Bioinorganic Chemistry

Faculty currently associated with this research theme.

Metallo-Biochemistry +

It is estimated that one-third of all proteins contain a tightly bound metal ion. Metallo-Biochemistry explores the roles of metal ions in biological samples. At Michigan, interests range from the synthesis of small-molecule mimics for enzyme active sites to the structural, spectroscopic, and enzymologic characterization of metal sites in proteins and nucleic acids (Figures 1-3).  A central theme guiding these studies is the effort to relate metal-ion structure and reactivity to biological function.

First example of specific theme: The secondary coordination sphere that surrounds a enzyme’s active site has long been appreciated to augment, or promote, reactivity through highly specific, directed interactions. However, the application of this approach is particularly underdeveloped in the case of small-molecular systems for catalytic transformations. To significantly advance our understanding of how secondary coordination sphere effects can be used to modulate small molecule activation and recognition, the Michigan team targets the development of ligand architectures that, when metalated, feature well-positioned appended functionality (namely hydrogen-bonding interactions) within the secondary coordination sphere of a metal complex. These functional groups are selected to favorably interact with, and promote the activation of a variety of small molecules. Synthetic coordination complexes relevant to the active site of ureases, copper monooxygenases, and nitrogenases are under investigation.

Second example of specific theme: Nitric oxide (NO) is a fascinating diatomic radical due to its notorious non-innocent behavior in transition-metal complexes. For example, NO adducts of iron(II) species could have electronic structures that vary from an Fe(I)-NO+ to an Fe(III)-NO- extreme with the Fe(II)-NO(radical) case in between. This distinction is significant, as NO+, NO(radical), and NO- have very different reactivities. However, characterizing the exact electronic structures of transition-metal nitrosyls has been found difficult. In the 1980s NO was found to be a central signaling molecule in the cardiovascular and neuronal systems (blood pressure control and nerve signal transduction) and a crucial anti-bacterial agent in immune defense in all mammals including humans. Importantly, the biosynthesis, sensing, regulation, transport, and detoxification of nitric oxide in biological systems is largely mediated by metalloenzymes. The important goal of the Michigan team is to use modern spectroscopic and theoretical methods, including electron paramagnetic resonance (EPR), magnetic circular dichroism (MCD), resonance Raman, and nuclear resonance vibrational spectroscopy (NRVS) combined with DFT calculations to achieve more precise descriptions of the electronic structures of heme- and non-heme iron-nitrosyls, and based on these results, develop a better understanding their functions in biological systems.
Further work in the Michigan team is focused on developing a mechanistic understanding of the biologically very important NO reductase reaction, which protects cells from NO toxicity by reducing NO to less toxic N2O and water. Importantly, these NO reductases (NORs) are highly significant for bacterial pathogenesis in humans. As mentioned above, NO is produced by macrophages at micromolar concentrations in humans to kill invading pathogens. At such high concentrations, NO is able to inactivate important metalloenzymes, and this has been linked to NO toxicity against microbes. However, a number of pathogens (e.g., Helicobacter pylori, Neisseria meningitides, Salmonella enterica) have evolved defenses against NO toxicity by expressing NORs, capable of detoxifying NO by reduction to N2O. NORs therefore contribute to the infectious potential of pathogens, as they allow them to proliferate in the human body, and cause harmful chronic infections and inflammations. However, despite this significance for microbial pathogenesis, the mechanisms of NORs are largely unknown. The two classes of bacterial NORs, NorBC and FNOR, belong to completely different protein families, but interestingly, both have diiron cores as their active sites: NorBC contains a mixed heme/non-heme iron center, whereas the active site of FNORs corresponds to a more common non-heme diiron core similar to ribonucleotide reductase. The Michigan team is using model complexes of heme and non-heme iron-nitrosyls to gain detailed insight into the cata­lytic mechanisms of these NORs.

Figure 1. The de novo designed protein Hg(II),Zn(II)[CSL9CL23H]3 is a functional analogue of the human carbonic anhydrases, catalyzing CO2 hydration and ester hydrolysis at very fast rates. Related structures containing copper are functional nitrite reductases.

Figure 2. Hydrogen bonding network on the metal center.

Figure 3. Crystal structure of the ferrous non-heme iron-nitrosyl model complex {Fe(BMPA-Pr)(NO)}6(OTf)6 showing an unexpected metallacrown hexamer structure. All solvent molecules and H atoms have been omitted for clarity.

Metallo-Neurochemistry +

Distinct features of human neurodegenerative diseases, such as Alzheimer’s disease, are accumulation of misfolded proteins (e.g., amyloid-beta) and metal ion dyshomeostasis. Interaction and reactivity of metal ions with misfolded proteins have been suggested to be involved in neurodegneration. These aspects in disease development, however, have not been clearly elucidated. In order to advance this understanding and contribute to drug discovery, several researches at Michigan have been pursued. One example, chemical tools, capable of specifically targeting metal-associated misfolded proteins and modulating their interaction and reactivity, have been developed (Figure 1).

Figure 1. Design of chemical tools for studying the involvement of metal-associated amyloid-beta species in the pathogenesis of Alzheimer’s disease, as well as discovery of new drugs for the disease.

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