First-row transition metals play several roles in biological processes and in medicine, but can be toxic in high concentrations. Here the authors comment on the sensitive biochemistry and speciation chemistry of the first-row transition metals, and outline some of the remaining questions that have yet to be answered. Five of the ten first-row transition metals are essential to human health, including manganese, iron, cobalt, copper, and zinc 1,2. Three more first-row transition elements have shown some beneficial biological effects including chromium, vanadium, and nickel. Typically, these metals are consumed in a varied diet or as nutritional additives where, in the human body, they serve both structural and functional roles including the maintenance of cellular functions involved in a wide range of biological activities. However, normal function requires that the levels of the metal ions are maintained within an acceptable range; lower concentrations may result in a nutritional deficiency and higher concentrations may result in toxicity (Fig. 1) 3. In addition, the physical properties of first-row elements, particularly titanium and nickel, are important for preparation of new materials and alloys, resulting in technological advantages that improve the quality of life. Nine of the ten first-row transition metals have densities larger than 5.0 g/cm 3 which, by some definitions, classifies them as 'heavy metals'. Although this definition may be commonly used by some, it is not embraced by chemists primarily because this definition depends on the density of the metal rather than its chemical properties. Furthermore, the negative connotation associated with the term 'heavy metal' and the toxicity of metals such as cadmium and mercury stands in opposition to the fact that five of the first-row transition elements are essential to life. A more concise definition of the vague term 'heavy metal' can be based on chemical properties and would include the block of metals in Groups 3 to 16 that are in periods 4 and greater 4. This definition of 'heavy metals' does not involve first-row elements but only second and third-row transition metals. However, even this definition is debated 4. It is however clear that none of the five essential first-row transition metals are toxic 'heavy metals'. The chemistry of all first-row transition metals is very sensitive to their environment 6. In the presence of water, each metal ion forms hydrated ions which undergo pH and concentrationdependent chemistry that is dictated by the presence of metabolites, proteins, and other biological components (Fig. 1a). It is important to recognize that redox active metal ions do not exist

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Lipoquinones, such as ubiquinones (UQ) and menaquinones (MK), function as essential lipid components of the electron transport system (ETS) by shuttling electrons and protons to facilitate the production of ATP in eukaryotes and prokaryotes. Lipoquinone function in membrane systems has been widely studied, but the exact location and conformation within membranes remains controversial. Lipoquinones, such as Coenzyme Q (UQ-10), are generally depicted simply as “Q” in life science diagrams or in extended conformations in primary literature even though specific conformations are important for function in the ETS. In this study, our goal was to determine the location, orientation, and conformation of UQ-2, a truncated analog of UQ-10, in model membrane systems and to compare our results to previously studied MK-2. Herein, we first carried out a six-step synthesis to yield UQ-2 and then demonstrated that UQ-2 adopts a folded conformation in organic solvents using 1H-1H 2D NOESY and ROESY NMR spectroscopic studies. Similarly, using 1H-1H 2D NOESY NMR spectroscopic studies, UQ-2 was found to adopt a folded, U-shaped conformation within the interface of an AOT reverse micelle model membrane system. UQ-2 was located slightly closer to the surfactant-water interface compared to the more hydrophobic MK-2. In addition, Langmuir monolayer studies determined UQ-2 resided within the monolayer water-phospholipid interface causing expansion, whereas MK-2 was more likely to be compressed out and reside within the phospholipid tails. All together these results support the model that lipoquinones fold regardless of the headgroup structure but that the polarity of the headgroup influences lipoquinone location within the membrane interface. These results have implications regarding the redox activity near the interface as quinone vs. quinol forms may facilitate locomotion of lipoquinones within the membrane. The location, orientation, and conformation of lipoquinones are critical for their function in generating cellular energy within membrane ETS, and the studies described herein shed light on the behavior of lipoquinones within membrane-like environments.

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