The Role of Complexes of Biogenic Metals in Living Organisms

Abstract

Biogenic metals and their various inorganic, organometallic, and coordination compounds are comprehensively studied and extensively used in medical practice. Since the biogenic metals have various chemical properties corresponding to their position in the periodic table, their biological functions are different. Almost all of the discussed biogenic elements have an ability to form coordination complexes. Furthermore, the different accessible oxidation states occupied by most of these elements enables the body to catalyze oxy-reduction interactions, depending on the biological conditions. As they are biogenic in nature, their deficiency or their excess in the body leads to numerous pathological obstructions. The application of metal-based compounds as medications is connected with the oxy-reduction properties and the capability to form coordination complexes, which are involved in many bioreactions. The usefulness of these metals as therapeutic and diagnostic agents is also pointed out.

1. Introduction

Biogenic elements include the following ten vital metals: Na, K, Mg, and Ca (s elements); Mn, Fe, Co, Cu, and Zn (3d elements) and only one 4d element: Mo. It has been established that many other metals, except for the ten ones that have been mentioned, also exhibit biogenic properties, but their role is not yet fully understood [1,2,3,4,5,6,7,8,9,10,11].

The biosphere is a medium with a fluid equilibrium at both the macro- and micro-levels. Different elements in the biosphere are characterized by different distributions in the intra- or extracellular spaces. Therefore, the extracellular biogenic elements are Na, Ca, Cu, and Mo, and intracellular elements are K, Mg, Fe, Co, Zn, and Mn.

s elements are filled with electrons in the s subshell. Depending on the degree of filling of the s subshell, s elements are classified into IA and IIA groups of the periodic table: s¹ elements (alkali metals) and s² elements (alkaline earth metals), which are located in groups IA and IIA, respectively. These elements have constant oxidation states because they have one (s¹ elements) or two (s² elements) electrons at the external electronic level, which the atoms of the s elements easily give up, turning into one- (s¹ elements) and two-charged (s² elements) ions. It is generally accepted that although they can form complex compounds with organic and inorganic ligands, the kinetic stability of these coordination complexes is very minimal, since the bonds of the s elements with the ligands are mainly ionic in nature. It should be mentioned anyway that stability depends on the ligands, and there are some exceptions to this rule [12,13,14,15]. The alkali metal ions, which are least capable of forming coordination bonds, are involved in the creation of the electrolyte environment of the body, and they determine the processes of absorption of substances due to differences in the amount of osmotic pressure in the organs and tissues.

Of the alkali and alkaline earth biometals, the most important ones are sodium, potassium, magnesium, and calcium, which operate to preserve the charge and osmotic equilibrium, or they act as structural elements, respectively [1,2]. Biogenic s elements participate mainly in the implementation of triggering and control mechanisms [16,17,18]. Na⁺, K⁺, Mg²⁺, and Ca²⁺ ions regulate muscle contractions and the release of hormones and mediators; moreover, ions K⁺ and Mg²⁺, being intracellular cations, stabilize the architecture of the cell and activate a number of enzymes [19]. In contrast, the Na⁺ and Ca²⁺ ions are extracellular cations, and their functions are, in many ways, opposite to their chemical analogues. Mg²⁺ and Ca²⁺ ions are very significant for maintaining certain nucleic acids conformations [20,21]. These ions are involved in the hardening of numerous lipoprotein membranes. Mn²⁺, Mg²⁺, and Ca²⁺ ions act as a basis for the orientation of functional groups in the enzyme catalysis of the type E–M–S (where E is an enzyme, M is a metal ion, and S is a substrate), which involves a number of enzymes. Ca²⁺ ions, which form poorly soluble compounds, serve as the basis for the "bearing" systems of the body: the skeleton and cartilage.

The typical biochemical properties of the vital d-metals and their compounds are oxidation–reduction and complex formation reactions. The transition metals have unfilled or partially filled d-orbitals, therefore their oxidation states in the compounds are variable, which explains their affinity to participate in a great range of oxidation–reduction reactions, thus influencing the magnetic and electronic properties of their complexes.

All of these elements are highly capable of forming coordination complexes because of the free s- and p-orbitals and partially vacant d-orbitals, which enable them to form additional donor–acceptor bonds in the coordination complexes, thus acting as perfect complexing agents. Transition biogenic metals have special properties (

Table 1. Classification of cations in biological systems.

Ions	Na+ and K+	Mg2+ and Ca2+	Zn2+	Fe, Cu, Co, Mn, and Mo (in the Form of Mn+)
Function	Charge carriers	Solid structures	Acids and catalysts	Catalysts for oxidation–reduction reactions
Characteristics	Mobile	Moderately mobile	Static and inert	Static, inert
Stability in biological systems	Weak stability complexes	Moderate stability complexes	Stable complexes	Stable complexes
Preferred donor atoms	Coordination with donor O atoms	Coordination with donor O atoms	Coordination with donor N atoms	Coordination with donor N and S atoms

) due to their good complex-forming ability. While forming a variety of complexes with numerous bioligands of a living organism, transition bio-metals essentially behave as the "organizers of life".

Principally, transition metals are expected to undergo oxy-reduction reactions. The ions of the biogenic transition metals are the best-known constituents of a great number of enzymes, hormones, other proteins, vitamins, and many vital bio-compounds. These elements exist mostly in the form of coordination compounds in the organism. The essential d elements are often called the metals of life. Some examples of biologically active complex compounds are shown in

Table 2. Metal-containing proteins and enzymes of biogenic metals.

Biometal	Biological System/Bioligand
Na	Extracellular cation; buffer systems, osmosis, Na+/K+- pump; activator of Na-specific ATP-ase [22]
K	Membrane pumps Na+/K+ ATPase; activator of pyruvate phosphokinase and K-specific ATPase [23]
Mg	Chlorophyll; activator of phosphotransferase, phosphohydrase [24]
Ca	Ca2+-ATPase membrane pump; calmodulin transduces Ca2+ signals in cells; calcitonin, aspartates, glutamates [25]
Mn	Activator of enzymes - pyruvate carboxylase, arginase, cholinesterase, phosphoglucomutase, peroxidase, aminophenol oxidase; glutamine synthetase; Mn superoxide dismutase in mitochondria [26]
Fe Fe (heme) Fe (non-heme)	Hematopoietic processes and electron transfer [27]. Hemoglobin; cytochromes; catalase; peroxidase; tryptophan, dioxygenase. Pyrocatechase, ferredoxins, hemerythrin, transferrin, aconitase.
Co (B12 coenzyme) Co (non-corrin)	Vitamin B12 (cyanocobalamin); glutamate mutase, dioldehydrase, methionine synthetase [28]. Dipeptidase, ribonucleotide reductase.
Cu	Processes of hematopoiesis, respiration, angiogenesis and neuromodulation; Cu-containing metalloproteins and metalloenzymes (about 1% of total proteome): cytochromes, Cu(histidine)2, tyrosinase, amino oxidase, laccase, peroxidase, ascorbate oxidase, ceruloplasmin, superoxide dismutase, plastocyanin, and methionine synthetase [29].
Zn	Processes of reproduction; the enzymes carbonic anhydrase, Zn(gluconate)2, carboxypeptidase, and alcohol dehydrogenase [30].
Mo	Enzymes oxidases: aldehyde, sulfite, molybdopterin, a xanthine oxidases in purine metabolism [31].

.

Natural coordination compounds with proteins and other biopolymers are important in many aspects. Porfinic system forms stable complex compounds with metal ions such as Mg²⁺ and Fe²⁺, which act as the central atoms in biomolecules such as heme, the constituent of hemoglobin and chlorophyll, a complex of porphyrin and magnesium(II) ion. The cobalt(III) porphin complex is a part of cobalamin (vitamin B₁₂). Numerous transition metals form complexes with different proteins in metalloenzymes. In bio-redox catalysis, metal ions help to trigger coordinated substrates, as well as take part in the respective redox-active sites for the accumulation of charges. In this connection, transition metals that are capable of realizing several stable oxidation states are distinguished: copper(I, II), iron(II, III), cobalt(II, III), and molybdenum(IV, VI). For example, it is enough to mention the iron-containing systems such as catalase and cytochromes or the copper-containing ones such as superoxide dismutase and cytochrome c-oxidase. Biogenic metals are the centers of about 30% of all enzymatic systems (Table 2). Metals such as Mg and Zn participate in enzymatic hydrolysis reactions. Metals exhibiting variable valence and variable coordination numbers (Cu, Fe, and Mo) regulate many redox processes [6,7,8].

It is worth mentioning that the functions of the biogenic d-metals have a dual character. At the ordinary levels, they are vital for the cellular structures’ stabilization, but at deficient levels, they may activate alternative pathways, thus causing diseases, and in high levels they are poisonous. The metabolism in the human body that supports the complexation processes and metal-ligand homeostasis violation can result in the different diseases, for instance, iron deficiency anemia. Pathologies in the vital activity of the body that are associated with deviations from the normal content of biogenic metals are presented (

Table 3. Pathologies in the vital activity of the body associated with deviations from the normal content of biogenic metals.

