# Bioinorganic chemistry: where from and where to?

Clotilde Policar

► To cite this version:

Clotilde Policar. Bioinorganic chemistry: where from and where to?. Journal of Biological Inorganic Chemistry, 2025, 10.1007/s00775-025-02112-1. hal-05119184

HAL Id: hal-05119184

https://hal.sorbonne-universite.fr/hal-05119184v1

Submitted on 18 Jun 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Bioinorganic chemistry: where from and where to?

Clotilde Policar<fnref n="1" />

Received: 15 November 2024 / Accepted: 7 March 2025

© The Author(s), under exclusive licence to Society for Biological Inorganic Chemistry (SBIC) 2025

## Abstract

Bioinorganic chemistry is a multidisciplinary field that bridges the apparent divide between inorganic chemistry and biology. The very name “bioinorganic” is an intriguing oxymoron, as “inorganic” chemistry traditionally refers to the study of the inanimate world, while the “bio” prefix refers to living systems. Bioinorganic chemistry focuses on metallic systems within biological environments, with the dual aims of better understanding these natural systems and leveraging the solutions developed through evolution to design new industrial or therapeutic applications. As a close cousin of the field of metallomics, bioinorganic chemistry shares the fundamental principles that underpin metallomics’ systemic analyses of metal-containing biomolecules. In this article, we trace the historical development of bioinorganic chemistry, highlighting its recent advances and outlining future research challenges in this dynamic interdisciplinary area.

## Graphical abstract

<figure><img src="image_2.png" /></figure>

**Keywords** Bioinorganic chemistry · Inorganic chemical biology · Metallomics · Metal ions essentialities · Metal ions cellular economy

## Introduction

The aim of bioinorganic chemistry is to identify, understand and control inorganic metal-based molecules within living organisms, whether they are endogenous (e.g., metalloproteins) or exogenous (e.g., metallodrugs). The purpose is, on the one hand, to characterize these molecules and explain how they work in the biological environments, and, on the

<figure><img src="image_3.png" /></figure>

<footnote>Clotilde Policar
clotilde.policar@ens.psl.eu</footnote>

<footnote n="1">¹ Laboratoire Chimie physique et chimie du vivant, CPCV, Département de Chimie de l'ENS-PSL, Ecole Normale Supérieure, ENS-PSL, PSL University, Sorbonne Université, CNRS, 24 rue Lhomond, 75005 Paris, France</footnote>
other hand, to prepare synthetic compounds with biological activity. These metallic compounds may be systems with no endogenous equivalent but likely to play a role in a biological environment (such as cisPt or contrast agents, for example). Alternately, they may be inspired by biological molecules (in which case they are called bio-inspired [1]) and reproduce an activity of potential therapeutic or industrial interest, to be used in biological systems (therapeutic agents) or as biomimetic or bio-inspired catalysts (industrial catalysts).

But what is a metal? In vernacular language, metal refers to broken stones for use in making roads: to metal a road means to make or mend it. Historically, metals all come from the mines as ores: *mέταλλον* in Greek or *metallum* in Latin means *mine*. For astrophysicists, a metal is anything but H and He and the metallicity of a star is an indication of its age: the older, the more elevated are the abundance of the elements heavier than H and He. In this article, we will use the more conventional definition from physics, chemistry, geochemistry, biology, etc.: a metal element is characterized in its 0 oxidation-state by good electrical and thermal conductivities —in the terrestrial conditions; note that H can become a liquid metal at elevated pressions found in Jupiter for instance! This metallic state M(0) is also fusible, malleable, ductile, and shines a special metallic luster. It readily loses electrons to form metal cations Mⁿ⁺ that show specific properties used by Nature, notably at the active site of metalloproteins.

## Metal compounds in medicine or as biocides

Various metals and metal ions such as those of zinc, iron, magnesium, mercury or gold were used in pharmacopeia very early in the human history. We can take the example of khôl (or kohl) used in Ancient Egypt as make-up for men and women alike. Analyzed by modern techniques (X-fluorescence), ancient khôl showed the presence of lead compounds that were clearly manufactured and not of natural origin [2]. Khôl was used explicitly to heal wounds and to protect eye against infection, probably associated with the lead present that is able to activate macrophages [2, 3]. Lead-based paintings, such as natural or man-made lead acetate called cerusite, were used for their toxicity as biocides not only to prevent the development of algae or infestation of shipworms on the hull and floors of Royal navy ships [4] but also in flats to prevent mold on walls. Children in rundown housing are prone to eat the crumbling “white lead” paint because cerusite tastes sweet, inducing potentially lead-poisoning. For that reason, the White Lead Convention was established in 1921 to advance the prohibition of using lead paints [5].

But toxicity also carries therapeutic properties and, if one thinks, most drugs are characterized by a targeted toxicity:

antibacterial, antifungal and anti-cancerous are meant to kill or limit the growth of bacteria, fungi or cancerous cells, respectively. Few drugs, among which antioxidants for instance, are meant to restore normal life in a biological system that has been driven to imbalance.

In the early twentieth century, Paul Ehrlich, from the Royal Institute of Experimental Therapy in Frankfurt, founded chemotherapy by developing the metal-based antibacterial arsphenamine (or salvarsan: ‘the arsenic that saves’) and its more water-soluble analog, neosalvarsan (see Fig. 1), against syphilis, a disease caused by *Treponema palidum*, a spirochete. These metallodrugs replaced the deadly treatment with mercury that had been used for centuries, in different chemical forms and administration modes [6]. Very early in his career, Paul Ehrlich, like many others in the XIXth century, was interested in the use of newly developed artificial synthetic dyes to stain bacteria. The fact some dyes, such as azo dyes (see Fig. 1), caused bacteria to stop swimming under the microscope led to the idea that such chemicals could kill them [7]. With the microbiologist Sahachiro Hata, who joined his group from Japan, Paul Ehrlich tested a number of dyes against spirilla and spirochetes and then came to an As-based compound synthesized in 1863 by Antoine Béchamp (Atoxyl) [8]. Together with his colleague Alfred Bertheim, they derivatized this compound, which led to salvarsan. As Ehrlich analyzed himself in the preface of [8] “The difficulty of my work is due especially to the fact it extends over three different territories which touch and complete each other: chemistry, biology and experimental therapy”. This makes this collaboration, involving several disciplines in a horizontal manner (as opposed to vertical monodisciplinary collaboration, between a master and their student for instance), one of the first highly productive interdisciplinary work in science history. Thought by Ehrlich, Bertheim and Hata to have an As = As double bond, by analogy with azo-dyes (see Fig. 1), it was demonstrated in 2005 to be a mixture of As-based metallacycles [9]. Penicillin was used as of the end of World War II and salvarsan derivatives were then retrieved due to side effects. The reborn of inorganic medicinal chemistry had to wait the late 1960 with the serendipitous discovery (see “INSERT”) of cis-diamminedichloroplatinum(II) (cisPt) by Barnett Rosenberg and Loretta Van Camp et al.. In the course of a program against cancer, they wanted to evaluate how electric fields could impact the growth of tumors. They started by investigating the effect of electric field on the growing of *E. coli*. To do so, they used Pt electrodes to generate the electric field, but that could have been any other type of electrodes. It happens that electrolysis at the Pt-electrode, within a culture medium rich in amino-acids and chloride, produced Pt-derivatives, including cisPt. This particular derivative was found to modify the growth of *E. coli* leading to long spaghetti-like bacteria [10, 11]. Its antiproliferative
<figure><img src="image_4.png" /><figcaption>**Fig. 1** Salvarsan and neosalvarsan: the first molecules developed for chemotherapy. A: Structure of an azo-compound, shown to kill some bacteria by observation under the microscope. B and C: Structure of the molecules Paul Ehrlich et al. thought they had synthesized as salvarsan (B) and neosalvarsan, its water-soluble analog (C). D and E.</figcaption></figure>

Salvarsan was in fact a mixture of two As-metallacycles D and E, as shown in 2005 [9]. F. Photograph of a commercial neosalvarsan doses, with the curtesy of the Museu de farmacia, Lisboa, https://www.museudafarmacia.pt/

effect on eukaryotic cells was soon after demonstrated [12]. This initiated an intense program of research on the use of heavy metal complexes in medicine [13].

Despite the fact that the first chemotherapeutic agent was a metal-based complex, the medicinal industry built up during the XXth century and until now relies mainly on organic molecules. So far, only few metal-based drugs have been approved clinically and found their way to the market [14]. This is difficult to draw reason for that, and that may confine at “science history fiction”. However, let us try. One key feature of the first-row transition-metal complexes is their intrinsic lability and dynamic nature. As fast ligand-exchangers [15], they are efficient catalytic centers, able to cycle: to welcome a substrate in their coordination sphere, to modify its electronic distribution and thus its reactivity, leading to the product that can be released from the coordination sphere, freeing the catalytic center for a next cycle. However, as exemplified in the case of salvarsan, it makes the structure of transition-metal-based derivatives not easy to characterize. Because biological media abound with metal ions and Lewis bases, metal complexes characterization is all the more difficult in any biological environment. The idea that a mixture, as salvarsan was, can be active and used as a medicine goes against the ‘holy’ Grail of the chemists, who, since the XIXth century, long for the separation, isolation,

purification and characterization of the so-called “molecular active principle”. This might be the reason why there is still so few metallic systems developed as medicine by the pharmaceutical industry. To that extent, this is worth noting that the only clinically approved metallodrugs involve heavier metal compounds from the second row or below in the periodic table, as cisPt and its analogs or a Pd-porphyrin*, more inert than those from the first row. One aluminum complex is also in the list, with a porphyrin as a ligand. In clinical trials, we can count at this time Ru complexes, notably Nami-A in Phase II, and two first-row transition-metal complexes, Mn with a macrocycle or a porphyrin* as a ligand and ferroquine** [14, 16].

However, in the context of the threat of antibiotic resistance, the clear role of metal ions on the virulence of bacteria and on fight between the host and bacteria [17–19], may put metal systems or ligands more to the forefront. Indeed, bacteria require metal ions in a way that may be more fundamental than other pathways, and difficult or even impossible to bypass. The emergence of bacterial resistance is due to the ability of bacteria to mutate in order to bypass pathways that are impaired by a drug. The pathways involving metal economy could be more difficult to bypass paving the way for the development of metal- or ligand-based antibacterial
agents for which bacterial resistance would be less to fear [20].

