic Agents in Medicine and Pharmacy.

Silver is a non-essential element with promising antimicrobial and anticancer properties. This work is a detailed summary of the newest findings on the bioinorganic chemistry of silver, with a special focus on the applications of Ag+ complexes and nanoparticles. The coordination chemistry of silver is given a reasonable amount of attention, summarizing the most common silver binding sites and giving examples of such binding motifs in biologically important proteins.

The effect of a membrane-mimicking environment on the interactions of Cu with an amyloidogenic fragment of chicken prion protein.

Prion proteins (PrP) from different species have the ability to tightly bind Cu ions. Copper coordination sites are located in the disordered and flexible N-terminal region which contains several His anchoring sites. Among them, two His residues are found in the so called amyloidogenic PrP region which is believed to play a key role in the process leading to oligomer and fibril formation.

Poly-Xaa Sequences in Proteins - Biological Role and Interactions with Metal Ions: Chemical and Medical Aspects.

Background: The understanding of the bioinorganic and coordination chemistry of metalloproteins containing unusual poly-Xaa sequences, in which a single amino acid is repeated consecutively, is crucial for describing their metal binding-structure-function relationship, and therefore also crucial for understanding their medicinal potential. To the best of our knowledge, this is the first systematic review on metal complexes with polyXaa sequences.

Methods: We performed a thorough search of high quality peer reviewed literature on poly-Xaa type of sequences in proteins, focusing on their biological importance and on their interactions with metal ions.

HENRYK - An endless source of metal coordination surprises.

The basic knowledge about biological inorganic chemistry, thermodynamics and metal binding sites of metalloproteins is crucial for the understanding of their metal binding-structure-function relationship. Metal-peptide complexes are useful and commonly used models of metal-enzyme active sites, among which copper and zinc models are one of the most extensively studied. HENRYK is a peptide sequence present in numerous proteins, and serves as a potentially tempting binding site for Cu and Zn.

The Eighth Central European Conference "Chemistry towards Biology": Snapshot.

The Eighth Central European Conference "Chemistry towards Biology" was held in Brno, Czech Republic, on August 28-September 1, 2016 to bring together experts in biology, chemistry and design of bioactive compounds; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topics of the conference covered "Chemistry towards Biology", meaning that the event welcomed chemists working on biology-related problems, biologists using chemical methods, and students and other researchers of the respective areas that fall within the common scope of chemistry and biology. The authors of this manuscript are plenary speakers and other participants of the symposium and members of their research teams.

Specific binding modes of Cu(I) and Ag(I) with neurotoxic domain of the human prion protein.

Prion diseases are neurodegenerative disorders associated with a conformational change of the normal cellular isoform of the prion protein (PrP(C)) to an abnormal scrapie isoform (PrP(Sc)). human prion protein (hPrP(C)) is able to bind up to six Cu(II) ions. Four of them are distributed in the octarepeat domain, containing four tandem-repetitions of the sequence PHGGGWGQ.