Metal	Specific Function	Deficiency Signs	Excess/Toxic Effect and Antidotes
Sodium	Membrane pumps Na+/K+ ATPase	Hyponatremia [32]	Hypernatremia [33]
Potassium	Membrane pumps Na+/K+ ATPase	Hypokalemia [34]	Hyperkalemia [35]
Magnesium	MAGT1, magnesium transporter 1	Hypomagnesemia; cardiac arrest [36]	Hypermagnesemia is reversed by intravenous injection of a corresponding amount of Ca2+; hypotension [37]
Calcium	Ca2+-sensor protein troponin; Ca2+-ATPase membrane pump; calmodulin transduces Ca2+ signals in cells	Hypocalcemia; demineralization of bone [38]	Hypercalcemia; magnesium deficiency;hyperparathyroidism or malignancy [39]
Manganese	Carbohydrate metabolism; glutamine synthetase; Mn superoxide dismutase in mitochondria; pyruvate carboxylase, etc.	Growth depression; bone and cartilage deformities; membrane abnormalities connective tissue defects [40]	Psychiatric neurodegenerative disorder—manganism [41]; ROS production; interferes with iron metabolism
Iron	Hemoglobin (Fe2+); catalase and peroxidase (Fe2+ → Fe3+); cytochrome c (Fe2+ → Fe3+); non-heme Fe proteins ca1% of human proteome	Iron deficiency anemia; general weakness [42]	Hemochromatosis; cirrhosis of the liver; blockage of blood vessels; antidote—desferrioxamine [43]
Cobalt	Constituent of vitamin B12; hematopoietic processes are involved in the synthesis of hemoglobin uptake and carrier proteins for vitamin B12	Anemia; anorexia; growth retardation; need for vitamin B12 [44]	Hypothyroidism; overproduction of erythrocytes; interferes with the synthesis of hemoglobin; inhibits the consumption of O2 in heart mitochondria [45]
Copper	Cu- containing metalloproteins and oxidative metalloenzymes involved in heme synthesis; Cu proteins ca 1% of human proteome	Anemia; ataxia; defective melamine production and keratinization, circulatory disorders, bone defects [46]	Excess of Cu―liver necrosis in Wilson’s disease; hypertension; rheumatoid arthritis; antidote—cysteine; D-penicillamine [47]
Zinc	The enzyme carbonic anhydrase, endocrine glands, the processes of reproduction; Zn2+ proteins ca 10% of human proteome	Deficiencies in the development of the skeleton, sexual development; anorexia; growth reduction; depression of immune response a pronounced need for vitamin A [48]	Relatively non-toxic except at high doses; excess is quickly removed and does not harm; antidote—D-penicillamine
Molybdenum	Oxidases: aldehyde; sulfite; xanthine; molybdopterin; purine metabolism	Growth depression; defective keratinization; need for specific enzymes [49]	Excess disturbs purine metabolism—endemic gout; urate deposits; osteoporosis; anemia [50]

).

The toxic effects of d elements, are in many cases, due to their ability to form coordination bonds with the functional groups of bioligands present in the body. Consequently, a poison is created with the compounds of d elements due to the formation of strong complexes with the proteins and enzymes in the body, resulting in the disruption of important metabolic processes (Table 3). Raw materials and foods are contaminated with toxic elements through gaseous, liquid, and solid emissions and waste from industrial and energy enterprises, communal and agro-industrial enterprises, vehicles, and through the use of technological equipment, etc. These elements move into plants, animals, and fish in the air, water, and soil, and as a result, they move into the human body with food products.

Many metal complex compounds are used as medicinal substances and therapeutic agents [1,2,9]. Compounds of iron are used for the treatment of iron deficiency anemia, preparations of zinc are used for dermatology, and chelating (complexation) agents are used as antioxidants and detoxicants, as well as for the fastening of heavy metals during poisoning (lead, mercury, cadmium, and others).

2. Biologically Active Complex Compounds: Theoretical Overview

2.1. Mutual Selectivity and Affinity of Metals to Ligands

In the body, there is a great number of potential complexing agents [10,11]. The theoretical quantum-chemical explanation is more accurate and wide ranging, but the complex structures of the substances and the diversity of the vital bioprocesses are a precondition for the development of semi-empirical concepts characterizing the joint affinity and selectivity of the metal ions and bioligands in the formation of coordination bonds at a highly theoretical level. In this regard, the following aspects are the most imperative ones: (a) the creation of functional groups of biologically active molecules coordinated to the cation; (b) the regulation of the competitive bioprocesses including various ligands (together with drugs) for the respective metal for therapeutic or diagnostic purposes.

One of the most important theoretical approaches in the field is the usage of the hard and soft acids and bases principle (HSAB), which were developed by R. Pearson. In accordance with the HSAB principle, acid–base reactions take place in such a way that hard the acids preferably bind to hard bases, but soft acids bind to soft bases. The assignment of compounds to a specific group must take into account chemical and electronic structures and the relative complex stability:

M + :L ↔ M : L,

where M is a Lewis acid and L is a Lewis base.

Typical features of acids and bases, corresponding to HSAB principle, are given in

Table 4. Characteristics of acids and bases according to the HSAB principle.

Type	Acid	Base
Hard	Acceptors with high positive charges, low polarizability, land ow LUMO energy; difficult to reduce	Donors with low polarizability, high electronegativity, and low HOMO energy; difficult to oxidize
Soft	acceptors; with lower positive charges, high polarizability, and high LUMO energy; easily reduced ones.	donors with high polarizability, low electronegativity, and high HOMO energy; easily oxidized ones.

.

The preferred binding of Lewis acids and bases is clarified by the fact that the interaction of orbitals that have similar energies is most efficient. If the reagents are hard, then the interaction is mainly electrostatic, and for the soft reagents, the preferred interaction is covalent in nature. A comparison of the stability of the obtained complexes in relation to the basic representatives has made it possible to divide the acids and bases into groups. In

Table 5. Classification of hard and soft acids and bases.

Type	Acid	Base
Hard	Na+, K+, Mg2+, and Ca2+, Mn2+	F−, Cl−, OH−, H2O, ROH, CH3CO2−, NH3, ClO4−, CO32−, PO43−, SO42−, and NO3−
Intermediate	Fe2+, Co2+, Cu2+, and Zn2+	aniline, pyridine, N3−, Br−, NO2−, and SO32−
Soft	Cu+, Ag+, Cd2+, Hg+, and Hg2+	I−, H−, CO, CN−, R3P, R2S, RSH, SCN−, S2O32−, alkenes, and arenes

, examples of the main groups are given.

The HSAB principle has proven itself taking into account the specific interactions, considering the competing reactions, explaining the binding of cations in biosystems. Therefore, the increase in the oxidation state of the metal increases its hardness according to this principle. It is noticed that different oxidative states can be stabilized by the respective ligands. It is necessary to draw attention to the possible symbiosis of the ligands. This means a preferential inclusion in the complex of ligands that are close in their degree of hardness or softness. Consequently, alkaline and alkaline earth biogenic metals will form complex compounds with water or inorganic ions (CO₃²⁻, PO₄³⁻, and SO₄²⁻), as well as with carboxyl-containing organic compounds (glutamate and lactate, etc.) [51]. Transition metals have a preference for N-containing and S-containing compounds, and the most effective donor depends on the metal oxidation state [52].

Based on this approach, it is easy to explain the well-known toxicity of compounds of a number of heavy metals: the so-called thiol poisons (cadmium, lead, and mercury) [53]. They firmly block thiol functions in the active centers of many enzymes, and the body normally lacks compounds that can compete with them. Considering other features of the M–L interaction, it should be taken into consideration that the metal cation can alter the selectivity of the bioligand by affecting the electron distribution in the organic molecule, increasing the reactivity of the ligand’s active center; providing the possibility of electron transfer; producing a conformational change in the ligand; increasing the ligand’s lipophilicity, and therefore, its capability to penetrate cells.

2.2. Inorganic Substances as Bioligands

Water is the main inorganic bioligand. This unique solvent has a fairly high donor capacity for coordination. In this process, the acidity of the medium plays a chief role. Thus, when the pH decreases, protons effectively compete with metal ions for water molecules, and H₂O is displaced from the complex by acido-ligands, and when the pH increases, another potential donor appears in the system, namely OH⁻ anion. The formation of a coordination bond facilitates the dissociation of water by acidic type, which can lead to hydrolysis. The result of hydrolysis should be the formation of poorly soluble basic salts and metal hydroxides. Thus, in accordance with the values of their solubility products in blood at pH = 7.4, Fe^{3 +}, Cu^{2 +}, and Zn²⁺ ions should go into precipitate. However, this does not happen, since most biogenic metals in the body are bound in various complexes with other bioligands, and aqua complexes are not dominant. Probably, aqua complexes represent a temporary form of biometal bonding that is important in a number of biochemical processes [1,2]. Examples of vital hydroxo complexes are hydroxyapatite, hydroxocobalamin, and ferritin, etc.

One of the buffer systems in the body is formed by anions of phosphoric acid. They play a critical role in the metabolic processes of carbohydrates. A number of bonds of phosphate with organic radicals are macroergic, which is used for condensation and transformation of energy [54]. Sulfate ions are also intracellular, and sulfate conjugation is one of the most important ways to solubilize xenobiotics in order to facilitate their excretion from the body [55].

The chloride anion Cl⁻ is the main extracellular anion. Accordingly, its role in maintaining osmotic pressure and membrane equilibrium is important. This ion is also necessary for the generation of hydrochloric acid in gastric juice. Other halide ions are represented in the body in smaller quantities, but they perform similarly important functions [56]. Thus, fluoride anions F⁻ are essential for normal bone tissue formation, especially teeth, where they are concentrated in the form of fluorapatite. For the bromide ion Br⁻, a sedative effect is noted. The iodide anion I⁻, after organification, is a part of the thyroid hormones (thyroxine and triiodothyronine).