Note that the development of inorganic medicinal chemistry has also led bioinorganic chemists to ask questions on more integrated scales. The pharmacological properties of a molecule are closely linked to its ability to reach a biological target, possibly deeply buried in cellular compartments. This has raised the question of the cellular penetration of complexes and complexing agents, as well as their targeting to a given receptor, cell type or tissue, of their bioavailability, of their distribution and of their speciation (nature). In these matters, there is a strong overlapping with the field of metallomics, as discussed below (see the section Bioinorganic chemistry and metallomics).

## Endogenous metal ions and essentiality

Even if metallic derivatives have been used as medicine for centuries, the recognition of their endogenous physiological role is much more recent. The conception that metals or metal ions were endogenous constituents of the living world was not taken for granted. As a matter of fact, inorganic (or mineral) chemistry is etymologically that of the inanimate. Organic chemistry, a term that was coined at the end of the XIXth for “chemistry of organized bodies” [21–23], was considered as that of matter derived

from the living. The essentiality of metal cations in living organisms in general, and in humans in particular, was considered to be a relevant question only at the beginning of the XXth century. These elements have been called trace or ultratrace (see below for a comment on that term). The essentiality of trace elements was gradually established for different cations and different species (see Table 1).

## Iron

Iron, one of the most abundant among the metallic elements in the universe and in living systems (see Table 1 and Fig. 2), was one of the first to be identified as a natural component of living systems, through a rather long pathway. Iron was discovered in the human body by Louis Lemery [24], the son of Nicolas Lemery. However, he considered that iron was adsorbed and carried by blood but not that it was a natural constituent for it [25, 26]. Vincenzo Menghini established in 1746 that iron accumulates in the red vesicles previously discovered in blood fluids by Antoni van Leeuwenhoeke in 1674 [27]. In the mid XIXth century, iron was identified by Louis René Canu (1830) [26] as a component of the red blood pigment called then globuline or hematosine, soon after identified as the

<table><caption>**Table 1** Elements and date of the discovery of their essentiality for mammals. Concentration of the elements in human blood plasma and sea water</caption><thead><tr><th>"Trace" elements essential to mammals</th><th>Symbol</th><th>Date of the discovery of essentiality in mammals<sup>a</sup></th><th>Sea water concentration (µg/L)<sup>b</sup></th><th>Blood plasma concentration (µg/L)<sup>b</sup></th></tr></thead><tbody><tr><td>Iron</td><td>Fe</td><td>End of XIX<sup>th</sup> century (see references in the text)</td><td>0.000 03</td><td>1.2</td></tr><tr><td>Iodine</td><td>I</td><td>1850</td><td>0.058</td><td>0.000007</td></tr><tr><td>Magnesium</td><td>Mg</td><td>1932 (rat) [38]</td><td>1280</td><td>17.5</td></tr><tr><td>Copper</td><td>Cu</td><td>1928 (rat) [39], 1931-2 (infants) [40]</td><td>0.00015</td><td>0.75</td></tr><tr><td>Manganese</td><td>Mn</td><td>1931 (mouse) [41]</td><td>0.00002</td><td>0.00057</td></tr><tr><td>Zinc</td><td>Zn</td><td>1934 (rat) [42]</td><td>0.00035</td><td>0.651</td></tr><tr><td>Cobalt</td><td>Co</td><td>1935 (merino sheep) [43]</td><td>0.000001 2</td><td>0.00011</td></tr><tr><td>Molybdene</td><td>Mo</td><td>1956 (rat) [44]</td><td>0.010</td><td>0.00095</td></tr><tr><td>Selenium<sup>c</sup></td><td>Se</td><td>1957 [45] — Se as a component of GSH peroxidase 1973 [46]</td><td>0.00016</td><td>0.16</td></tr><tr><td>Chromium</td><td>Cr</td><td>1959 [47]</td><td>0.00021</td><td>0.000069</td></tr><tr><td>Tin</td><td>Sn</td><td>1970 [48, 49]</td><td>0.000000 5</td><td>0.00051</td></tr><tr><td>Vanadium</td><td>V</td><td>1970 [49]</td><td>0.002</td><td>0.000031</td></tr><tr><td>Fluorine</td><td>F</td><td>1972 [50]</td><td>1.3</td><td>0.019</td></tr><tr><td>Silicon</td><td>Si</td><td>1972 [51]</td><td>2.8</td><td>0.14</td></tr><tr><td>Nickel</td><td>Ni</td><td>1972 [52]</td><td>0.00048</td><td>0.00023</td></tr><tr><td>Arsenic</td><td>As</td><td>1976 [53]</td><td>0.0012</td><td>0.00045</td></tr></tbody></table>

<footnote><sup>a</sup> Dates from [33] and references indicated in the table</footnote>

<footnote><sup>b</sup> Data from [55]</footnote>

<footnote><sup>c</sup> We have indicated here Se although it is a non-metal element</footnote>
<figure><img src="image_5.png" /><figcaption>**Fig. 2** **a** Concentration of the elements in human blood serum and sea water. Data from [33]. : In green: the “trace” elements listed in Table 1; in gray: some other essentials elements; in black: other ele-</figcaption></figure>

<figure><img src="image_6.png" /><figcaption>**b** Plot of the ratio [blood serum]/[sea water] showing those of the elements that accumulate in biology (blood) in comparison with the environment (sea water)</figcaption></figure>

dioxygen carrier by Friedrich Ludwig Hünefeld (1840) [28] and to reversibly bind dioxygen by Felix Hoppe-Seyler [29].

## Zinc

Zinc being one of the next more abundant metal ions in living systems (see Table 1 and Fig. 2), this is not surprising that it was also identified very early. Jules Raulin, a collaborator of Louis Pasteur at the *Ecole Normale Supérieure* in Paris and working on Louis Pasteur's minimal media for bacteria, showed in 1869 that zinc salts were required to the growing of a fungus, namely *Aspergillus niger* [30–32]. The idea that a metal ion was not replaceable in a living system, and in other term, essential, was thus born. This point was immediately recognized as important by plant physiologists and bacteriologists of the XIXth century, but overlooked by animal nutritionists, including human nutritionists. Because of that, iron remained the only metal “trace” element considered as essential for animals including humans until the end of first quarter of the XXth century [33].

The amount of iron in a human being is only about twice that of zinc (see Table 1, data for blood plasma). However, there is a difference of about half a century for the date of the discovery of their respective essentiality. Two possibilities can be suggested to explain this difference. Firstly, iron complexes are colored (Fe(II) being d⁶ and Fe(III) d⁵) whereas Zn(II) complexes are not (d¹⁰). But also Zn is distributed in more different proteins than Fe (about 2800 for Zn [34] versus 400 for Fe [35] in the human genome, with 60 to 80 % of iron being in hemoglobin [36]): a similar amount distributed in a larger number of different proteins makes each of them less abundant in the case of Zn, and thus less easy to identify or purify.

## Endogenous metal ions and essentiality

During the XXth century, there were two major periods in the history of the establishment of essentiality of metal ions in animals [33, 37]. From 1925 to 1955, most of the discovery were at random, by accident or in response to outbreak of unexplained diseases in livestock. As often when a new scientific area is being explored, serendipity presided over the initial advances of a science in the making (see “INSERT”). This led to the discovery of essentiality of copper, zinc, cobalt, manganese and molybdenum in animals (see Table 1 for the date of discovery for mammals [33]).

From 1955 to 1980, under the aegis of Klaus Schwarz who was based at the Laboratory of Experimental Metabolic Diseases, Medical Research Program, Veterans Hospital, Long Beach, systematic programs were set up based on the experimental induction of trace-element deficiencies in animal models. In a world where metals were already everywhere, as of the industrial revolution, learning how to strictly induce nutritional deficiencies of metal ions and study them in animal models had to be associated with technical developments: designed synthetic and semisynthetic diets, specific metal-free environments (plastic cage, filtration of the air...) [54]. The increased in sensitivity of analytical techniques dedicated to metal ions [55–59] also favored these discoveries. Selenium, chromium, tin, vanadium, fluorine, silicon, nickel, and lithium but also surprisingly lead, cadmium and arsenic were then suggested as elements essential to mammals by Klaus Schwarz at the end of his life [33, 37].

As pointed out by Robert Goyer in [60] and earlier by Klaus Schwarz as reported by Gerhard Schrauzer [33], toxicity and essentiality are not related: a toxic element can be essential and have a biological function. Indeed, toxicity is
a matter of dose, as expressed by Paracelsus [61, 62]. For some metal ions, essentiality may be in a concentration window so weak that it makes experimentation difficult, due to environmental contamination. For both lead and arsenic, a biological role has been suggested and their deficiency has been shown to cause adverse effects (Pb [60, 63, 64] and As [65–67]). However, the evidence presented for Pb has not led to an official declaration of Pb as a dietary requirement for rats [60]. In contrast, As has been suggested to be an essential element even for humans with 7 mg/human 70 kg for As to be compared to 43 kg O, 16 kg C, 7 kg H, 1.8 kg N, 4.2 g Fe and 2.3 g Zn [65] and is proposed to have a link with methionine metabolism [66] and to interact with Se and Zn-fingers [67].

Cadmium has been found to be essential for *Thalassiosira weissflogii* [68], but there is currently no evidence of its essentiality to mammals.

Note that the list may be not closed yet. Indeed, as of 2010, early lanthanides (La, Ce, Pr, Nd, Pm, Sm, Eu) were found essential, if not to human beings, to bacteria living in volcano muds where these elements are in rather high concentration [69].

## Concept of essentiality

The concept of essentiality was defined during this second period, notably by George Cotzias, from the Rockefeller Institute for Medical Research and Brookhaven national Laboratory, with four criteria [33, 37, 70, 71].

(1) the element's tissue concentration is comparable from one individual to another within a species, which means it is genetically controlled;

(2) its elimination through strict dietary deficiency induces a physiologic or structural deficiency;

(3) a normal physiology is restored by a return to usual doses of this element;

(4) a specific biochemical function is associated with this element. This fourth point is the center of bioinorganic chemistry as a field.

