Abstract
Many enzymes in Nature utilize a free arginine (L-Arg) amino acid to initiate the biosynthesis of natural products. Examples of those are the nitric oxide synthases, which generate NO from L-Arg for blood pressure control, and various arginine hydroxylases involved in antibiotics biosynthesis. Among the groups of arginine hydroxylases there are a number that utilize a nonheme iron(II) active site, and react L-Arg with dioxygen and -ketoglutarate to perform either the C3-hydroxylation, C4-hydroxylation, C5-hydroxylation or C4−C5-desaturation. How these seemingly similar enzymes can react with high specificity and selectivity to form different products remains unknown. Over the past few years our groups have investigated the mechanisms of L-Arg activating nonheme iron dioxygenases, including the viomycin biosynthesis enzyme VioC, the naphthyridinomycin biosynthesis enzyme NapI and the streptothricin biosynthesis enzyme OrfP, using computational approaches and applied, molecular dynamics, quantum mechanics on cluster models and quantum mechanics/molecular mechanics approaches. These studies highlight the differences in substrate and oxidant binding and positioning, but also emphasize on electronic and electrostatic differences in the substrate binding pockets of the enzymes. In particular, due to charge differences in the active site structures there are changes in the local electric field and electric dipole moment orientations that either strengthen or weaken specific substrate C−H bonds. The local field effects, therefore, influence and guide reaction selectivity and specificity and give the enzymes their unique reactivity patterns. Computational work using either quantum mechanics/molecular mechanics or density functional theory on cluster models can give valuable insight into catalytic reaction mechanisms and produces accurate and reliable data that can be used to engineer proteins and synthetic catalysts to perform novel reaction pathways.
Original language | English |
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Journal | ACS Catalysis |
Publication status | Accepted/In press - 22 Jan 2024 |
Keywords
- QM/MM
- Cluster models
- Enzyme catalysis
- Inorganic Reaction Mechanisms
- Iron enzymes
- Dioxygenases