Carbonic acid anions are continuously formed by complex organic substances. There is even a problem of their utilization, which is solved by gas exchange in the lungs. The required rate of establishing the equilibrium H₂CO₃ ↔ H₂O + CO₂ is maintained by a special enzyme: carbonic anhydrase [57]. Carbonate and bicarbonate ions implement a buffering effect in the blood. However, their coordination affinity is small and manifests itself only when they are interacting with hard acceptors. This statement is true for most of the other oxyanions. Many other common inorganic bioligands such as ammonia and nitrogen oxides, etc., are parts of biologically active complexes [1,2,5,6,7,8]. Inorganic bioligands are further discussed.

2.3. Organic Substances as Bioligands

Various organic molecules can act as bioligands, both those that are present in the body initially (endogenous ligands) and those entering the body from the outside (exogenous ligands): vitamins, drugs, and toxic substances in the external environment, etc. [1,2,5,6,7,8,52].

The body has a relatively small set of simple molecules involved in biochemical processes. Most of the endogenous ligands interact with each other, forming macromolecules (biopolymers) with very complex structures. The properties of such macromolecules depend on the nature of the simple molecules that make up their composition, on the order of their binding to each other, as well as on the spatial structure of the resulting biopolymer. Of course, in the aqueous phase of the body, there are also simple inorganic anions (chloride, sulfate, carbonate, and phosphate, etc.) that interact with metal ions [52,58]. However, one of the most characteristic features of living systems is the formation of coordination bonds with macromolecules, viz. biopolymers. There are three most important types of biopolymers in the body: polysaccharides, proteins, and nucleic acids.

Polysaccharide molecules are built from a large number of identical, repetitive structural units, the role of which can be played, for example, by simple carbohydrates (glucose or fructose).

The main type of cell biopolymers are proteins [18,58]. They are formed as a result of combinations of 21 amino acids. When the amino acids interact, peptides are obtained, which after interacting with the amino acid, form polypeptides. Polypeptide chains are organized into spatial configurations that determine the structure of a given protein. All amino acids, peptides, and proteins are bioligands with active donor atoms (O, N, and S, etc.), and they can form stable coordination compounds with ions of various metals. Some proteins contain four strongly bound pyrrole nuclei that form the skeleton of porphin.

A very important class of biopolymers are nucleic acids. These compounds perform functions related to the storage and transmission of biological information. It is in the molecules of nucleic acids that all the necessary information is encoded for the synthesis of diverse proteins necessary for a given organism. Just as polysaccharides are built from simple sugars and proteins are constructed from amino acids, nucleic acids are made up of nucleotides [18,52,58]. The most important nucleotide is adenosine triphosphoric acid (ATP). In terms of coordination chemistry principles, ATP is an active ligand because it contains many different donor atoms that coordinate with the metal ions. These are heterocyclic nitrogen atoms of the nitrogen-bearing base, oxygen atoms of the ribose fragment, and oxygen atoms of the phosphate group. The wide variety of organic bioligands are further discussed in the relevant sections.

2.4. Main Factors for the Formation of Stable Metal Complexes

Many studies are devoted to the factors that determine the affinity of metals and ligands during complexation. The type of reactants and the bond strength can be substantiated using the HSAB concept. though it deals principally with the atoms’ characteristics which directly form the bond, although spatial aspects are also important in complexation. The ligand structure presupposes the existence of appropriate donor groups and their suitability to the respective geometry of the complex ion. Two characteristics can be taken into account: (1) the primary structural ligand organization and the option of implementing the essential conformations of the molecule; (2) the structural correspondence among the binding centers of donors and acceptors. If the ligand’s spatial region size, where the donors are localized, is bulky, then in that area, a large number of bonds can be formed. The opposite is also right: the cation will not be able to enter into a very small area. The idea of dimensional correspondence has been widely applied to explain biocoordination reactions and to develop suitable models. The most stable metal complexes can be formed with the ligands of suitable radius sizes. Nevertheless, the optimal distance between the reaction centers is a necessary, but not satisfactory, condition for the stable complex formation. One significant factor is the metal ion topography, i.e., the optimal polyhedral geometry. Additionally, if for biogenic metals of the IA and IIA groups there is no strict requirement for polyhedral geometries, for transition biogenic metals, the bonds direction is a decisive factor for the complex’s stability. However, due to the hypothesis of dimensional correspondence, an important factor such as the orientation of donor atoms in relation to metal ions often goes unnoticed. For covalent bonds, the orbital correspondence is important, and for ionic bonds, optimal electrostatic interaction is important. Additionally, if the binding of polydentate ligands does not lead to a strong angular stress, then a fairly stable complex is formed. For instance, it was established that ethylenediamine forms stable five-membered chelates with metal ions of large radius, and propylene diamine forms six-membered chelates with ions of a small radius. The study of a large number of systems (in particular, polyamines and polyesters) has led to the following improvement: complexes of larger cations are more destabilized with a rise in the number of bonds in the chelate ring. There is a linear correlation between the stability constants and the energy of these angular stresses. Thus, the factors discussed above make it possible to take into account and possibly minimize the structural stresses arising from possible deformations of the bond lengths, valence, and torsion angles.

Biogenic metal ions can have various functions depending on their position in the biosystems [1,2,59,60,61,62,63,64,65,66,67,68]. Depending on the prevailing coordination environment, the metal ion charge can be changed to produce cationic, anionic, or neutral species. Metal ions, such as Zn(II), serve as structural elements in SOD and zinc fingers, while Ca(II) ions serve as triggers for protein activity in calmodulin or troponin C. The transition metals that occur in various oxidation states function as electron carriers such as Fe cations in cytochromes, hemoglobin, and Fe-S clusters of nitrogenase or Cu cations in hemocyanin, azurin, and plastocyanin, etc.

Table 6. Biogenic metal ions in biological systems.

Biogenic Metal Ion	Typical Coordination Number and Geometry	Preferred Donor Atoms and Bioligands	Biological Functions
Sodium, Na+ Potassium, K+	6, octahedral 6-8, flexible	O-Ether, hydroxyl, carboxylate O-Ether, hydroxyl, carboxylate	Charge carrier, osmotic balance, nerve impulses, and muscle contractions [69]. Charge carrier, osmotic balance, nerve impulses, and muscle contractions [70].
Magnesium, Mg2+ Calcium, Ca2+	6, octahedral 6-8, flexible	O-Carboxylate, phosphate O-Carboxylate, carbonyl, phosphate	Structural function in hydrolases, isomerases, phosphate transfer, and trigger reactions [71]. Structure, charge carrier, phosphate transfer, and trigger reactions [72].
Manganese, Mn2+ (d5) Manganese, Mn3+ (d4)	6, octahedral 6, tetragonal	O-Carboxylate, phosphate, N-imidazole O-Carboxylate, phosphate, hydroxide	Structural function in oxidases, and photosynthesis. Structural function in oxidases, and photosynthesis [73].
Iron, Fe2+ (d6) Iron, Fe2+ (d6) Iron, Fe3+ (d5) Iron, Fe3+ (d5) Iron, Fe2+ (d6)	4, tetrahedral 6, octahedral 4, tetrahedral 6, octahedral 6, octahedral	S-Thiolate O-Carboxylate, alkoxide, oxide, phenolate S-Thiolate O-Carboxylate, alkoxide, oxide, phenolate N-Imidazole, porphyrin	Electron transfer, nitrogen fixation in nitrogenases, and electron transfer in oxidases. Electron transfer, nitrogen fixation in nitrogenases, and electron transfer in oxidases [74]. Dioxygen transport in hemoglobin and myoglobin [75].
Cobalt, Co2+ (d7) Cobalt, Co3+ (d6) Cobalt, Co2+ (d7) Cobalt, Co+ (d8)	4, tetrahedral 6, octahedral 6, octahedral 6, octahedral, missing ligand	S-Thiolate, thioether, N-imidazole O-Carboxylate, N-imidazole O-Carboxylate, N-imidazole O-Carboxylate, N-imidazole	Enzyme catalysis: Alkyl group transfer, oxidases. Enzyme catalysis: Alkyl group transfer in Vitamin B12 (cyanocobalamin). Enzyme catalysis: Alkyl group transfer in Vitamin B12r [76]. Enzyme catalysis: Alkyl group transfer in vitamin B12s [77].
Copper, Cu+ (d10) Copper, Cu2+ (d9) Copper, Cu2+ (d9)	4, tetrahedral 5, square pyramid 6, tetragonal 4, square planar	S-Thiolate, thioether, N-imidazole O-Carboxylate N-Imidazole O-Carboxylate, N-imidazole	Electron transfer in Type I blue copper proteins [78]. Type II copper oxidases, hydroxylases Type III copper hydroxylases, dioxygen transport in hemocyanin. Enzyme catalysis: Type II copper in oxidases.
Zinc, Zn2+ (d10) Zinc, Zn2+ (d10)	4, tetrahedral 5, square pyramid	O-Carboxylate, carbonyl, S-thiolate, N-imidazole O-Carboxylate, carbonyl, N-imidazole	Structural function in zinc fingers [79]; gene regulation, anhydrases, and dehydrogenases. Structural function in hydrolases, peptidases.
Molybdenum, Mo4+ (d2)	6, octahedral	O-Oxide, carboxylate, phenolate, S-sulfide, thiolate	Enzyme catalysis, nitrogen fixation in nitrogenases [80], and oxo transfer in oxidases.

represents the classification of the biogenic metals and their main functions in the biological systems.