## Advent of bioinorganic chemistry as a field

Once the involvement of exogenous and endogenous inorganic entities in biological systems had been demonstrated, the focus shifted to the understanding of how these entities function: a new field of knowledge emerged, bioinorganic chemistry, born at the confluence of inorganic chemistry, physical chemistry, biochemistry, biology, and biophysics in the late 1970s, early 1980s. Prior to this period, there had been works on the characterization of metallobiomolecules, and more particularly metalloproteins, and their function, with for instance the seminal work of Linus Pauling and

Charles Coryell on hemoglobin [72]. Works on complexes of biological interest were also conducted, such as those of James Collman mimicking the reversible binding of dioxygen by globins using metalloporphyrins [73]. But after 1980's these approaches were systematized and gradually organized into an independent research field.

Bioinorganic chemistry unquestionably became a discipline in its own right in 1983, when the first session of the International Conference in Bio-Inorganic Chemistry (ICBIC) was held, and in 1995 the Society of Bio-Inorganic Chemistry (SBIC, https://www.sbichem.org) was founded. Note that other local societies have emerged at the same period, such as SAMBAS (standing for *Sites actifs métalliques en biologie et analogues synthétiques* or Metallic active sites in biology and synthetic analogues), a French network dealing with synthetic analogs of metalloproteins that first met in 1987 in France, then in 1989 with the German community, and led to the congress EUROBIC that was first held in Newcastle in 1992. SAMBAS evolved into FrenchBIC (https://frenchbic.cnrs.fr/) in 2024. AsBIC (Asian BioInorganic Chemistry) conference was first held in 2002 and LABIC (Latin America Bioinorganic Chemistry) congress in 2008.

## A multidisciplinary corpus for an inventive fundamental chemistry to understand metal-based biological mechanisms

The study of metallobiomolecules and metal complexes in a biological context, or for biological applications, requires expertise shared between organic and inorganic chemists, biochemists, biophysicists, physical chemists, and, more recently, cell biologists and theoretical chemists. With the development of new, highly demanding techniques, in imaging, mass spectrometry (MS), metallomics, or directed evolution, not to mention artificial intelligence, dense and dynamic networks of collaborations have favorably developed all over the world.

Chemistry, with its formalisms and tools for studying structure–property relationships and dynamic phenomena, with fundamental concepts in thermodynamics and kinetics, is essential to the understanding of the mechanisms of these metallobiomolecules or to the design and study of metal-based compounds in a biological context or as biomimetic catalysts. In return, chemistry has much to gain from the study of these systems, Nature being, in a way, an endless reservoir of challenges and ideas [74].

One of the contributions of chemistry involves the synthesis and study of transition-metal complexes with biological activity and of bio-inspired catalysts. There are two types of approach here, not mutually exclusive: informative or functional perspective (see Fig. 3).

In the **informative perspective**, the aim is to better describe and understand metallobiomolecules. The study of low-molecular-weight complexes is of interest here because they are more
<figure><img src="image_7.png" /><figcaption>**Fig. 3** Research in bioinorganic chemistry, delineating the informative and functional perspectives. In the field of inorganic chemical biology, metal complexes are now reintroduced in biological environments, when the field of biochemistry is proceeding by extraction</figcaption></figure>

of proteins from their biological environment, for crystallization and physico-chemical studies (see arrows in orange, opposite movement)
Adapted from [1]. Copyright 2024 American Chemical Society

amenable to systematic variations than metallobiomolecules. The synthetic modeling helped greatly in identifying (i) references of spectral signatures in a range of spectroscopies (electronic absorption, vibrational, Mössbauer, electron paramagnetic resonance, etc.), and (ii) structural and functional properties of metallobiomolecules [74]. In addition, these low-molecular-weight complexes can be manipulated in organic solvents, i.e.,

at low temperatures in a solvent remaining liquid, enabling the study of reactivity and the characterization of fugitive species at low temperature (metal-oxo called in the IUPAC nomenclature [75] metal-oxido M=O, or metal-peroxido M-OO for example) [76–79]. With regard to catalysts inspired by metalloproteins, reactivities have been finely rationalized with regard to the chemical nature of the catalyst (control of the redox potential
for instance), to the bulkiness of the environment, but also at the spin state level [80]. This enables chemists to design catalysts with a tuned reactivity but it also provides the understanding of how exquisite the control of reactivity of metalloenzymes can be.

In metalloenzymes, metal cations can be found in an unusual environment imposed by the protein matrix. “Unusual” may mean a low coordination number, which is difficult to maintain in small, unconstrained systems in solution, as “being soluble” rhymes with “interacting with the solvent”, this solvent being able most of time to act as an additional ligand that fills in the coordination sphere.

Unusual may also involve a coordination geometry distorted from that preferred by the metal ion, this distorted geometry being not controlled by the configuration (dⁿ) of the metal ion. This can induce unusual properties (spectral signatures, redox potential shift, substitutional inertia/lability...). This is the case for instance for the spectral signature of blue copper proteins [81]. This is also the case in the distorted environment of Mn-based superoxide dismutases: low coordination number to keep room for the substrate superoxide to enter the coordination sphere of the metal ion and a distorted axial geometry in bipyramidal trigonal geometry to stabilize the Mn(III) d⁴ (Jahn–Teller stabilization) and therefore tuning the redox potential of the Mn(II/III) couple [82, 83].

Indeed, deviations from the ideal geometry —ideal meaning controlled by the electronic configuration dⁿ— of these structures are accompanied by a destabilization that is responsible for the reactivity of the site: this is known as the entatic state [84–88]. Reproducing such distorted and activated environments by designing constrained ligands is a challenge for the chemists [84, 85].

The activities of metalloenzymes, like those of enzymes in general, are often of high added value (functionalization of alkanes, dihydrogen and dioxygen production, carbon dioxide reduction, electron flow, energy conversions, control of oxidative stress, etc.) and the chemist can find in them a source of inspiration for designing metallic entities, or more broadly molecules, with controlled properties of industrial or pharmaceutical interest. This is the second type of approach, with a **functional perspective**, targeting activity (see Fig. 3). The aim is then not to chemically copy the structure or spectroscopic features of an active site, but rather to forge new intuitions by studying and understanding the mechanisms selected in the course of the slow process of Darwinian evolution. Armed with this new dimension of reflection, the bioinorganic chemist can then, in the words of S. Diekmann [89], open their toolbox (organic, inorganic, biochemical and theoretical) to build entities with controlled reactivity, be they efficient catalysts or modified proteins with hijacked activity.

In this design, there has been a gradual change in scale, at several levels, over the years. Low-molecular-weight metal complexes have been encapsulated into large matrices designed to modulate their activity, possibly mimicking the second coordination sphere and beyond (H-bond network, electrostatic interactions, etc.) [90]. These matrices include materials such as clays or zeolites [91], or macrobiomolecules such as antibodies [92], polypeptides [93] and protein scaffolds [94]. These artificial enzymes design, notably to perform abiotic reactions [95], has gained significant attention in the last two decades, involving rational design, aided by computation, artificial intelligence, or directed evolution [96].

The status or role of cells has also evolved. They are used as nano-plants to produce material catalysts, such as metallic nanoparticles [97]. They are also increasingly considered as non-conventional nanoreactors to perform catalysis [98], either for therapeutic applications [99] or to benefit from the cell economy. Indeed, the cell can provide catalysis partners (reducing agents, cofactors, etc.), and enable a continual renewal of the metal complex's ligands or matrix through biosynthesis.

In a sense, there is here an opposite, “antiparallel”, movement between (i) inorganic chemical biology, that can be considered as a subfield of both bioinorganic chemistry and chemical biology, with this introduction of artificial metallic structures into biological systems, and (ii) biochemistry that purifies (metallo)proteins to study them out of any cellular contexts (see Fig. 3, bottom). But more and more, proteins are studied in their native biological environment as the specific nature of the biological media (viscosity, overcrowding, see below [100]) is now recognized as key to their mechanism.

## Bioinorganic chemistry and metallomics

Organization of cells at mesoscopic scales is increasingly studied and this knowledge is important to the understanding of the cellular metal ions economy [101]: compartmentalization within organelles, organization of enzymatic (or metalloenzymatic) complexes in membranes, flow of protons or electrons across membranes from one cellular compartment to another (with the question of their coupling and of the role of metal ions in this matter), flow of metal ions in and out cells and between compartments, etc. With these questions, central to bioinorganic chemistry, there is a strong overlap with metallomics, a field defined in 2004 by Hiroki Haraguchi [55], after the term metallome was coined by Robert Williams in 2001 [102]. Metallomics integrates with other “omics” to emphasize the importance of inorganic elements, including metal ions, in biology and refers to the characterization of metal species within biological systems [103]. But we believe that metallomics can be extended to the tracking
<table><caption>**Table 2** Concentration of some ions in sea water and blood plasma, from [110]</caption><thead><tr><th>Ion</th><th>Concentration in sea water (mM)</th><th>Concentration in blood plasma (mM)</th></tr></thead><tbody><tr><td>Cl<sup>-</sup></td><td>570</td><td>100</td></tr><tr><td>Na<sup>+</sup></td><td>470</td><td>140</td></tr><tr><td>Mg<sup>2+</sup></td><td>50</td><td>2</td></tr><tr><td>K<sup>+</sup></td><td>10</td><td>10</td></tr><tr><td>Ca<sup>2+</sup></td><td>10</td><td>3</td></tr><tr><td>MoO<sub>4</sub><sup>2-</sup></td><td>0.2 µM</td><td>2–20 µM</td></tr><tr><td>First row transition-metal ions</td><td>1–10 nM</td><td>2–20 µM</td></tr></tbody></table>

and characterization of metallic species in the environment (mines for instance) or in art (paintings for instance [104]). In a way, bioinorganic chemistry, as defined at the beginning of this article, provides many of the fundamental principles and understanding that metallomics builds upon for its system-wide analyses.

