Nobel symposium #168 Visions of bio-inorganic chemistry: metals and the molecules of life

The Nobel symposium “Visions of bio-inorganic chemistry: metals and the molecules of life” was held at the end of May 2022 in Stockholm, Sweden. The current special issue of FEBS Letters contains contributions from speakers at the symposium and, even though only representing a small part of the field, illustrate its immense breadth, progress and potential. The study of metals in biology, bioinorganic chemistry, is inherently multidisciplinary drawing on methods and expertise from physics, inorganic chemistry, biochemistry and biology. This continuously expands with recent tools including de-novo protein design and numerous big data and -omics methods, just to name a few. The overall goal is to answer central scientific questions regarding acquisition and utilization of metals and radicals, as well as to address the most pressing challenges for humankind by understanding, utilizing, mimicking and extending this chemistry. As with so many other meetings, the symposium had been postponed due to the Covid-19 pandemic. Before the pandemic, at the 2019 metals in biology GRC, Harry Gray painted a picture that stuck with me. He concluded that we have four bulk resources on earth we will have forever: nitrogen (N2), carbon dioxide (CO2), water (H2O) and sunlight. In a sustainable future, humankind has no alternative but to produce the food, materials and energy we require from those molecules and solar photons. From a chemist's perspective, this forms a formidable challenge; these are notoriously inert compounds that resist most attempts to be converted into anything more complex. Luckily, by observing nature, we know it is possible. Photosynthesis and nitrogen fixation are the two basic reactions that enter these compounds into biochemistry and the subsequent enormous chemical space and potential of biology. The key is to combine the redox chemistry of metals and radicals with the exquisite specificity and selectivity of enzymes. It is estimated that almost half of all enzymes require metal cofactors for function [[1]]. This issue describes a number of such examples. Lubitz, Yano and Siegbahn [[2-4]] contribute three fascinating accounts of how work using various experimental techniques together with theory now allows us to paint a detailed picture of how photosystem II functions in oxygenic photosynthesis. This is a reaction that has fascinated scientists since the first clues obtained by Joliot in 1969, observing the flash-induced period-four oscillations of oxygen evolution [[5]]. The level of understanding that has now been achieved is a wonderful testament to the multidisciplinary nature of the field. Siegbahn also describes computational studies of nitrogenase, an enzyme further described from an experimental perspective by Rees [[6]]. Rees gives a fascinating account of how the knowledge of the system evolved from the early experiments to the current understanding informed by a great number of experimental approaches. The advances have certainly been astonishing and still, nitrogenase retains some secrets regarding the mechanism of its beautifully complicated 7Fe-9S-C-Mo-homocitrate cofactor. In a research article, Gray and coworkers [[7]] describe the Flavocytochrome P450 from Bacillus megaterium, a heme enzyme capable of hydroxylating non-activated aliphatic lipids. The focus is, however, not on the substrate chemistry per se but rather the mechanisms put in place to protect the enzyme from self-inactivation by runaway oxidizing species when substrate oxidation is not possible. Solomon provides an account on the mechanism of binuclear copper monooxygenases [[8]]. These enzymes constitute a number of families with varied functions. The article describes the current state of knowledge as well as how the recent characterization of the ternary intermediate of Tyrosinase has contributed to the longstanding goal of understanding the monooxygenation mechanism of binuclear copper monooxygenases. Klinman [[9]] paints a fascinating picture of how function in metalloenzymes can be activated by dynamics and how the interplay between protein dynamics and function can be addressed using novel experimental and theoretical approaches. Broderick and Hoffman review the vast “radical SAM” family of proteins [[10]]. Enzymes utilizing a 4Fe-4S cluster together with S-adenosyl-methionine to perform a hugely diverse set of radical-based chemical reactions. Recent discoveries have revealed a central intermediate “Ω” with mechanistic analogies to the adenosyl cobalamine (coenzyme B12) cofactor, establishing common principles in enzymatic radical generation. Ferredoxins constitute another large family of iron–sulfur proteins. Lill reviews the mitochondrial 2Fe-2S ferredoxins and their function in very diverse biochemistry, some functions identified more than half a century ago, while others have just recently been discovered [[11]]. While enzymatic chemistry is perhaps the most well-known example of metal use in biology, metal ions function in a plethora of other essential roles such as signaling, electron transfer, regulation, transport as well as maintenance of osmotic pressure and electrochemical gradients. The symposium provided some fascinating examples. Banci and Butler [[12, 13]] provide perspectives on the central questions of how metals are acquired and transported in the cell, a fundamental requirement for any subsequent function. These papers serve well to illustrate how new methods such as mining of genome sequences and in-cell spectroscopic methods provide insight that was until recently completely out of reach. Robinson [[14]] takes the next step and describes how proteins in the cell can acquire the correct metal for function in competition with other metals as well as other metal-binding proteins. The answer lies in both specific and general control mechanisms such as chaperones and a strict maintenance of metal availability. Lippard provides an intriguing perspective of how mobile zinc influences the amplitude of sensory response in the central nervous system [[15]]. Analytical tools in the form of Zn2+-specific chelators that have been developed to study these processes and effects are also described. Giese provides a perspective on the architecture of long-distance electron transfer pathways [[16]]. This encompasses distances we are unused to thinking about in the biochemical context, for example, cable bacteria that conduct electrons over cm-distances to connect electron donors and acceptors in aquatic sediments. Bren and Casini [[17, 18]] provide examples of applications of bioinorganic and bioinspired systems. Bren considers the key current issue of energy storage by finding inspiration for proton and carbon dioxide reduction in nature. Casini discusses the use of supramolecular coordination complexes to create versatile materials for use in biomedical applications such as drug delivery and imaging. The goal of the symposium was to define the state-of-the-art, but perhaps more importantly, provide inspiration across sub-fields and define directions and possibilities for the future. Reading these papers, I cannot but marvel at the recent progress. I hope they will provide inspiration for new ideas and combinations of methods to probe even deeper into the properties and possibilities that arise when metals interact with the molecules of life. Martin Högbom is Professor of Structural Biochemistry, Wallenberg Scholar and Head of the Department of Biochemistry and Biophysics at Stockholm University. His research focusses on bioinorganic enzymology, in particular radical and metal redox catalysis in Ribonucleotide Reductase, Methane Monooxygenase and respiratory complexes. He was a visiting professor at Stanford University School of Medicine in 2018 and at Stanford University Department of Chemistry in 2016. Martin was awarded the European Medal for Bio-Inorganic Chemistry in 2010, served as president of the Young Academy of Sweden during 2014–2015 and was elected member of the Royal Swedish Academy of Sciences in 2020.