3. Biological Activity of Biogenic Metals and Their Coordination Compounds

3.1. Sodium and Potassium

Of the alkali metals, the most important ones are sodium and potassium. They do not produce solid complex compounds, but these ions can form associates through dipole–ion interaction. Hence, due to the larger surface charge density, the radius of the hydrated Na⁺ is bigger than that of the hydrated potassium cation. If in the geosphere, sodium and potassium cations permanently meet together, their separation is not an easy task, but in the biosphere, these cations are localized on different cell membrane sides. The sodium cation is the key extracellular ion in the body, while the potassium cation is intracellular. In spite of the resemblance in their chemical behaviors, Na⁺ and K⁺ cations display biological antagonism. The two biogenic metals are crucial elements in maintaining osmotic balance, transmitting nerve impulses, and regulating the contractions of muscles. Their source for consumption by the human body is plant food and table salt. Losses are associated with sweating (NaCl) and urination (urates and lactates of potassium and sodium). The process of life is associated with the maintenance of a non-equilibrium state. For these metals, this is their distribution relative to the cell membranes. The most studied one is the energy-dependent Na/K pump in animal cells, thanks to which a higher amount of K⁺ cations and a smaller amount of Na⁺ cations are maintained in the cell in comparison with those in the environment, and ATP energy is spent on this process [12,16,17,22,23]. The energy needed to transport Na⁺(in) → Na⁺(ex) and K⁺(ex) → K⁺(in) contrary to the concentration gradient is produced by ATP hydrolysis [81]. Ionophores are employed for the selective trans-membrane transport of Na⁺ und K⁺ through the cell’s membrane [82]. Ionophores are macrocycles with oxygen-functional groups that produce stable complexes in vivo, particularly with sodium and potassium ions. They are heterocyclic structures such as crown ethers, cryptands, and calixarenes [83]. Naturally occurring ionophores are antamanide (for Na⁺) and nonactin and enniatine (for K⁺).

The Na⁺-K⁺ ATPase plays a prominent role in thyroid pathophysiology [84], cardiovascular pharmacology [85], and in the etiology of bipolar disorders [86], and it is a potential target for drug development for treatments. Na⁺-K⁺ ATPase holds promise as an antiviral strategy to minimize the resistance to antiviral drugs, and it has been proved to be effective [87]. There is evidence for a cycle of enhancement of Na/K-ATPase oxidant in the processes of aging, obesity, and cardiovascular disease [88]. There are reports of abnormal expression levels or activity of the Na⁺K⁺ pump in hypertension, diabetes, Alzheimer’s disease, and in various tumors including non-small-cell lung carcinoma, glioblastoma, melanoma, colorectal carcinoma, and breast and bladder cancers [89].

The transmembrane Na⁺/H⁺ antiporters or exchangers (NHEs) transport Na⁺ (or some other monovalent cations) in exchange for H⁺ across lipid bilayers in all kingdoms of life, which is crucial in the pH homeostasis of the cytoplasm and/or organelles [90]. Sodium/proton exchangers are integral membrane proteins that are present in almost all living organisms. In mammals, these transporters are critical for numerous physiological processes. Altered NHEs activity has been linked to the pathogenesis of several diseases, including cancer, heart failure, diabetes, epilepsy, hypertension, and tissue damage caused by ischemia/reperfusion [91,92].

In the human body, sodium comes mainly in the form of sodium chloride. NaHCO₃ is used to increase the acidity of gastric juice and to treat peptic ulcers of the stomach and duodenum, as well as inflammatory diseases of the eyes and the mucous membranes of the upper respiratory tract. Na₂SO₄·10H₂O is used as a laxative. Na₂B₄O₇·10H₂O is applied as an antiseptic for douching, rinsing, and lubrication. NaI and KI are used as iodine preparations for thyroid diseases. NaBr and KBr are sedatives. NaF is used in dentistry. NaNO₂ is prescribed orally, subcutaneously, and intravenously (1% solution) as a coronary dilator agent for angina pectoris. Na₂S₂O₃ is applied as an antitoxic and desensitizing agent. Sodium citrate is used in the form of a solution for blood preservation. Radioactive ²⁴Na is used as a label to determine the blood flow velocity and to treat some forms of leukemia. The complex compound sodium nitroprusside Na₂[Fe(CN)₅NO] (Figure 1) serves as a means for lowering blood pressure, since this drug relaxes the muscles of blood vessels [93,94].

Potassium chloride used in conditions accompanied by a violation of electrolyte metabolism in the body (uncontrollable vomiting and profuse diarrhea), as well as for the relief of cardiac arrhythmias. KMnO₄ is used externally as an antiseptic solution for washing wounds, rinsing the mouth and throat, and lubricating ulcerative and burn surfaces, etc. The natural radioisotope ⁴⁰K (β-emitter) poses a health hazard under both β-particles and γ-rays.

The increased level of Na⁺ in the serum (hypernatremia) leads to high blood pressure and peripheral and pulmonary edemas with respiratory failure [33]. In contrast, low levels of serum Na⁺ (hyponatremia) occur in nephrosis, acute Addison’s disease, burns, intestinal obstruction, vomiting, diarrhea, and sweating, etc. [32,33]. The serious decrease in sodium cations in the extracellular space may lead to hypotension, circulatory collapse, and syncope.

High levels of K⁺ in the serum (hyperkalemia) occur in Addison’s disease, advanced chronic renal failure, chronic dehydration, and shock [35]. The main symptoms of hyperkaliemia manifest themselves generally in the nervous system and in the heart (ECG changes, bradycardia, and arrhythmias). On the other hand, low levels of serum K⁺ (hypokalemia) lead to metabolic alkalosis, diarrhea, and episodic paralysis [34]. The primarily observed symptoms of hypokalemia are nausea, anorexia, irregular pulse, a decrease in blood pressure, and muscle weakness, as well as mental depression.

3.2. Magnesium and Calcium

Magnesium and calcium ions of alkaline earth metals are less polarizable than Na⁺ and K⁺ ions are, and they can form complex compounds with coordination number 6. There are many more Mg²⁺ ions inside the cell, whereas Ca²⁺ is principally an extracellular ion [12,13,14,15,20]. Chemical bonds in most of Mg compounds have a covalent nature. Mg²⁺ ions are involved in the formation of the tertiary DNA structure, the transmission of nerve impulses, and the activation of enzymes (hexokinase, phosphate transferases, ligase, and arginase, etc.) [24,71]. Ca²⁺ ions are essential for bone tissue formation, in lactation, during the realization of heart contractions, for the activation of enzymes, and they also cause coagulation [25,72]. Calcium levels are regulated by a special hormone: calcitonin.

Magnesium has a crucial role in the phosphate metabolism where it interacts with phosphate or diphosphate and carboxylate, consequently activating the molecules and triggering the activation paths. It serves as a center of some metalloenzymes (kinases, ATPases, phosphatases, isomerases, enolases, protein synthases, and polymerases). Magnesium catalyzes such an important hydrolysis process of ATP (Figure 2).

The complex of magnesium with ATP is included in the substrate of the enzyme kinase, which is responsible for the transfer of phosphate groups. The Mg²⁺ coordination sphere is enhanced by H₂O and OH⁻ anions. Kinases are regulated by calmodulin and similar proteins, and they represent the basis of the signaling systems in living organisms [12,13,14,15,71].

In plants, Mg²⁺ is a coordination center of two key enzymes that regulate photosynthesis, which consists of the conversion of H₂O and CO₂ into carbohydrates and O₂ under the influence of light. In the dark stage of photosynthesis, Mg²⁺ is the center of an enzyme comprising ribulose-1,5-diphosphate (Figure 3) carboxylate, called "rubisco".

It is very common that in the biosphere, the enzyme controls the sequestration of atmospheric CO₂ and the creation of biomasses. In the initial form of the enzyme, the Mg²⁺ cation with a coordination number of six octahedrally coordinates the carboxylate groups of aspartic and glutamic acid residues, three water molecules, and carbamate from lysine residue. The carbamate is formed when the initial portion of external CO₂ reacts with the terminal amino group of lysine, i.e., the CO₂ initially present "triggers" the mechanism of photosynthesis. In the catalytic cycle, ribulose-1,5-diphosphate carboxylate replaces two water molecules in the magnesium octahedra to form the rubisco properly, and then, in the presence of protons, it includes further portions of CO₂ in the ribulose fragment to form a new C–C bond. In the "light" stage of photosynthesis, the enzyme chlorophyll, in the center of which is the Mg²⁺ ion, is photochemically excited, and with the participation of iron–sulphur proteins, it reduces CO₂. The next stages of photosynthesis include a series of redox reactions involving the molecules of ADP, ATP, quinone derivatives, Mn²⁺ and Mn⁴⁺ complexes, as a result of which H₂O, which is a part of the coordination sphere of magnesium, is oxidized into O₂.

In mammals, 95% of the calcium is in the hard tissues: teeth and bones, being in the form of fluorapatite (Ca₅(PO₄)₃F) and hydroxyapatite (Ca₅(PO₄)₃OH). In the organisms of birds and mollusks, CaCO₃ predominates. In the walls of blood arteries and vessels, Ca²⁺ is present in the form of CaCO₃ or a cholesterol complex, and in the kidneys, it is present in the form of oxalates or urates (uric acid salts).

As they are different from Mg²⁺ ions, which prefer octahedral coordination, calcium ions have a tendency to form complex compounds with higher coordination numbers. The preferred ligands are water molecules, carbonyl groups of the peptide bonds, carboxylate (Asp and Glu), and alcoholate (Ser). Ca²⁺ ions, which form weak coordination complexes, and they have small formation constants of different coordination numbers (six, seven, or eight), a mobile coordination sphere, and high ligand exchange rates. Consequently, Ca²⁺ complexes are appropriate for participation in signaling systems [25,72]. They control the contraction of muscle fibers, activate numerous enzymes, and determine the blood coagulation process. The Ca²⁺ concentration is controlled by the parathyroid hormone calcitonin, and absorption is dependent on the content of vitamin D. A lack of vitamin D leads to a decrease in the Ca²⁺ absorption rate.