As shown in Tables 1 and 2, there is a rough homothetic relationship between the composition of seawater and human plasma, revealing our marine origin. But the metal ions fall out that trend and accumulate in living organisms. These metal ions have been referred to as “trace” elements, but this is clearly a misnomer [101]. Firstly, qualitatively, because of the key importance of metal-based bio-catalysts for physiology, even at low concentrations. Secondly, quantitatively: even if they are globally low in amount, because they are not homogeneously distributed in biological systems between sub-compartments as organelles, intracellular metal ions can actually not be in so weak concentrations in subcellular compartments of low volume where they are present. Indeed, they are maintained at levels from a few ten of micromolar (Cu, Mo, Mn, Ni, Se, Cr, V...) to levels as high as the millimolar (Fe-Zn) in E. coli, as shown by the pioneering work of Thomas O’Halloran and Caryn Outten [105]. Over the past 30 years, it has become increasingly clear that metal ions play an important role in cellular regulation and metabolic pathways, participating in the control the chemical and biological states of cells. This is why there is such a tight control of metal homeostasis. This involves an intricate network of sensing, importing, exporting, and storage. Transient/short storage involve intermediate proteins to shuttle metal ions where they are needed (metallochaperones known for Cu [106] and Zn [107]). Longer storage can also exist, as for iron in an internal “cellular attic”, in the solid oxide form into ferritin, with a fast mobilization when needed through simple triggers (pH [108] or reduction [109] for instance).

Thorough studies applying concepts of thermodynamics and kinetics in the new context of cell interior led to a better picture of these processes, initiating new innovative ways

to look at them [111–114]. These studies brought evidence for the important role of the very specific physico-chemical characteristics of biological media. Beside the reductive nature of the cell interior, its high viscosity, molecular overcrowding, compartmented environment, or high content in Lewis bases and metal ions [100], can impact kinetics and thermodynamics (see also [115] for a film simulating of the cell interior). As delineated by Nigel Robinson and Kevin Waldron, cells are definitely not ideal solutions and kinetics factors may be at stake with regard to inertia of multiprotein complexes or metal ions availability/distribution and protein metalation status [112]. For instance, for a given complex LM with a given dissociation constant $K_d$, the actual position in the association equilibrium ($L+M=LM$), that can be reported by the percentage of metal within the LM species, is dependent on the concentration: upon dilution, a complex dissociates, whatever its $K_d$. This is similar to a weak acid becoming strong when diluted: no change of the absolute pKa of course, but a behavior of complete dissociation when diluted [116]. The reverse is true: for a given system, association can be favored by an increase in concentration. For these reasons, studies performed using spectroscopies directly in whole cells are essential.

Compartmentalisation of biological media is a key feature. The localization into small-volume compartments, organelles like mitochondria or vesicles like zincosomes [117–119] or ferrosomes [120–122], explains how minute amounts of a metal ion correspond locally to not so weak concentrations. Fragile and crucial multiprotein complexes from the respiratory chain or photosynthesis, the basis for the energy production and storage in cells***, are embedded into a membrane, a very small volume “compartment”. Intramembrane embedment of proteins or other molecules increases their effective concentration and limits their diffusion to 2D, entropically favoring interactions. This embedment probably also impacts vibrational structure, which has been suggested to be optimized for charge separation [123]: limiting vibrational desexcitation favors other pathways. Compartmentalization of metal ions (Mn/Cu) was also shown to prevent competitive metal ions such as Cu from coordinating to proteins meant to work with Mn [124]: this is a challenge considering that Mn(II), for a same ligand, has a lower association constant than Cu(II), as identified by the Irving and Williams series (see also below) [125].

## Detection and imaging: which pool?

The increasing occurrence of the usage of metal-based artificial systems in biology leads to the question of their detection and of their mapping within cells [83], as well as their in vivo or in-cells speciation. To that extent, the techniques developed not only in metallomics but also in geochemistry,
with the aim notably to characterize the speciation of metal
ions in the environment, can cross-fertilize bioinorganic
chemistry.

Because of the dynamic nature of the ligand to metal bond,
there is always the question of the speciation of metal ions,
already stressed above in the case of metal-based drugs: what
is the nature of a metal ion of interest in cells or in bacteria? To
address this question, techniques able to assess the molecular
structure, such as MS possibly hyphenated to another tech-
nique, are essential. One very efficient technique consists to
couple MS with ion mobility meant to separate ions depend-
ing on their mass and shape. This technique, very efficient to
address protein folding for instance [126], involves the move-
ment of ions under an applied electric field, with a gas flow
that either push or retain molecules depending on their rota-
tionally averaged collision cross-section (CCS in Å²). It has
been shown to be powerful enough to discriminate between
low-molecular weight divalent metal complexes from the same
ligand across the first-row transition elements [127]. In order
to have as little effect as possible on speciation, more and more
experiments are being designed to reduce sample preparation
to a minimum.

John Lisher and David Giedroc have proposed a very
enlightening classification of metal ions, as competitive
or bioavailable [128]. When exploring metals ions in cells,
one should carefully distinguish (a) the total cell-associated
metal ions, (b) the pool of metal ions that is not labile, typi-
cally tightly bound to proteins or other biomolecules, and (c)
the pool that is loosely bound, more often to low-molecular
weight biological non proteinaceous Lewis bases, such as non-
proteic amino acids, nucleosides, nucleotides, orthophosphate,
citrate, or carbonate [128, 129] (with a=b+c). Note that metal
ions in a solid form mainly belong to (b) as the interior of
solids is not very accessible but surfaces or small particles
may be fastly mobilized, as for iron in ferritine: they may then
belong to (c). The solid form is not considered below (for a
discussion see [130]).

As the cell interior is reductive, we only consider here the
reduced form of the metal ions. Cu(I) and Zn(II) d¹⁰ metal
ions show an association constants, for a given unconstrained
ligand, higher than Mn(II) and Fe(II) do, as known from the
Irving and Williams series [125, 131]. Interestingly, the bacter-
tial sensors association constants for metal ions follow this
series [113]. The homeostasis machinery identifying metal
overload activates for Cu and Zn at much lower thresholds than
for Mn and Fe. This means that import is cut off and export
activated at lower concentration for Cu/Zn than for Mn, which
contributes to maintaining the availability of the metal ions to
the inverse of the Irving and Williams series [113]. Cu and Zn
are tightly controlled by proteins: as soon as they get inside
cells, they are taken up by metallochaperones that deliver the
metal to the protein of interest to which it tightly binds. The
Cu and Zn pool of cell-associated metal ion is similar to the

protein-associated pool, with less than one ion of Cu or Zn
per bacteria for the loosely bound pool (see in bacteria: [132]
and [105]). In contrast, there is dynamic and richer exchange-
able pool for Mn(II), available to protein/ligand metalation and
which has been described to play a role in the control of oxida-
tive stress notably in diverse microorganisms [133]. We wish
to stress here two implications.

(a) The first one is a paradox, but can be understood in terms of thermodynamic competition: for a Mn(II)-complex to be stable in a biological environment, the requirement in terms of association constant is less drastic than with Cu(II) or Zn(II), because of this exchangeable bio-available Mn-pool that contributes to shift the L+Mn=LMn equilibrium toward LMn [83, 134].

(b) When performing quantification or imaging, it is very
important to assess the type of pool that is probed. Many
reviews have delineated the main features of metal-quantifi-
cation and imaging techniques, their limits and applicabilities
and we encourage the reader interested to refer to them [56, 57,
135–142]. Here, we just wish to stress the intrinsic difference
with regard to the pool detected between techniques probing
the metal ion based on its elemental properties and those based
on its coordination properties as a Lewis acid.

In the first category fall mass-based techniques such as
inductive-coupled-plasma mass spectrometry (ICP-MS) (for
detection, and associated to laser ablation for imaging, LA-
ICP-MS) and secondary ion mass spectrometry (nanoSIMS)
or micro-X-fluorescence. They can be used for imaging by
focalization of the beams (laser for LA-ICP-MS, ion beam
for nanoSIMS, X-ray light for µXRF). These techniques,
called also *elemental imaging*, probe the total element
content. In X-fluorescence, there is a potential access to
information about the redox state using XANES and on the
coordination sphere using EXAFS, however, this is not easy
to combine with imaging performed on cell layer or tissue
sections due to the small voxel probed.

In the second category, are the reporters interacting with the
metal ions [143]. Due to the widespread of fluorescent micro-
scopes, most of these reporters are fluorescent. They can be syn-
thetic or genetically-encoded. Recently, probes able to report
metal content by vibrational detection have also been developed
[144]. In all cases, the detection relies on a change of the spectro-
scopic properties of the sensor upon metal ion coordination and
depends on the competition between association to the biologi-
cal ligand(s) and to the sensor. These techniques probe, not the
whole pool, but the metal ion pool available to the sensor: that
means the pool in the same compartment, kinetically and ther-
modynamically available, with a threshold that is determined by
the association constant (K_a) of the probe itself.

Clearly, the imaging of metal ions has brought the under-
standing of their roles in biological systems a step further
and this will probably even advance faster with the capacity
<caption>**Table 3** Information to retrieve the unconventional or old references that do not have an available doi. NB: In the list of references below, the doi or link to the reference is systematically indicated. For the references that are older or non-conventional in a scientific paper (letter,</caption>

simulation for instance), the doi is not always available. The reader will find the way to retrieve them in Table 3 with an open url and, for books, the ISBN is indicated

