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Nicolai Lehnert

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Primary Appointment: LSA Chemistry
Primary PIBS Dept.: Biophysics
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  Research projects that are currently pursued in my group relate to the biological nitric oxide (NO) metabolism; i.e. the synthesis, function and degradation of nitric oxide in the biosphere. Nitric oxide is a poisonous gas, which, however, has proven to be of great biological significance. In 1992, it was therefore voted as 'the molecule of the year' by the magazine Science. These pioneering results triggered further research and up to this day, it is known that NO plays a key role in nerve signal transduction, vasodilation, blood clotting and immune response by white blood cells. New biological functions of NO and the corresponding, one electron reduced nitroxyl ion are still discovered. Many of the biologically important reactions of nitric oxide are mediated by heme proteins. NO is produced in vivo by the nitric oxide synthase (NOS) family of enzymes. The cardiovascular regulation by NO (produced by endothelial(e-) NOS) is then mediated by soluble guanylate cyclase (sGC), which is activated by coordination of NO to its ferrous heme active site. In addition, the role of nitric oxide in vasodilation is exploited by certain blood-sucking insects that inject NO into the bites of their victims using small NO-carrier heme proteins, the so-called Nitrophorins (Np). Furthermore, nitric oxide occurs as intermediate in dissimilatory denitrification, which corresponds to the stepwise reduction of nitrate to dinitrogen. NO is produced by nitrite reductase (NIR) and further reduced to nitrous oxide by the nitric oxide reductases (NOR). I am especially interested in the latter class of enzymes.

Bacterial NOR (NorBC) reduces NO to nitrous oxide (N2O) at a mixed heme/non-heme active site, where the heme shows axial histidine coordination. In comparison, the same reaction is performed by fungal nitric oxide reductase (P450nor) at a single heme active site, which, in contrast, has an axial cysteine ligand. Hence, the bacterial and fungal enzymes catalyze the same reaction, but utilize different mechanisms. Central research goals are the elucidation of the reaction mechanisms of these enzymes and the properties of heme-nitrosyls in general as a function of porphyrin substitutions and trans-ligands to NO. To this end, a dual strategy is applied. First, model complexes of type [Fe(TPP*)(L)(NO)]n+ (TPP* = tetraphenylporphyrin type ligand; L = N-donor, thiolate, etc.) are synthesized, which allow for the routine investigation of the porphyrin substituent and trans-ligand effect on the coordinated NO. Complementarily, we are working on cytochrome P450 and mutants as well as the NO reductase from E. coli.

Besides the research on the biological role of nitric oxide, I am also very interested in the fields of (a) Bioorganometallic Chemistry; i.e. the conduction of organometallic chemistry in aqueous solution using proteins with modified active sites. In this respect, I am especially interested in the usage of small heme proteins for organometallic reactions; and (b) Anti-Cancer Drugs based on Ru-NO compounds, especially their interaction with DNA, their photophysical properties, and their mechanisms of activation. These research areas are currently developed in my group.