The most studied Ca-based enzyme is calmodulin (a calcium-modulating protein). It catalyzes the phosphorylation of proteins, and it activates protein kinase and the Fe-based enzyme NO-synthetase. The coordination number of the Ca²⁺ ion in calmodulin is six. It is surrounded by three monodentate carboxyl groups of aspartic acid, a bidentate glutamic acid, and H₂O. As it has the ability to increase its coordination number, the Ca²⁺ ion in calmodulin additionally coordinates the peptide CO group of proteins, thereby changing its structure, and hence, the functions. Ca²⁺ ions can occupy the role of co-factors in hydrolases and nucleases, which are responsible for the hydrolysis of phosphodiester bonds, and they have structural functions in proteins (in thermolysin and proteinase-K), resembling Zn²⁺ ions [20,25,72]. Malfunctions in Ca metabolism may lead to the deposition of low soluble Ca compounds (phosphate, oxalate, and steroids) in the blood, causing calcification and cardiovascular obstructions, as well as in the secretion organs, where Ca deposits are the reason for different gall bladder stones.

The chelation of the Mg(II) cofactors plays an essential role in the life cycle of many viruses, representing an attractive strategy for the development of new antiviral agents [95]. The review of Rogolino et al. has focused on the catalytic and biological properties of Mg(II) cofactors and on the structural features of the most relevant metal chelating compounds that have been established as antiviral agents against some of the most significant viral targets: HIV integrase, reverse transcriptase RNase H, influenza virus endonuclease, and hepatitis C virus polymerase [96]. SARS-CoV enzymes and the HIV replication machinery require the same divalent cations, such as magnesium, manganese, cobalt, iron and zinc. Mg²⁺, Mn²⁺, and Zn²⁺, which act coherently [97]. Fe²⁺ is required in HIV-1 transcription, packaging, and RT activity. Cu²⁺ is essential in the cellular anti-oxidative system, but it exerts anti-microbial properties, and among them, it inhibits HIV-1 protease activity [98].

Low levels of serum Mg²⁺ occur in malabsorptive syndrome, the cirrhosis of the liver, diabetic acidosis, high renal losses (intake of diuretics, gentamycin), and primary renal disease, as well as prolonged Mg intravenous administration. The symptoms of hypomagnesemia [36] are neuromuscular disorders that manifest as muscle fasciculations, weakness, tremors, and disorders of the central nervous system (delirium and psychosis). It has been found that a severe Mg deficiency can result in hypocalcemia or hypokalemia.

Higher serum levels of Mg²⁺ (hypermagnesemia) may cause the blood pressure to drop (hypotension) [37]. Some of the forthcoming effects of magnesium toxicity, such as confusion, lethargy, disturbances in normal cardiac rhythm, and the deterioration of kidney function, are related to hypotension. Severe hypermagnesemia may result in cardiac arrest.

A deficient supply of calcium (hypocalcemia) [38] results in the demineralization of bone with symptoms such as muscle spasms, leg cramps, osteoporosis, and brittle bones. When the organism does not get enough calcium, it uses the calcium that is stored in the bones, which makes the bones thinner and more brittle. A calcium deficiency is a result of its insufficient intake, the malabsorption of fat, and extreme urinary losses of Ca²⁺ in chronic renal conditions.

A high concentration of serum Ca²⁺ (hypercalcemia) [39] leads to hyperparathyroidism or malignancy. Slight hypercalcemia may have no serious symptoms, or it may result in a loss of appetite, nausea, abdominal pain, vomiting, fatigue, and hypertension. More serious hypercalcemia may cause delirium and coma. Calcium ions are involved in human metabolism, and the disruption of the normal metabolism leads to deposits of calcium salts in various organs (the formation of "stones", glaucoma, and atherosclerotic changes in blood vessels, etc.).

Preparations of biogenic metals Mg and Ca, together with complex ones, are common antacid agents, and some of them are well-known drugs [99,100,101,102].

In medicine, MgO and MgCO₃ are well-known antacids that are used to reduce the acidity of the gastric juice. MgSO₄·7H₂O is used as a laxative, a choleretic, and an analgesic for spasms of the gallbladder. A parenterally administered MgSO₄·7H₂O solution acts as an anticonvulsant for epilepsy and as an antispastic for bronchial asthma, urinary retention, and hypertension. The salt solution can cause hypnotic or narcotic effect. Magnesium carbonate is an anti-ulcer agent. Various additives for the oral administration of MgCO₃, magnesium citrate, orotate, aspartate, or lactate are used in Mg²⁺ deficiency conditions in the body [26,85,86].

Calcium salts are widely used in medicine. CaCl₂·6H₂O is used in allergic complications. CaCO₃ has a pronounced antacid activity, enhances the secretion of gastric juice, and it is used a part of tooth powders. Calcium oxalate, lactate, pantothenate, and gluconate are used as hemostatic agents and in Ca²⁺ deficiency conditions in the body. The radioactive isotope ⁴⁵Ca is widely used in biology and medicine for studying the processes of mineral metabolism in living organisms [20].

For the physiological functions of Na, K, Mg, and Ca, the charge density is of dominant importance, which is 1.02 for Na⁺, 1.38 for K⁺, 0.72 for Mg²⁺, and 1.00 for Ca²⁺. The larger the charge density is, the higher the ion’s capability to polarize the molecule is. The Mg²⁺ charge density is principally close to that of transition metal ions. That is why Mg²⁺ ions form stable complexes with nitrogen donors, for instance, chlorophyll. The metal ions of IA and IIA groups are rather mobile. Normally, their complexes are characterized by stability constants with low values. In a water solution and in the absence of other ligands, these cations exist in a hydrated form. For contrasting aqua complexes of transition metals, the number of hydration H₂O molecules is hardly determined, and the interactions are predominantly weak. The rate constants for water exchange in the hydration sphere for the equilibrium [M(H₂O)_x]ⁿ⁺ ↔ Mⁿ⁺ + xH₂O are in the orders of magnitude of 10⁻⁷–10⁻⁵ s⁻¹ for Mg²⁺ ions and 10⁻¹⁰–10⁻⁷ s⁻¹ for Na⁺, K⁺, and Ca²⁺ ions. Thus, magnesium complexes are thermodynamically and kinetically more stable than the complexes of other alkaline and alkaline earth metal ions are [20,21].

Biogenic transition metals and complexes of endogenous and exogenous organic and inorganic ligands, as well as their physiological functions, have been widely studied in the literature [103,104,105,106,107,108]. Kaim et al. have discussed the cooperation of biogenic transition metals with electroactive ligands of biochemical relevance such as porphyrin, flavin (Figure 4), pterin, alloxazine, isoalloxazine (flavin), histidine, quinone, topaquinone, phenoxyl radical, and tyrosyl radical (Figure 5).

A porphyrin ring represents a tetradentate ligand. The metal (Mg, Fe) complexes of porphyrin are among the most important ones in the living world (chlorophyll, hemoglobin, and myoglobin, etc.). Vitamin B₁₂ is a bioinorganic complex compound, in which the complexing ion is Co³⁺ with a coordination number that is equal to six, whereas cobalt(III) is surrounded by a macrocyclic ring structure called corrin, which is similar to the porphyrin ring. Flavin is a constituent of dehydrogenases.

Along with the widely studied biometal complexes of porphyrin, corrin, and flavin, there are other systems in which transition metals and redox-active cofactors such as pterin, alloxazine, isoalloxazine (flavin), histidine, quinone, topaquinone, phenoxyl radical, and tyrosyl radical cooperate in electron transfer and substrate activation [108]. Molybdenum is present mainly as a cofactor in molybdopterin (MoCo), involving pyranopterin as essential ligand in the xanthine oxidoreductase, nitrate reductase, carbon monoxide dehydrogenase, and sulphite oxidase family enzymes. This family of molybdenum-containing enzymes, called molybdopterins, have a core containing a MoS₂ group and an organic ring structure that is known as a pterin system. Reduced pterins and the related dihydroflavins containing a reduced isoalloxazine (flavin) ring are mostly known to interact with the metal sites (Fe and Cu) in proteins to effect the oxidoreductase activities (nitric oxide synthase and aromatic amino acid hydroxylases). Copper(II) and zinc(II) form bioactive complexes with histidine in carbonic anhydrase. The other example concerns copper-dependent quinoproteins such as amine oxidases, which include ortho/para-quinone redox systems. Metals such as copper or iron are essential in complex formations with quinones in amine oxidases. Copper, iron, and manganese, involving tyrosyl radical as a ligand, are present as cofactors in galactose oxidase and ribonucleotide reductase [108].

3.3. Manganese

Despite the variation in oxidation states, Mn in living organisms is represented by complexes of Mn(+2) and Mn(+3), with a coordination number of six. The manganese ion Mn²⁺, whose charge density of 0.83, and ionic radii are close to that of Mg²⁺, forms complexes with O- and N-donor bioligands. Its pronounced affinity for carboxylic and phosphate groups has been noted, as well as some functional interchangeability with magnesium. Mn is part of the active centers of numerous enzymes such as amino acyltransferase, pyruvate carboxylase, Krebs cycle, mitochondrial superoxide dismutase, arginase, and glycosyl transferase [109,110,111]. It is involved in the enzymic mechanisms of carbohydrate and lipid metabolism. As part of the enzymes arginase and cholinesterase, manganese with vitamin K is involved in blood clotting. Acting with B complex vitamins, Mn helps control stress effects. In the structure of peroxidase and aminophenol oxidase, it controls O₂ conversion. In pyruvate carboxylase and phospho-gluco-dismutase, Mn affects the carbohydrate metabolism. Manganese participates in the syntheses of vitamins B and hemoglobin. The specific role of manganese in the synthesis of mucopolysaccharides of cartilage tissue has been proven. The cluster fragment of the enzyme with an "oxygen-releasing center" contains four Mn atoms with the coordination numbers four, five, and six (which suggests different degrees of oxidation of manganese) associated with the residues of aspartic and glutamic acids and water molecules. Only one coordinating place in the entire cluster is occupied by an N-donor atom of histidine. This cluster also includes a Ca²⁺ ion.