<table><thead><tr><th>Ref</th><th>References linked to their internet page/ISBN for books/date of access if appropriate</th></tr></thead><tbody><tr><td>[4]</td><td>Hough R (1994) Captain James Cook. Hodder and Stoughton, New York, NY, USA ISBN 978-0-340-82556-3</td></tr><tr><td>[5]</td><td>(1921) C013—White Lead (Painting) Convention, 1921 (No. 13) https://normlex.ilo.org/dyn/nrmlx_en/f/?p=NORMLEXPUB:12100:0:: NO::P12100_INSTRUMENT_ID:312158. Accessed 27 Oct 2024</td></tr><tr><td>[6]</td><td>(2023) The history of syphilis part two: Treatments, cures and legislation https://www.sciencemuseum.org.uk/objects-and-stories/history-syphilis-part-two-treatments-cures-and-legislation. Accessed Oct 2024</td></tr><tr><td>[8]</td><td>Ehrlich P, Hata S (1911) The experimental therapy of spirilloses, Rebman limited. London, New York https://curiosity.lib.harvard.edu/ contagion/catalog/36-990113594300203941?locale=ar Accessed Feb 2025</td></tr><tr><td>[15]</td><td>Basolo F, Pearson RG (1967) Mechanisms of Inorganic Reactions: A Study of Metal Complexes in Solution. Wiley ISBN 978-0-608- 18195-0 https://books.google.fr/books?id=dMg4wQEACAAJ Accessed Nov 2024</td></tr><tr><td>[21]</td><td>Berzelius JJ (1806) Föreläsningar i Djurkemien, Förra Delen (Traité de chimie animale, dernière partie). Carl Delén, Stockholm Reference found in: https://www.vialibri.net/years/books/520463125/1806-berzelius-jons-jacob-forelasningar-i-djurkemien-forra-delen-sedna re. Accessed Oct 2024</td></tr><tr><td>[22]</td><td>Berzelius JJ (1808) Lärbok i Kemien, Förra Delen (Manuel de chimie, partie 1). Tryckt hos Henr. A. Nordström, Stockholm https://galli ca.bnf.fr/ark:/12148/bpt6k72967 for the French translation Accessed Oct 2024</td></tr><tr><td>[24]</td><td>Lemery L (1713) Examen de la manière dont le fer opère sur les liqueurs de notre corps, &amp; dont il doit être préparé pour servir utilement dans la pratique de la médecine. Par M. Lemerì le Fils. Mémoires de l'académie royale des sciences 31-44 https://gallica.bnf.fr/ark:/ 12148/bpt6k3516x/f118 double Accessed Oct 2024</td></tr><tr><td>[25]</td><td>Hebbert F (1950) Some Historical Aspects of Iron Therapy. Glasgow medical journal 31:385-96 https://pmc.ncbi.nlm.nih.gov/articles/ PMC5970923/ PDMI 14784250 Accessed Oct 2024</td></tr><tr><td>[28]</td><td>Hünefeld FL (1840) Der Chemismus in der Thierischen Organisation. F.A. Brockhaus, Liepzig https://www.digitale-sammlungen.de/de/ view/bsb10368567?page=7 Accessed Oct 2024</td></tr><tr><td>[29]</td><td>Mathews AP (1898) Popular Science Monthly Volume 53 August 1898 — The Life and Work of Felix Hoppe-Seyler https://en.wikis ource.org/wiki/Popular_Science_Monthly/Volume_53/August_1898/The_Life_and_Work_of_Felix_Hoppe-Seyler Accessed Oct 2024</td></tr><tr><td>[30]</td><td>Raulin J (1869) Etudes sur la végétation. In: Annales des sciences botaniques, 5e série. pp 93-299 https://www.biodiversitylibrary.org/ item/135764#page/99/mode/lup Accessed Oct 2024</td></tr><tr><td>[31]</td><td>Raulin J (1870) Thesis — Etudes chimiques sur la végétation. Université de Paris Gallica https://gallica.bnf.fr/ark:/12148/bpt6k95197h/ fl.item Accessed Oct 2024</td></tr><tr><td>[33]</td><td>Schrauzer GN (1984) The Discovery of the Essential Trace Elements: An Outline of the History of Biological Trace Element Research. In: Frieden E (ed) Biochemistry of the Essential Ultratrace Elements. Springer US, Boston, MA, pp 17-31 ISBN: 978-1-4684-4777-4 and 978-1-4684-4775-0 http://link.springer.com/10.1007/978-1-4684-4775-0_2 Accessed Oct 2024</td></tr><tr><td>[61]</td><td>Paracelsus (1538) “Die dritte Defension wegen des Schreibens der neuen Rezepte,” Septem Defensiones http://www.zeno.org/Philo sophie/M/Paracelsus/Septem+Defensiones/Die+dritte+Defension Accessed Feb 2025 Original sentence: Alle Dinge sind Gift, und nichts ist ohne Gift; allein die Dosis macht, dass ein Ding kein Gift ist. Translation: All things are poison, and nothing is without poison; the dosage alone makes it so a thing is not a poison</td></tr><tr><td>[70]</td><td>Cotzias GC, Papavasiliou PS, Miller ST (1968) Neutron activation analysis: clinical and biologic studies of manganese. France https:// www.osti.gov/biblio/4094217 Accessed Oct 2024</td></tr><tr><td>[110]</td><td>Wilkins PC, Wilkins RG (2005) Inorganic chemistry in biology, Oxford University Press, Oxford ISBN 978-0-19-855,933-7</td></tr><tr><td>[90]</td><td>Bhagi-Damodaran A, Lu Y (2019) The Periodic Table's Impact on Bioinorganic Chemistry and Biology's Selective Use of Metal Ions. In: Mingos DMP (ed) The Periodic Table II. Springer International Publishing, Cham, pp 153-173 ISBN 978-3-030-40009-5 and 978-3-030-40010-1 http://link.springer.com/10.1007/430_2019_45 Accessed Oct 2024</td></tr><tr><td>[101]</td><td>Gilston BA, O'Halloran TV (2013) Mechanisms controlling the cellular economy. In: Metals in cells. Ed. V. Culotta and R.A. Scott, John Wiley &amp; Sons, Ltd ISBN: 978-1-118-63,621-3 https://www.wiley.com/en-us/Metals+in+Cells-p-9781118636213 Accessed Nov 2024</td></tr><tr><td>[103]</td><td>Banci L, Bertini I (2013) Metallomics and the Cell: Some Definitions and General Comments. In: Banci L (ed) Metallomics and the Cell. Springer Netherlands, Dordrecht, pp 1-13 ISBN: 978-94-007-5560-4 and 978-94-007-5561-1 https://link.springer.com/10.1007/978- 94-007-5561-1_1 Accessed Nov 2024</td></tr><tr><td>[115]</td><td>Sugita Y, Mori T, Yu I, Jung J, Harada R, Tadashi A, Feig M, Music: Morishita Y (2017) Simulation of Biomolecules in Cellular Envi- ronments. Cybernet https://youtu.be/5JcFgj2gHx8?feature=shared and https://www.youtube.com/@rikenchannel Accessed Oct 2024</td></tr><tr><td>[145]</td><td>Walpole H (1754) Letter to Horace Mann, introducing the word Serendipity, 1754 Jan. 28 https://mimisawhney.com/2020/02/26/horace- to-horace-serendipity/ Accessed Oct 2024</td></tr></tbody></table>
of treatment, analyses and comparison of images now avail-
able with artificial intelligence.

**Conclusion: bio-inorganic chemistry:**
*a fertile chimera*

The field of bioinorganic chemistry really shows how the
intricate, dynamic, and highly regulated environments of liv-
ing systems can challenge our traditional understanding of

perspective is essential. By taking inspiration from biologi-
cal systems, chemists can devise transformative technolo-
gies or therapies that address global needs. Embracing the
bioinorganic worldview is thus crucial not only for advanc-
ing fundamental science, but for developing practical solu-
tions that improve our world.

**INSERT: Serendipity** is a term coined by Horace Walpole in 1754 [145] from the Persian tale « *Three Princes of Serendip* » in which three princes are sent by their father king to explore the world. During their journey, they solve many questions they were not asked to look at by mere observation.

It describes a process of discovery where research leads to something that was neither programmed nor anticipated and that can be much more valuable than the initial prospect. Serendipity also refers to the ability to set aside an initial goal for a greater one, not anticipated. Note that this is not "discovery by luck" or "at random", but "discovery closeby".

In the case of the discovery of cisPt, this applies perfectly. Barnett Rosenberg and Loretta Van Camp et al. were looking for a way to disrupt cell growth in a cancer research program and their idea was to use an electric field, for which they chose Pt electrodes. This choice was the lucky part. The important aspect here is that they did not just throw away an electric field experiment that did not work, but they took a step back and thought about it, which led eventually to identify cisPt and its potentialities.

As a researcher, we need a goal, but it is not essen tial as such. It is there to set us in motion, but it does not matter if we reach it or not, as long as we make other discoveries along the way, and sometimes these unplanned discoveries are more important than the initial goal: that's the magic of research!

physico-chemical concepts and principles. For that reason,
the bioinorganic perspective is invaluable for teaching chem-
istry. By looking from a new angle, it gets students to think
beyond textbook models and develop a deeper understanding
of chemical principles. By grappling with the intricacies of
metalloenzymes, or metal trafficking, the next generation
of chemists will be better equipped to tackle complex, real-
world challenges at the interface of chemistry and biology.

In turn, these insights gleaned from natural systems can
spark innovative solutions in areas like catalysis, medicine,
and materials science amenable to solve societal key issues.
In a way, it is almost like the tension between “bio” and
“inorganic”, etymologically embedded in its very name, is
precisely what makes this field so rewarding to explore. The
lessons of bioinorganic chemistry are not just academic. As
we confront pressing societal issues like sustainable energy,
environmental remediation, and improved human health, this

**References and notes**

*Porphyrins and macrocycles are ligands that provide a high association constant. **Ferroquine is also quite inert in biological media.

*** We suggest to prefer the expression “in cells” or “in-cells” to “in cellulo”. If one wants to use Latin, it should be “in cellulam” or “in cellam” (from *cella*, *ae*, room, attic and *cellula*, *ae*, small room), “in cellulo” not being an existing expression in Latin.

**Acknowledgements** The author wants to acknowledge ENS-PSL, PSL University, CNRS, MITI-CNRS, Sorbonne University (SU), Paris-Saclay University, ENS-Paris-Saclay, and the other bodies that funded her work through the following contracts: ANR-15-CE07-0027 MAGIC ; DEI20151234413 (Fondation pour la recherche médi-cale 2016), and BACTMAN and ANACOMDA (Mission pour les initiatives transverses et interdisciplinaires MITI-CNRS), the
Association François Aupetit (AFA, research fellowship 2015), ANR-23-CE20-0030-03 METALINFY, ANR 21-CE18-0053-02 MOBIDIC, ANR 20-CE07-0039-01-CATMAN, Idex PSL Qlife project Main ANR Q-life ANR-17-CONV-0005; CEFIPRA project no. 6505-1; ANR-22-PEBI-0003 (PEPR). Flaticon is acknowledged for icons occasionally used in figures.

Museu de farmacia, Lisboa, is acknowledged for allowing to use the picture of commercial neosalvarsan dosage https://www.museu dafarmacia.pt/.

