Hemoglobin (Hb) is known as the oxygen (O2) carrier protein in blood. Human adult Hb is a tetrameric protein, consisting of two α and two β subunits. Within each subunit, an O2 molecule binds to the iron porphyrin, heme, by forming a bond with the iron center. It has been discovered, however, that small nitroso compounds (RNOs) can also bind to the heme in the active site of Hb because the nitroso functional group is valence isoelectronic with O2. The binding of RNOs to Hb is potentially problematic because the ligands may inhibit the normal function of Hb and may cause damage to the protein. RNOs can be derived from the reduction of nitro compounds (RNO2) and the oxidation of N-hydroxylamines (RNHOHs). Nitroalkanes and N-alkylhydroxylamines are routinely used in industrial and pharmaceutical processes. RNO2 compounds are known to be toxic to the body and can be reduced by human red blood cells into their RNO forms. Studies have demonstrated the formation of Hb-RNO adducts from RNO2 compounds. Through the oxidative route, amines are hydroxylated into their RNHOH derivatives by cytochrome P450 proteins in the body. Research in our lab has shown that small aryl RNHOHs can be oxidized into their RNO forms upon interactions with Hb, leading to inhibition or damage to Hb. To further understand the interaction between Hb and RNOs, this study extends the investigation to other precursors of small RNOs, specifically small alkyl RNO2 and RNHOH compounds. From the reductive pathway, nitroethane (EtNO2) is investigated for its ability to react with Hb and form the Hb-nitrosoethane (EtNO) adduct. From the oxidative pathway, N-methylhydroxylamine (MeNHOH) and N-tert-butylhydroxylamine (tBuNHOH) are studied for their interactions with Hb. Presented here are the UV-vis spectra and the X-ray crystal structures of the complexes resulting from the interactions between Hb and EtNO2, MeNHOH, and tBuNHOH. The results reveal inhibitory and damaging effects to Hb, which provide insights into mechanisms of anemia induced by precursors of RNOs. Furthermore, the results hold value for future drug development, as the nitro and hydroxylamine functional groups are commonly found in prescription drugs and their metabolites.

Structural characterization of hemoglobin-nitrosoalkane complexes

2019 Spring National Meeting

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