In the body, manganese is concentrated in the liver, kidneys, and pancreas. Manganese deficiency leads to altered carbohydrate and lipid metabolism, impaired growth, depressed reproductive functions, skeletal abnormalities, and impaired synthesis of the vitamin-K-dependent blood clotting factors [26,40]. There is a connection between a poor Mn intake and a higher risk of skin cancer. Manganese deficiency is rare; it can be easily avoided with a good, balanced diet.

Extremely high levels of manganese in the body can be toxic [41]. Excessive Mn results in the production of reactive oxygen species (ROS), altered mitochondrial ATP production, and the formation of toxic metabolites and neurodegeneration conditions, such as Parkinson’s disease. Industrial manganese toxicity and its accumulation in the brain, combined with the overexposure to and production of ROS and toxic metabolites, causes a neurological disorder known as manganism.

Manganese inorganic and complex compounds are experimental ambiguous tumorigenic agents. Mn(II) ion has various properties that are beneficial for MRI contrast agents such as a long relaxation time, a high spin number, and kinetic lability, causing fast water exchange. It is supposed to be one of the most promising alternatives to Gd(III) [112]. Mn(II)-based complexes must be stable and inert because of their toxicity. It has been found that the thermodynamical stability and kinetic inertness of Mn(II) complex compounds are lower than those of Gd(III) or other transition metal ions, due to their smaller charge and lack of ligand field stabilization energy (d⁵ electron configuration). Evaluations of Mn(II) complexes with EDTA derivatives, containing a moiety that binds the complex compound noncovalently to serum albumin, have been described [109]. Mn(II) complexes that are formed by open-chain ligands are known to be kinetically labile, but a few exceptions involve the rigid CDTA and its derivatives [113,114,115]. On the other hand, for the majority of macrocyclic Mn(II) complexes, i.e., [Mn(DOTA)]²⁻, seem to limit the potential in vivo applications [116,117,118] (Structures of the ligands EDTA, CDTA, and DOTA, that are mentioned in the text, are included in Figure 6). As it is an essential metal ion, Mn(II) is efficiently eliminated from the living system.

The complex [Mn(N₄MacLn)(NO₃)₂], where N₄MacLn is a tetraazamacrocyclic ligand, has been tested in vitro against several pathogenic fungi and bacteria to evaluate its growth inhibiting potential [111].

3.4. Iron

Iron is the most important bio-metal, and it is necessary for almost all forms of life. Its bio-coordination compounds are characterized principally by the typical oxidation states, Fe(+2) and Fe(+3), as well as the coordination number six. The amount of iron in the body is proportioned as follows: in the composition of hemoglobin—70%; ferritin and hemosiderin—almost 15%; oxidoreductase—15%; around 1% of the iron occurs in the transport protein transferrin and in many Fe-dependent enzymes of the heme type and in iron–sulphur proteins such as ferredoxins, Rieske proteins, and ribonucleotide reductase, etc.

Iron takes over a central role in essential physiological functions which is because of its wide-ranging availability (Fe is abundant in the geosphere and biosphere). Iron possesses specific properties, of which there are fewer in other biogenic metals: (1) it easily changes its main oxidation states +2 and +3; (2) it forms hexa-aqua ions in aqueous solutions which are typical Brønsted acids; (3) it readily changes its high- and low-spin states in the medium strength ligand fields; (4) it has a predisposition to form oligo- and polymers by condensation; (5) it has flexibility with regard to the character of the donating ligand function, the coordination number, and the geometry.

The daily requirement of Fe is compensated by meat products. Iron deficiency leads to the development of iron deficiency anemia, and excess amount of it leads to sideroses [2,27,41,42,43]. The biogenic metal iron is poorly absorbed from the environment, but on the other hand, excess amount of iron in the body causes a toxicity risk. Difficulties in the absorption of iron are associated with an extremely low solubility of Fe(III) compounds contained in its minerals. As soon as the Fe(III) compounds dissolve, hydrolysis occurs, leading to the precipitation of polymerized hydrated oxide, which is difficult to access for the cells. The toxicity is connected with the ability of Fe(III) ions to catalyze the formation of hydroxyl radicals. Nature has created a system of the primary capture, transport, and accumulation of iron in vivo, based solely on the ability of Fe(II) and Fe(III) ions to form stable complex compounds that are resistant to hydrolysis.

The key functions of iron(II) and iron(III) bio complexes are their involvement in oxygen transport, enzymatic systems, and electron transport chains. The oxidation state of iron in bio-complexes is dependable on the role performed, for instance, it is +2 in hemoglobin, +3 in oxidases (Figure 4), and it is flexible in cytochromes [108].

By exhibiting variable oxidation states and coordination numbers of four and six, iron is very mobile in its compounds, easily moving from one type of bioligand coordination to another one. The capture of iron from the external environment is carried out by specific ligands: siderophores. The transfer and circulation of iron in the bioliquids of higher organisms occurs with the help of transferrin proteins, which together with ferritins, are responsible for the accumulation of iron in the body. Among the proteins that carry oxygen in higher animals, complexes of iron with porphyrin (Figure 4) are most important ones [2,27,75,108]. The forms of iron that exist in the human body are divided into heme (hemoglobin and myoglobin) and non-heme forms.

Siderophores are small polydentate ligands with a high affinity for Fe³⁺ [2,27,41,42,43,75]. They are produced by the cells of many bacteria and are ejected into the external environment, where they capture iron. There are two main types of siderophores: one of them contains phenolates and catecholates (enterobactin). The other type is hydroxamic ligands (ferrichrome). All siderophores with Fe(III) are high-spin complexes with an octahedral structure.

Ferritins are Fe-containing proteins with similar structures that serve to transport and store iron [2,27,41,42,43,75]. Ferritins are the main depot of non-heme iron in the body of animals and, when they are fully loaded, they can contain up to 20% iron by weight. They are built with a hollow protein sphere. Their inner surfaces have carboxylate functional groups, which coordinate with Fe(III) ions. The iron centers are linked by bridging oxide and hydroxide groups in the colloid form of Fe(OH)₃ to a great extent. Ferritins, similar to various other proteins, display high symmetry. The most studied of ferritins are: serum albumin (in blood plasma), ovotransferrin (in egg protein), and lactoferrin (in milk).

All transferrin proteins belong to glycoproteins, and they contain two separate and nearly equal iron binding sites to Fe(III) in the C- and N-teminal lobes. In transferrins, the Fe(III) ion has a distorted octahedral environment, and it coordinates two oxygen atoms of phenolic tyrosine groups: one imidazole N atom is from histidine, as well as a COO⁻ asparaginate group and a HCO₃⁻ or CO₃²⁻ group (sometimes the carbonate is replaced by phosphate) [2,27,42,75]. The binding constant of Fe(III) is highly dependent on the pH. Transferrin is an operative transporter for other metal ions in +3 and +2 oxidation states and for some anions such as vanadate.

Iron is involved in the transport of oxygen in the respiratory cycle in the form of hemoglobin and myoglobin proteins containing a complex of iron with porphyrin (Figure 4). In the pulmonary alveoli, oxygen is taken up by hemoglobin. Simultaneously, hydrogen carbonate is converted to H₂CO₃, which in turn is catalytically degraded into carbon dioxide and water (by Zn-based enzyme carbonic anhydrase):

Hb·H⁺ + O₂ + HCO₃⁻ ↔ Hb·O₂ + H₂CO₃

H₂CO₃ ↔ H₂O + CO₂

The key steps in the participation of hemoglobin in the respiratory cycle are the coordination of O₂ molecules, the retraction of a fragment of hemoglobin Fe-O₂ into the so-called "imidazole pocket", and then the distribution of O₂ via the blood flow through the vessels. The toxic effect of molecules and ions similar to the O₂ molecule (CN⁻ and CO, etc.) is due to their stronger binding with the iron ion.

Myoglobin is a blue-red deoxy form containing a high-spin Fe²⁺ ion with a coordination number of five [2,27,42,75]. Myoglobin reacts rapidly and reversibly with O₂ to form a low-spin six-coordinated bright red Fe(II) complex. The next step is a slow oxidation reaction leading to O₂⁻ ion release and the formation of the iron(III) complex (metmyoglobin), which is no longer open to O₂ binding. In healthy tissues, under the action of the enzyme methemoglobin reductase, the Fe(III) complex with methemoglobin is reduced to a similar complex as that with Fe(II).

Hemoglobin is a tetramer of myoglobin-like subunits with four iron atoms that jointly bind oxygen [2,27,42,75,108]. Hemoglobin is an oxygen-carrying protein that is found in special cells: erythrocytes (red blood cells). In general, hemoglobin has a low level of activity against oxygen, and therefore, it cannot carry O₂ to the myoglobin. With an increase in the oxygen pressure, the affinity of hemoglobin to O₂ increases, and as a result, hemoglobin in the lungs captures O₂. Therefore, there are two conformations of hemoglobin: a tense state with a low affinity for O₂ and a relaxed state with a high affinity for O₂.