The author wants to thank Nicolas Delsuc, Alice Balfourier, and Christine Rampon for their help in generating Fig. 2 and Julien Fournigault for his design of the graphical abstract. She also wants to deeply thank her PhD students and post-doctoral fellows, and her direct collaborators from the research group Metal in biology and redox homeostasis (https://ens-bic.fr/) for useful discussions that often raises new challenges, and for sharing a same idea of science. Overall, this article benefits from the rich discussions within the extended bioinorganic community, from synthesis, analytical chemistry, physical chemistry, cell biology to metallomics.

**Author contributions** CP wrote and revised the manuscript.

**Data Availability** No datasets were generated or analysed during the current study.

## References

1. Policar C (2024) Bioinorganic chemistry: a field where biomimetry and bioinspiration are central. Inorg Chem 63:23475-23478. https://doi.org/10.1021/acs.inorgchem.4c04868

2. Walter P, Martinetto P, Tsoucaris G et al (1999) Making make-up in ancient Egypt. Nature 397:483-484

3. Tapsoba I, Arbault S, Walter P, Amatore C (2010) Finding out Egyptian gods' secret using analytical chemistry: biomedical properties of egyptian black makeup revealed by amperometry at single cells. Anal Chem 82:457-460. https://doi.org/10.1021/ac902348g

4. Hough R (1994) Captain James Cook. Hodder and Stoughton, New York

5. (1921) C013 - White Lead (Painting) Convention, 1921 (No. 13). https://normlex.ilo.org/dyn/normlex/en/f?p=NORMLEXPUB:12100:0::NO::P12100_INSTRUMENT_ID:312158. Accessed 27 Oct 2024

6. (2023) The history of syphilis part two: treatments, cures and legislation. https://www.sciencemuseum.org.uk/objects-and-stories/history-syphilis-part-two-treatments-cures-and-legislation. Accessed 27 Oct 2024

7. Riethmiller S (2005) From atoxyl to salvarsan: searching for the magic bullet. Chemotherapy 51:234-242. https://doi.org/10.1159/000087453

8. Ehrlich P, Hata S (1911) The experimental therapy of spirilloses. Rebman limited, New York

9. Lloyd NC, Morgan HW, Nicholson BK, Ronimus RS (2005) The composition of ehrlich's salvarsan: resolution of a century-old debate. Angew Chem Int Ed 44:941-944. https://doi.org/10.1002/anie.200461471

10. Muggia FM, Bonetti A, Hoeschele JD et al (2015) Platinum anti-tumor complexes: 50 years since Barnett Rosenberg's discovery. JCO 33:4219-4226. https://doi.org/10.1200/JCO.2015.60.7481

11. Rosenberg B, Van Camp L, Krigas T (1965) Inhibition of cell division in escherichia coli by electrolysis products from a platinum electrode. Nature 205:698-699. https://doi.org/10.1038/205698a0

12. Rosenberg B, Vancamp L, Trosko JE, Mansour VH (1969) Platinum compounds: a new class of potent antitumour agents. Nature 222:385-386. https://doi.org/10.1038/222385a0

13. Franz KJ, Metzler-Nolte N (2019) Introduction: metals in medicine. Chem Rev 119:727-729. https://doi.org/10.1021/acs.chemrev.8b00685

14. Boros E, Dyson PJ, Gasser G (2020) Classification of metal-based drugs according to their mechanisms of action. Chem 6:41-60. https://doi.org/10.1016/j.chempr.2019.10.013

15. Basolo F, Pearson RG (1967) Mechanisms of inorganic reactions: a study of metal complexes in solution. Wiley, New York

16. Kumar Singh A, Kumar A, Singh H et al (2023) Metal complexes in cancer treatment: journey so far. Chem Biodivers 20:e202300061. https://doi.org/10.1002/cbdv.202300061

17. Neyrolles O, Wolschendorf F, Mitra A, Niederweis M (2015) Mycobacteria, metals, and the macrophage. Immunol Rev 264:249-263. https://doi.org/10.1111/imr.12265

18. Jordan MR, Wang J, Capdevila DA, Giedroc DP (2020) Multimetal nutrient restriction and crosstalk in metallostasis systems in microbial pathogens. Curr Opin Microbiol 55:17-25. https://doi.org/10.1016/j.mib.2020.01.010

19. Focarelli F, Giachino A, Waldron KJ (2022) Copper microenvironments in the human body define patterns of copper adaptation in pathogenic bacteria. PLoS Pathog 18:e1010617. https://doi.org/10.1371/journal.ppat.1010617

20. Frei A, Zuegg J, Elliott AG et al (2020) Metal complexes as a promising source for new antibiotics. Chem Sci 11:2627-2639. https://doi.org/10.1039/C9SC06460E

21. Berzelius JJ (1806) Föreläsningar i Djurkemien, Förra Delen (Traité de chimie animale, dernière partie). Carl Delén, Stockholm

22. Berzelius JJ (1808) Lärbok i Kemien, Förra Delen (translation in French, 1808, Manuel de chimie, partie 1), found in https://galli.ca.bnf.fr/ark:/12148/bpt6k72967. Tryckt hos Henr. A. Nordström, Stockholm

23. Abbri F (2019) Discovering Elements in a Scandinavian Context: Berzelius's Lärbok i Kemien and the Order of the Chemical Substances. Substantia 49-58 Pages. https://doi.org/10.13128/SUBSTANTIA-378

24. Lemery L (1713) Examen de la manière dont le fer opère sur les liqueurs de notre corps, & dont il doit être préparé pour servir utilement dans la pratique de la médecine. Par M. Lemerle i Fils. Mémoires de l'académie royale des sciences 31-44

25. Hebbert F (1950) Some historical aspects of iron therapy. Glasgow Med J 31:385-96 (PDMI 14784250)

26. Sheftel AD, Mason AB, Ponka P (2012) The long history of iron in the Universe and in health and disease. Biochimica et Biophysica Acta (BBA) - General Subjects 1820:161-187. https://doi.org/10.1016/j.bbagen.2011.08.002

27. Leeuwenhoek VA (1674) More microscopical observations made by the same M. Leeuwenhoeck and promised in numb. 97. of these tracts; communicated in his letters of August 15. 1673 and of April 7. 1674. Phil Trans R Soc 9:23-25. https://doi.org/10.1098/rstl.1674.0010

28. Hünefeld FL (1840) Der Chemismus in der Thierischen Organisation. F.A. Brockhaus, Liepzig

29. Mathews AP (1898) Popular Science Monthly Volume 53 August 1898 — The Life and Work of Felix Hoppe-Seyler

30. Raulin J (1869) Etudes sur la végétation. In: Annales des sciences botaniques, 5e série. pp 93-299

31. Raulin J (1870) Thesis — Etudes chimiques sur la végétation. Université de Paris

32. Maret W (2016) The metals in the biological periodic system of the elements: concepts and conjectures. IJMS 17:66. https://doi.org/10.3390/ijms17010066

33. Schrauzer GN (1984) The discovery of the essential trace elements: an outline of the history of biological trace element
research. In: Frieden E (ed) Biochemistry of the essential
ultratrace elements. Springer, US, Boston, MA, pp 17–31

34. Andreini C, Banci L, Bertini I, Rosato A (2006) Counting the zinc-proteins encoded in the human genome. J Proteome Res 5:196–201. https://doi.org/10.1021/pr050361j

35. Andreini C, Putignano V, Rosato A, Banci L (2018) The human iron-proteome. Metallomics 10:1223–1231. https://doi.org/10.1039/c8mt00146d

36. Andara L, Salamunic I (2012) Iron metabolism: current facts and future directions. Biochemia Medica 22:311–328. https://doi.org/10.11613/bm.2012.034

37. Frieden E (1985) New perspectives on the essential trace ele-
ments. J Chem Educ 62:917. https://doi.org/10.1021/ed062
p917

38. Kruse HD, Orent ER, McCollum EV (1932) Studies on magnesium deficiency in animals. J Biol Chem 96:519–539. https://doi.org/10.1016/S0021-9258(18)76290-X

39. Hart EB, Steenbock H, Waddell J, et al (1928) Iron in nutrition VII. Copper as a supplement for iron in hemoglobin building in the rats. J Biol Chem 77:797–812. https://doi.org/10.1016/S0021-9258(20)74028-7

40. Josephs HW (1932) Studies on iron metabolism and the influ-
ence of copper. J Biol Chemist 96:559-571. https://doi.org/10.
1016/S0021-9258(18)76292-3

41. Kemmerer AR, Elvehjem CA, Hart EB (1931) Studies on the relation of manganese to the nutrition of the mouse. J Biol Chem 92:623–630. https://doi.org/10.1016/S0021-9258(17) 32608-X

42. Todd WR, Elvehjem CA, Hart EB (2009) Zinc nutrition of the rat. Nutr Rev 38:151–154. https://doi.org/10.1111/j.1753-4887.1980.tb05879.x

43. Underwood EJ, Filmer JF (1935) Enzootic Marasmus: the deter-
mination of the biologically potent element (cobalt) in limonite.
Aust Veterinary J 11:84–92. https://doi.org/10.1111/j.1751-0813.
1935.tb04062.x

44. Higgins ES, Richert DA, Westerfeld WW (1956) Molybdenum deficiency and tungstate inhibition studies. J Nutr 59:539–559. https://doi.org/10.1093/jjn/59.4.539

45. Schwarz K, Foltz C (1957) Selenium as an integral part of Factor 3 againts dietary necrotic liver degeneration. J Am Chem Soc 79:3292–3293. https://doi.org/10.1021/ja01569a087

46. Rotruck JT, Pope AL, Ganther HE et al (1973) Selenium: bio-
chemical role as a component of glutathione peroxidase. Science
179:588–590. https://doi.org/10.1126/science.179.4073.588

47. Schwarz K, Mertz W (1959) Chromium(III) and the glucose tolerance factor. Arch Biochem Biophys 85:292-295. https://doi.org/10.1016/0003-9861(59)90479-5

48. Schwarz K, Milne DB, Vinyard E (1970) Growth effects of Tin compounds in rats maintained in a trace-element controlled environment. BBRC 40:22-29

49. Nielsen FH, Sandstead HH (1974) Are nickel, vanadium, silicon, fluorine, and tin essential for man? a review. Am J Clin Nutr 27:515-520. https://doi.org/10.1093/ajcn/27.5.515