Iron which readily changes its oxidation states can serve as catalytic electron carriers [2,27,75,108]. Iron, in the form of Fe²⁺ and Fe³⁺ ions, has many functions within the body, including oxygen transport and enzyme activity. In addition to the Fe-containing O₂ transporter proteins, there are also electron carrier proteins, cytochromes, which contain some metals, including iron. In Fe-containing cytochromes, the coordination number of iron is usually six, thee amino acid fragments are always in axial positions (unlike hemoglobin, where one axial place is either empty or occupied by H₂O), and iron is in its low-spin state for both of the oxidation states.

Electron transporter proteins also include iron–sulphur proteins, which contain fragments of a (Fe-S)_n cluster called ferredoxin [2,27,42,108]. In them, iron is tetrahedrally surrounded by sulfur atoms of thiolate fragments of cysteine. In addition to sulfur atoms, there are also examples of iron coordination to the carboxylate ligands, imidazole, the alkoxy groups (in serine), and the external ligands, H₂O and OH⁻. In this case, the coordination number of the iron ion increases to six. In addition to cubic clusters of type [4Fe-4S], larger ones are also known: [8Fe-7S] and [Mo-7Fe-8S-X] (in nitrogenase).

Iron produces oxidized substrates that are used for various metabolic cycles [2,43]. The utilization of O₂ unavoidably involves the production of toxic reactive oxygen species. Therefore, to survive, aerobic cells must have intracellular enzymes with chief activity to convert O₂⁻ and H₂O₂ into innocuous forms of O₂ or H₂O, respectively, as represented below:

2O₂⁻ + 2H⁺ → H₂O₂ + O₂  superoxide dismutase

2H₂O₂ → 2H₂O + O₂  catalase

AH₂ + H₂O₂ → 2H₂O + A  peroxidase

Catalase and several peroxidases are characteristic heme enzymes which require Fe.

There are various reports on the anticancer activity of Fe(II) and Fe(III) chelated complexes [119]. The complexes of iron with different types of ligands have exhibited good antiviral [97] and anticancer [119] properties against various cancer cells. Their anticancer mechanism of action is different from that of Pt drugs. Iron(III) complexes of acetylacetone S-methyl-, allyl-, and propyl- thiosemicarbazone-based ligands have exhibited strong anticancer activity and the inhibition of DNA and reactive oxygen species (hydroxyl, superoxide radicals, and hydrogen peroxide) [120].

Hexadentate ligands including 2,3-dihydroxypyridonate and 2,3-dihydroxyterephthalamide moieties for Fe³⁺ have been applied as MRI contrast agents for diagnostic purposes [121]. DNA cleavage agents such as bleomycin (Figure 7) have potential anticancer applications. Both iron and O₂ serve as cofactors in DNA cleavage by bleomycin.

The antitumor, antibiotic Bleomycin forms a low-spin Fe(III) complex with significant distortions of the Fe octahedron [122]. In fact, initial interest in the anticancer activities of iron complexes stems from the prolific activities reported for naturally occurring iron bleomycins. Their efficacy was ascribed to the disruption of the oxidative homeostasis in cancer cells, thus causing oxidative DNA damage [123].

3.5. Cobalt

In the human body, cobalt is in the form of Co(II) chelates with coordination numbers of four, five, or six and Co(III) complexes with a coordination number of six [80,124,125,126,127,128,129,130]. It should be noted that metal ions such as Cu(II), Co(II), and Zn(II) exhibit high preferences for the formation of five-coordinate complexes or coordinate species [124,125]. The same also is true for Cu(I), which forms a three-coordinate ones.

This biogenic metal is a constituent of vitamin B₁₂ (Figure 8), and its deficiency causes the development of anemia [28,77]. Both vitamin B₁₂ and coenzyme B₁₂ have Co ions coordinated according to their equatorial positions by four nitrogen atoms of the macrocyclic ligand corrin.

Vitamin B₁₂ is an endogenous vitamin that is produced by the intestinal microflora. In cobalamin, the macrocyclic corrin ring is bound to the nucleotide and dimethyl-benzimidazole [28,77]. The cavity in the center of the corrin ring is occupied by a Co atom with a coordination number of five, and the sixth coordination place can be occupied, as is the case, for example, in coenzyme B₁₂ by 5-deoxyadenosine, which is bound to Co through –CH₂– group. Due to this, coenzyme B₁₂ is a rare case of a natural coordination compound. If the sixth coordinating place is occupied by any other small ligands, then aqua-cobalamin, hydroxocobalamin, and cyanocobalamin can be obtained. In cobalamin, the Co atom can be in three oxidation states: +3, +2, and +1, and all of them are low-spin ones. Co(III) with configuration d⁶ has a coordination number of six, while Co(II) has a coordination number of five, with an unpaired electron on the d(z²)–orbitals. Co(I) has a four-coordinate square-planar environment.

The main enzymatic role of cobalamin is associated with the exchange transfer of H or CH₃ radicals between the bioligands [28,77]. Other enzymes, cobalamins, catalyze the radical exchange in cases of isomerization (mutase) and dehydration (lyase). The exchange of radicals weakens the cobalt–carbon bond, which leads to the production of a low-spin five-coordinated Co(II) and CH₂R radicals, which are replaced by some other ones. CH₃ group transfer reactions are based on a highly nucleophilic Co(I) in a square-planar environment. This reaction occurs during the biosynthesis of methionine, as well as for the activity of methane-producing bacteria methanogens. Cobalamin is vital for higher organisms, but it is produced only by microorganisms. With a lack of vitamin B₁₂, malignant anemia often occurs.

Co(II) salts contribute to other vitamins’ accumulation: nicotinamide, and pyridoxine, which have a positive effect on the proteins, minerals, and carbohydrates. The most significant function of cobalt(II) is the enzyme activation (aldolases and carbonic anhydrases). The best-known Co enzyme is methyl-malonyl-Co A mutase, which catalyzes the rearrangement to succinyl Co A. The possibility of reversible O₂ transport with the contribution of Co(II) cations, as well as their participation in proteolysis, has been established [124,125,126,127].

Co compounds are well known as excellent mimics of some metalloenzymes. Many Co(II) and Co(III) compounds have been broadly studied for the design of new antitumor agents [128], DNA cleaving and hypoxic selective agents, enzyme inhibitors, drug delivery devices, and suitable agents for positron emission tomography [124,125,129,130,131,132].

Deficiencies of cobalt and vitamin B₁₂, respectively, lead to blood disease pernicious anemia with the deterioration of the cells in the bone marrow responsible for replacing blood [44]. The typical symptoms of anemia include a loss of energy, a loss of appetite, and moodiness. A lack of vitamin B₁₂ may also lead to disturbances in the nervous system. Cobalt deficiency is rare in young people, but it does sporadically occur in adults due to digestive disorders. Vitamin B₁₂ is found only in animal sources, thus vegetarians are at risk of vitamin B₁₂ deficiency.

Excessive amounts of Co suppress the functions of the thyroid gland, as it affects the content of iodine in its hormone [45]. This manifests itself in the form of a disease, an endemic goiter, which is common in regions with a high content of cobalt in the soil and drinking water.

It is interesting to note that the closest analogue of cobalt, nickel, is considered to be undesirable and even dangerous in the biosphere. However, Ni (in an undetermined oxidation state) is a constituent of the active center of urease (the enzyme responsible for the hydrolysis of urea), and also, in cooperation with the F-430 cofactor, it helps the methanogen bacteria to reduce the CH₃CO groups to CH₄. In the plant kingdom and in microorganisms, Ni has been identified to function in several enzymes such as urease, some hydrogenases, and CO dehydrogenase [133].

3.6. Copper

Two oxidation states of copper are found in the body: Cu(I) with coordination numbers of two, three, or four and Cu(II) with coordination numbers of four and six. Copper, which is deposited in the liver, is a central constituent of oxidoreductases (ascorbate and polyphenol oxidases). Numerous Cu-containing proteins have been isolated [78].

In plant and animal organisms, copper is found in the form of coordination compounds, and these are mainly copper-containing proteins. There are more than 20 enzymes containing copper in the active site, and most of them are oxidases. Their biological role is associated with the processes of hydroxylation, oxidative catalysis, and oxygen transfer. The role of Cu in the enzyme cytochrome oxidase controls the O₂ → H₂O and O₂ → H₂O₂ reactions. The mechanism of superoxide dismutation, which is catalyzed by the enzyme superoxide dismutase (SOD), can be expressed by equations:

[SODCu²⁺] + ·O₂⁻ = [SOD·Cu⁺] + O₂

[SODCu⁺] + ·O₂⁻ + 2H⁺ = [SOD·Cu²⁺] + H₂O₂

In this way, SOD converts the superoxide ion radical ·O₂⁻ into hydrogen peroxide, which is a relatively slight oxidant and decomposes rapidly into water and oxygen in the body by the enzyme catalase:

H₂O₂ + H₂O₂ → 2H₂O + O₂

Oxygen transporter proteins include the protein hemocyanin, which unlike hemoglobin, is extracellular, and it is generally characteristic of Cu-containing proteins [78]. Hemocyanin is an oligomer, and each monomeric unit contains two copper atoms that are located very close to one another. Deoxy hemocyanin is colorless, but it acquires a bright blue color when it binds to O₂. In deoxy hemocyanin, Cu(I) ion has a coordination number of three, and it pyramidally coordinates three histidine residues. After attaching the O₂ molecule, it forms two bridge bonds, thus connecting two copper atoms. Spectral studies have shown that in this case, O₂ is reduced to O₂²⁻. At the same time, protein residues are significantly congregated, and Cu atoms acquire a coordination number of five, which is typical only for Cu(II). Human serum contains a glycoprotein ceruloplasmin, which it a molecule that contains eight Cu ions. Its life function is undefined. Additional proteins, namely erythrocuprein, cerebrocuprein, and hepatocuprein, which are found in the erythrocytes, brain, and liver, with unknown functions, contain around 60% of all Cu in these tissues. The oxidizing enzyme ascorbic acid oxidase contains eight copper atoms in the molecule, and it is broadly distributed in microorganisms and plants. Copper has an essential function in enzyme tyrosinase, which catalyzes the production of melanin: a brown-black pigment in the skin, hair, and retinas.