50. Schwarz K, Milne DB (1972) Fluorine requirement for growth in the rat. Bioinorg Chem 1:331–338. https://doi.org/10.1016/S0006-3061(00)81006-6

51. Schwarz K, Milne DB (1972) Growth-promoting effects of silicon in rats. Nature 239:333-334. https://doi.org/10.1038/239333a0

52. Schnegg A, Kirchgessner M (1975) Zur Essentialität von Nickel für das tierische Wachstum. Z Tierphysiol Tierernahrer Futtermittelkd 36:63–74. https://doi.org/10.1111/j.1439-0396. 1975.tb01118.x

53. Anke M, Hennig A, Grün M et al (1976) Arsen — ein neues essentielles Spurenelement. Archiv für Tierernaehrung 26:742–743. https://doi.org/10.1080/17450397609426746

54. Smith JC, Schwarz K (1967) A controlled environment system for new trace element deficiencies. J Nutr 93:182-188. https://doi.org/10.1093/jn/93.2.182

55. Haraguchi H (2004) Metallomics as integrated biometal science. J Anal At Spectrom 19:5. https://doi.org/10.1039/b308213j

56. Lobinski R, Moulin C, Ortega R (2006) Imaging and speciation of trace elements in biological environment. Biochimie 88:1591–1604. https://doi.org/10.1016/j.biochi.2006.10.003

57. McRae R, Bagchi P, Sumalekshmy S, Fahrni CJ (2009) In Situ imaging of metals in cells and tissues. Chem Rev 109:4780–4827. https://doi.org/10.1021/cr900223a

58. Haraguchi H (2017) Metallomics: the history over the last decade and a future outlook. Metallomics 9:1001–1013. https://doi.org/10.1039/C7MT00023E

59. Zee DZ, MacRenaris KW, O'Halloran TV (2022) Quantitative imaging approaches to understanding biological processing of metal ions. Curr Opin Chem Biol 69:102152. https://doi.org/10.1016/j.cbpa.2022.102152

60. (1996) Lead, Cadmium and Mercury-Chap. 16. In: Trace ele-
ments in human nutrition and health. World Health Organization,
Geneva, pp 195–216

61. Paracelsus (1538) "Die dritte Defension wegen des Schreibens der neuen Rezepte," Septem Defensiones

62. Hunter P (2008) A toxic brew we cannot live without: micronutrients give insights into the interplay between geochemistry and evolutionary biology. EMBO Rep 9:15–18. https://doi.org/10.1038/sj.embor.7401148

63. Kirchgessner M, Reichlmayr-Lais AM, Stöckl KN (1988) Reten-
tion of lead in growing rats with varying dietary lead supple-
ments. J Trace Elem Electrolytes Health Dis 2:149–152

64. Reichlmayr-Lais AM, Kirchgessner M (1981) Hämatologische Veränderungen bei alimentärem Bleimangel. Ann Nutr Metab 25:281–288

65. Uthus EO (1992) Evidence for arsenic essentiality. Environ Geo-
chem Health 14:55–58. https://doi.org/10.1007/BF01783629

66. Uthus EO (2003) Arsenic essentiality: a role affecting methionine metabolism. J Trace Elem Exp Med 16:345-355. https://doi.org/10.1002/jtra.10044

67. Zeng H, Uthus EO, Combs GF Jr (2005) Mechanistic aspects of the interaction between selenium and arsenic. J Inorg Biochem 99:1269–1274. https://doi.org/10.1016/j.jinorgbio.2005.03.006

68. Lane TW, Morel FMM (2000) Regulation of carbonic anhydrase expression by zinc, cobalt, and carbon dioxide in the marine diatom *Thalassiosira weissflogii*. Plant Physiol 123:345–352. https://doi.org/10.1104/pp.123.1.345

69. Daumann LJ (2019) Essential and ubiquitous: the emergence of lanthanide metallobiochemistry. Angew Chem Int Ed 58:12795–12802. https://doi.org/10.1002/anie.201904090

70. Cotzias GC, Papavasiliou PS, Miller ST (1968) Neutron activ-
ation analysis: clinical and biological studies of manganese.
France

71. Nielsen FH (2000) Possibly Essential Trace Elements. In: Bogden JD, Klevay LM (eds) Clinical Nutrition of the Essential Trace Elements and Minerals: The Guide for Health Professionals. Humana Press, published by Springer Nature, Totowa, pp 11–31

72. Pauling L, Coryell CD (1936) The magnetic properties and structure of hemoglobin, oxyhemoglobin and carbonmonoxy-hemoglobin. Proc Natl Acad Sci USA 22:210-216. https://doi.org/10.1073/pnas.22.4.210

73. Collman JP, Gagne RR, Reed C et al (1975) Picket fence por-
phyrins. synthetic models for oxygen binding hemoproteins. J
Am Chem Soc 97:1427–1439. https://doi.org/10.1021/ja008
39a026
74. Lu Y (2006) Biosynthetic inorganic chemistry. Angew Chem Int Ed 45:5588-5601. https://doi.org/10.1002/anie.200600168

75. Connelly NG, Damhus T, Hartshorn RM, Hutton AT (2005) Nomenclature of inorganic chemistry–IUPAC recommendations 2005. Chemistry International–Newsmagazine for IUPAC 27(table IX). https://doi.org/10.1515/ci.2005.27.6.25

76. Rohde J-U, In J-H, Lim MH et al (2003) Crystallographic and spectroscopic characterization of a nonheme Fe(IV)=O complex. Science 299:1037-1039. https://doi.org/10.1126/science.299.5609.1037

77. Klinker EJ, Kaizer J, Brennessel WW et al (2005) Structures of nonheme oxoiron (IV) complexes from X-ray crystallography, NMR spectroscopy, and DFT calculations. Angew Chem Int Ed 44:3690-3694. https://doi.org/10.1002/anie.200500485

78. Dedushko MA, Greiner MB, Downing AN et al (2022) Electronic structure and reactivity of dioxygen-derived aliphatic thiolate-ligated Fe-Peroxo and Fe(IV) oxo compounds. J Am Chem Soc 144:8515-8528. https://doi.org/10.1021/jacs.1c07656

79. Mukherjee G, Sastri CV (2020) Eccentricities in spectroscopy and reactivity of non-heme metal intermediates contained in bispidine scaffolds. Isr J Chem 60:1032-1048. https://doi.org/10.1002/ijch.202000045

80. Larson VA, Battistella B, Ray K et al (2020) Iron and manganese oxo complexes, oxo wall and beyond. Nat Rev Chem 4:404-419. https://doi.org/10.1038/s41570-020-0197-9

81. Solomon EI, Szilagyi RK, DeBeer GS, Basumallick L (2004) Electronic structures of metal sites in proteins and models: contributions to function in blue copper proteins. Chem Rev 104:419-458. https://doi.org/10.1021/cr0206317

82. Sheng Y, Abreu IA, Cabelli DE et al (2014) Superoxide dismutases and superoxide reductases. Chem Rev 114:3854-3918. https://doi.org/10.1021/cr4005296

83. Policar C, Delsuc N, Bertrand HC (2024) Metal complexes in cells: from design of catalytic antioxidants to imaging metal ions and designing metal-based probes in X-ray fluorescence and IR-imaging, a multidisciplinary collaborative journey in bioinorganic chemistry and inorganic chemical biology. C R Chim 27:1-25. https://doi.org/10.5802/crchim.295

84. Comba P (2003) Fit and misfit between ligands and metal ions. Coord Chem Rev 238-239:21-29. https://doi.org/10.1016/S0010-8545(02)00294-1

85. Comba P (2000) Coordination compounds in the entatic state. Coord Chem Rev 200-202:217-245. https://doi.org/10.1016/S0010-8545(00)00265-4

86. Vallee BL, Williams RJ (1968) Metalloenzymes: the entatic nature of their active sites. Proc Natl Acad Sci USA 59:498. https://doi.org/10.1073/pnas.59.2.498

87. Schweitzer D, Shearer J, Rittenberg DK et al (2002) Enhancing reactivity via structural distortion. Inorg Chem 41:3128-3136. https://doi.org/10.1021/ic0109187

88. Stanek J, Hoffmann A, Herres-Pawlis S (2018) Renaissance of the entatic state principle. Coord Chem Rev 365:103-121. https://doi.org/10.1016/j.ccr.2018.03.009

89. Diekmann S, Weston J, Anders E et al (2002) Metal-mediated reactions modeled after nature. Rev Mol Biotechnol 90:73-94. https://doi.org/10.1016/S1389-0352(01)00067-8

90. Bhagi-Damodaran A, Lu Y (2019) The periodic table's impact on bioinorganic chemistry and biology's selective use of metal ions. In: Mingos DMP (ed) The Periodic Table II. Springer International Publishing, Cham, pp 153-173

91. Rhoda HM, Heyer AJ, Snyder BER et al (2022) Second-sphere lattice effects in copper and iron zeolite catalysis. Chem Rev 122:12207-12243. https://doi.org/10.1021/acs.chemrev.1c00915

92. Ghattas W, Mahy J, Réglier M, Simaan AJ (2021) Artificial enzymes for diels-alder reactions. ChemBioChem 22:443-459. https://doi.org/10.1002/cbic.202000316

93. Koebke KJ, Pinter TBJ, Pitts WC, Pecoraro VL (2022) Catalysis and electron transfer in De Novo designed metalloproteins. Chem Rev 122:12046-12109. https://doi.org/10.1021/acs.chemr ev.1c01025

94. Davis HJ, Ward TR (2019) Artificial metalloenzymes: challenges and opportunities. ACS Cent Sci 5:1120-1136. https://doi.org/10.1021/acscentsci.9b00397

95. Rosati F, Roelfes G (2010) Artificial metalloenzymes. Chem-CatChem 2:916-927. https://doi.org/10.1002/cctc.201000011

96. Arnold FH (2015) The nature of chemical innovation: new enzymes by evolution. Quart Rev Biophys 48:404-410. https://doi.org/10.1017/S003358351500013X

97. Kratošová G, Holišová V, Konvičková Z et al (2019) From biotechnology principles to functional and low-cost metallic bio-nanocatalysts. Biotechnol Adv 37:154-176. https://doi.org/10.1016/j.biotechadv.2018.11.012