Electron carriers are the so-called "blue" copper proteins, containing Cu(I) and Cu(II), and residues of thiolate groups, imidazole and cysteine [78]. In plastocyanin and azurin, a plane Cu(I) complex with a coordination number of three is present. When it is coordinating the fourth ligand (usually containing a donor sulfur atom), the coordination number of Cu(I) rises to four in a tetrahedral structure.

Cytochrome oxidase consists of heme and Cu in a ratio of 1:1. In the cytochrome c oxidase and N₂O reductase, the center of the enzyme is a binuclear complex in which two Cu atoms are bonded via bidentate cysteine residue, with each Cu atom coordinating the heterocyclic nitrogen atom of imidazole. Due to the one-electron oxidation of this form, a purple paramagnetic complex is formed, in which an unpaired electron belongs to both of the copper atoms.

The homeostasis of Cu is crucial in the body because its deficiency, as well as its excess, lead to different pathologies. If there is a lack of copper in the body, copper deficiency anemia can develop [29,46]. The genetic disorder causing copper deficiency is called Menke’s disease. An excess amount of copper is toxic. Similar to iron, copper ions are predisposed to participate in the formation of reactive oxygen species [41]. The copper-related genetic disorder, Wilson’s disease, causes excessive copper accumulation in the liver and brain, leading to liver failure, progressive neurological disorders, or psychiatric illness.

DNA cleavage agents such as Cu(II) and other biogenic metal ion complexes have potential anticancer applications [134,135,136]. It has been found that Cu(I) and Cu(II) complexes exhibit anticancer properties, of which the mechanism of action differs from that of cisplatin [137,138,139,140,141]. The range of their activity varies, and it depends on the ligand that is attached [142,143].

A series of ⁶⁴Cu-labeled macrocycles, consisting of bifunctional chelators, have been used as another possibility for labelling Cu radionuclides to biomolecules for diagnostic imaging and targeted radiotherapy [144]. It has been suggested that neutral or negatively charged copper(II) complexes of tetra-azamacrocyclic ligands with a cyclam backbone (tetradecane) are ideal for Cu radiopharmaceutical practices [145].

3.7. Zinc

Zinc is the second most abundant transition metal of great biological significance. Unlike Fe, Cu, Mn, and Mo, zinc has a stable electron configuration, d¹⁰. That is why in zinc-based proteins, Zn²⁺ possesses either a catalytic or a structural function. This element occurs in biosystems mainly in the form of zinc(II) complexes with a tetrahedral geometry and coordination number four or an octahedral structure and a coordination number of six. Zn²⁺ ions form complexes with ligands containing O and N donor atoms. Zn²⁺ complexes of coordination number four are tetrahedral ([Zn(SR)₄]²⁻) or square planar ([Zn(Gly)₂]). The complexes of coordination number five are square-pyramidal ones ([Zn(acac)₂H₂O], acac = acetylacetonate(1−), and of coordination number six they are octahedral [30]. This biogenic metal is represented in both plant and animal objects and, as a rule, it comes from food in sufficient amounts [48]. Zinc takes part in the formation of multimers of many important proteins, mainly catalyzing the reactions such as the hydrolysis of peptides, collagen, and phospholipids, etc. It activates all of the chief classes of enzymes: oxidoreductases, hydrolases, transferases, isomerases, lyases, and ligases. The Zn(II) ion attends as an acidic active center of the proteins that promote the hydrolysis of various chemical bonds. Zinc activates the enzyme carboanhydrase, which is responsible for the hydration of CO₂ in bioliquids and the transfer of H⁺ ions to CO₃²⁻, which regulates one of the most important buffer systems of the body.

Zinc-containing enzymes are remarkable in their shape; they have "zinc fingers” [79,146]. This is because DNA fragments form repetitive domains that fold around one or more zinc ions, and these characteristic folds are called "fingers". Zn fingers keep the zinc ions in a characteristic tetrahedral geometry using a combination of cysteine and histidine residues. The composition of the "fingers" includes fragments of the types (Cys)₂(His)₂, (Cys)₃(His), and (Cys)₄, or thiolate cluster complexes with bridged cysteine residues. Zinc normalizes sugar metabolism, and it is necessary for normal insulin secretion. The enzyme superoxide dismutase (SOD), which is isolated from eukaryotic cytoplasm, contains Cu and Zn. No active replacement of Cu has been observed, but practically, any transition metal can be substituted for Zn at its site retaining the enzymic activity. In the blood, Zn is transported by transferrin and albumin. Its storage is realized by the thioneins [30,48].

Deviations in the zinc content from the norm lead to serious diseases. The level of toxicity of zinc is low [48]. Zinc deficiency, which occurs due to insufficient dietary intake, is characterized with impaired wound healing and dermatitis, anemia, mental apathy, and damage to the reproductive organs [48]. An excess amount of zinc is toxic. The extreme inhalation of zinc compounds can cause toxic manifestations such as a fever, excessive salivation, a cough, and vomiting, but these effects are not permanent. Excess amounts of zinc may also disturb the copper status, with symptoms of neutropenia, anemia, and impaired immune function.

Among the different uses in medicinal chemistry, Zn-constructed complexes have shown preventive effects on infectious diseases and an anticancer activity, with a low level of toxicity [135,147]. Some of them are used as photosensitizers in photodynamic therapy [147].

3.8. Molybdenum

Molybdenum is able to exhibit both various oxidation states (+4, +5, and +6) and variable coordination numbers (four, five, six, and eight). Therefore, the biological action of Mo is diverse. It is the presence of Mo that allows legume plants to absorb atmospheric nitrogen [81]. In the body of animals, Mo is part of the redox enzymes [31,49]. In spite of the variety of oxidation states of Mo, the body is dominated by Mo(VI) oxo complexes. This biogenic metal activates xanthine oxidase, which is the most vital enzyme in nitrogen metabolism that is involved in the exchange of purines and the transfer of O₂. With an excess of molybdenum in the soil, it accumulates in the body, which contributes to the activation of xanthine oxidase and the synthesis of excessive amounts of uric acid. As a result, calcium salts of this acid are formed, urates, which are deposited in the joints, causing gout [31,49,50].

Mo-containing enzymes usually catalyze the oxidation and reduction of small molecules: the oxidation of SO₃²⁻, AsO₂⁻, xanthine, aldehydes, and CO, or the reduction of NO₃⁻ and DMSO, etc. The lack of these enzymes, which usually has a genetic cause, leads to serious pathologies [31,49,50]. The coordination mode of the Mo-containing enzyme is usually formed from thiolate ligands (for example, pterin) and cysteine residues, and it is supplemented with ligands with donor oxygen atoms: water molecules, OH⁻, and O²⁻ groups.

The role of Mo ions in the formation of the bonds between flavin coenzyme and apoenzymes is also well known [31,49]. In all molybdo-metalloenzymes (excluding nitrogenase), it exists as Mo cofactor, a complex with molybdopterin. In nitrogenase, Mo exists in a cluster holding Fe and S²⁻. Nitrogen-fixing bacteria use enzymes which contain both Mo and Fe [81]. Molybdenum has an antagonistic action against Cu, and in high amounts, it causes copper deficiency [50]. The impact of Mo compounds as antitumor agents has been recently reviewed [148,149].

In general, the toxicity of molybdenum compounds is relatively small [50]. The main symptoms that have been observed are joint pains, articular deformities, erythema, and edema. Molybdenum deficiency is also rare. Low levels of this element can result in neurological problems and mental retardation. A diet that is rich in refined and processed foods can lead to molybdenum deficiency, resulting in anemia, and a loss of appetite and weight.

In addition to the known 10 biogenic metals, the physiological effects of which are have been studied and proven, there is a lot of information in the medical, biochemical, and environmental literature about the influence on the vital activity in organisms of almost all of the elements of the periodic table. Generally, all of these elements belong to metals.

4. Conclusions

In this review, the ten most important biogenic metals are discussed in the context of their biological role and its chemical basis. The review attempts to highlight the notable features in their chemistry that relate to their biological activity. The knowledge about the biogenic metals’ chemistry and biological interactions impacts many areas, e.g., biochemistry, toxicology, and pharmacology. It can be concluded that biogenic metals significantly differ from each other in their positions in the periodic table, chemical behavior, oxidation states, and interactions and bonding, and this is connected with their content and metabolism in the human body and their specific biological activity. Metal-based compounds of the studied biogenic elements possess valuable functions as therapeutic or diagnostic agents. In all of the cases, the safe binding of the metal cation with suitable targeting functional groups is important to the success of these agents. Synergistic effects may well arise from combinations of biogenic metals and bioorganic endogenous and exogenous ligands. Many exciting challenges remain in this field. The future progress towards gaining an understanding of structure–function relationships is likely to include insights into the design of new therapeutic and diagnostic agents.