98. James CC, De Bruin B, Reek JNH (2023) Transition metal catalysis in living cells: progress, challenges, and novel supramolecular solutions. Angew Chem Int Ed 62:e202306645. https://doi.org/10.1002/anie.202306645

99. Policar C, Bouvet J, Bertrand HC, Delsuc N (2022) SOD mimics: From the tool box of the chemists to cellular studies. Curr Opin Chem Biol 67:102109. https://doi.org/10.1016/j.cbpa.2021.102109

100. Tsiapalis D, Zeugolis DI (2021) It is time to crowd your cell culture media – physicochemical considerations with biological consequences. Biomaterials 275:120943. https://doi.org/10.1016/j.biomaterials.2021.120943

101. Gilston BA, O'Halloran TV (2013) Mechanisms controlling the cellular economy. In: Scott RA (ed) Culotta V. Metals in cells. John Wiley & Sons Ltd, Chichester

102. Williams RJP (2001) Chemical selection of elements by cells. Coord Chem Rev 216-217:583-595. https://doi.org/10.1016/S0010-8545(00)00398-2

103. Banci L, Bertini I (2013) Metallomics and the cell: some definitions and general comments. In: Banci L (ed) Metallomics and the cell. Springer, Netherlands, Dordrecht, pp 1-13

104. de Viguerie L, Walter P, Laval E et al (2010) Revealing the sfumato technique of Leonardo da Vinci by X-Ray fluorescence spectroscopy. Angew Chem Int Ed 49:6125-6128. https://doi.org/10.1002/anie.201001116

105. Outten CE, O'Halloran T (2001) Femtomolar sensitivity of metalloregulatory proteins controlling zinc homeostasis. Science 292:2488-2492. https://doi.org/10.1126/science.1060331

106. Rosenzweig AC (2002) Metallochaperones. Chem Biol 9:673-677. https://doi.org/10.1016/S1074-5521(02)00156-4

107. Weiss A, Murdoch CC, Edmonds KA et al (2022) Zn-regulated GTPase metalloprotein activator 1 modulates vertebrate zinc homeostasis. Cell 185:2148-2163.e27. https://doi.org/10.1016/j.cell.2022.04.011

108. Sala D, Ciambellotti S, Giachetti A et al (2017) Investigation of the Iron(II) release mechanism of human H-Ferritin as a function of pH. J Chem Inf Model 57:2112-2118. https://doi.org/10.1021/acs.jcim.7b00306

109. Koochana PK, Mohanty A, Das S et al (2018) Releasing iron from ferritin protein nanocage by reductive method: the role of electron transfer mediator. Biochimica et Biophysica Acta BBA - General Subjects 1862:1190-1198. https://doi.org/10.1016/j.bbagen.2018.02.011

110. Wilkins PC, Wilkins RG (2005) Inorganic chemistry in biology. Oxford University Press, Oxford

111. Diekmann S, Hoischen C (2014) Biomolecular dynamics and binding studies in the living cell. Phys Life Rev 11:1-30. https://doi.org/10.1016/j.plrev.2013.11.011
112. Waldron KJ, Rutherford JC, Ford D, Robinson NJ (2009) Metalloproteins and metal sensing. Nature 460:823-830. https://doi.org/10.1038/nature08300

113. Robinson NJ, Glasfeld A (2020) Metalation: nature's challenge in bioinorganic chemistry. J Biol Inorg Chem 25:543-545. https://doi.org/10.1007/s00775-020-01790-3

114. Helmann JD (2025) Metals in motion: understanding labile metal pools in bacteria. Biochemistry 64:329-345. https://doi.org/10.1021/acs.biochem.4c0072

115. (2017) Simulation of Biomolecules in Cellular Environments. Cybernet

116. Thordarson P (2011) Determining association constants from titration experiments in supramolecular chemistry. Chem Soc Rev 40:1305-1323. https://doi.org/10.1039/C0CS00062K

117. Wellenreuther G, Cianci M, Tucoulou R et al (2009) The ligand environment of zinc stored in vesicles. Biochem Biophys Res Commun 380:198-203. https://doi.org/10.1016/j.bbrc.2009.01.074

118. Cousins RJ, Liuzzi JP, Lichten LA (2006) Mammalian zinc transport, trafficking, and signals. J Biol Chem 281:24085-24089. https://doi.org/10.1074/jbc.R600011200

119. Frederickson CJ, Suh SW, Silva D et al (2000) Importance of zinc in the central nervous system: the zinc-containing neuron. J Nutr 130:1471S-1483S. https://doi.org/10.1093/jn/130.5.1471S

120. Grant CR, Amor M, Trujillo HA et al (2022) Distinct gene clusters drive formation of ferroosome organelles in bacteria. Nature 606:160-164. https://doi.org/10.1038/s41586-022-04741-x

121. Murdoch CC, Skaar EP (2022) Nutritional immunity: the battle for nutrient metals at the host-pathogen interface. Nat Rev Microbiol 20:657-670. https://doi.org/10.1038/s41579-022-00745-6

122. Mridha S, Abt MC (2024) Starvation helps transition to abundance – a ferroosome story. Trends Microbiol 32:219-220. https://doi.org/10.1016/j.tim.2024.01.006

123. Novoderezhkin VI, Romero E, Van Grondelle R (2015) How exciton-vibrational coherences control charge separation in the photosystem II reaction center. Phys Chem Chem Phys 17:30828-30841. https://doi.org/10.1039/C5CP00582E

124. Tottey S, Waldron KJ, Firbank SJ et al (2008) Protein-folding location can regulate manganese-binding versus copper- or zinc-binding. Nature 455:1138-1142. https://doi.org/10.1038/nature07340

125. Irving H, Williams P (1948) Order of stability of metal complexes. Nature 162:746-747. https://doi.org/10.1038/162746a0

126. Martin EM, Kondrat FDL, Stewart AJ et al (2018) Native electrospray mass spectrometry approaches to probe the interaction between zinc and an anti-angiogenic peptide from histidine-rich glycoprotein. Sci Rep 8:8646. https://doi.org/10.1038/s41598-018-26924-1

127. Zoumpoulaki M, Schanne G, Delsuc N et al (2022) Deciphering the metal speciation in low-molecular-weight complexes by IMS-MS: application to the detection of manganese superoxide dismutase mimics in cell lysates. Angew Chem Int Ed 61:e202203066. https://doi.org/10.1002/ange.202203066

128. Lisher JP, Giedroc DP (2013) Manganese acquisition and homeostasis at the host-pathogen interface. Front Cell Infect Microbiol. https://doi.org/10.3389/fcimb.2013.00091

129. Aguirre JD, Culotta VC (2012) Battles with iron: manganese in oxidative stress protection. J Biol Chem 287:13541-13548. https://doi.org/10.1074/jbc.R111.312181

130. Policar C, Rampon C, Balfourier A, et al (2025) Inorganic chemical biology and metal complexes in cells: from the design of cellular models to evaluate antioxidant activity to the characterization of metal complexes in cells. Comptes Rendus Chimie. https://doi.org/10.5802/crchim.339

131. Irving H, Williams RJP (1953) The stability of transition-metal complexes. J Chem Soc. https://doi.org/10.1039/jr9530003192

132. Rae TD, Schmidt PJ, Pufahl RA et al (1999) Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science 284:805-808. https://doi.org/10.1126/science.284.5415.805

133. Policar C, Rampon C, Balfourier A, et al (2025) Inorganic chemical biology and metal complexes in cells: from the design of cellular models to evaluate antioxidant activity to the characterization of metal complexes in cells. Comptes Rendus Chimie. https://doi.org/10.5802/crchim.339

134. Mathieu E, Bernard A-S, Delsuc N et al (2017) A cell-penetrant manganese superoxide dismutase (MnSOD) mimic is able to complement MnSOD and exerts an antiinflammatory effect on cellular and animal models of inflammatory bowel diseases. Inorg Chem 56:2545-2555. https://doi.org/10.1021/acs.inorg.chem.6b02695

135. Becker JS (2013) Imaging of metals in biological tissue by laser ablation inductively coupled plasma spectrometry (LA-ICP-MS): state of the art and future developments: imaging of metals by LA-ICP-MS. J Mass Spectrom 48:255-268. https://doi.org/10.1002/jms.3168

136. Decelle J, Veronesi G, Gallet B et al (2020) Subcellular chemical imaging: new avenues in cell biology. Trends Cell Biol 30:173-188. https://doi.org/10.1016/j.tcb.2019.12.007

137. Da Cunha MML, Trepout S, Messaoudi C et al (2016) Overview of chemical imaging methods to address biological questions. Micron 84:23-36. https://doi.org/10.1016/j.micron.2016.02.005

138. New EJ, Wimmer VC, Hare DJ (2018) Promises and pitfalls of metal imaging in biology. Cell Chem Biol 25:7-18. https://doi.org/10.1016/j.chembiol.2017.10.006

139. Graziotto ME, Kidman CJ, Adair LD et al (2023) Towards multimodal cellular imaging: optical and X-ray fluorescence. Chem Soc Rev 52:8295-8318. https://doi.org/10.1039/D3CS00509G

140. Lovett JH, Harris HH (2021) Application of X-ray absorption and X-ray fluorescence techniques to the study of metallodrug action. Curr Opin Chem Biol 61:135-142. https://doi.org/10.1016/j.cbpa.2020.12.004

141. Victor-Lovelace TW, Miller LM (2022) The development and use of metal-based probes for X-ray fluorescence microscopy. Metallomics 14:mfac093. https://doi.org/10.1093/mtomcs/mfac093

142. Theiner S, Schoeberl A, Schweikert A et al (2021) Mass spectrometry techniques for imaging and detection of metallodrugs. Curr Opin Chem Biol 61:123-134. https://doi.org/10.1016/j.cbpa.2020.12.005

143. Buccella D, Fahrni CJ (2023) Editorial overview: imaging metal ions in biological systems. Curr Opin Chem Biol 77:102388. https://doi.org/10.1016/j.cbpa.2023.102388

144. Buccella D (2025) Expanding the Toolbox to Track Metals in Cells: Optical and Vibrational Probes, Gordon Research Conference, Ventura

145. Walpole H (1754) Letter to Horace Mann, introducing the word Serendipity, 1754 Jan. 28