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• W2073659765 endingPage "1474" @default.
• W2073659765 startingPage "1460" @default.
• W2073659765 abstract "Methionine synthase reductase (MSR) and cytochrome P450 reductase (CPR) transfer reducing equivalents from NADPH via an FAD and FMN cofactor to a redox partner protein. In both enzymes, hydride transfer from NADPH to FAD requires displacement of a conserved tryptophan that lies coplanar to the FAD isoalloxazine ring. Swapping the tryptophan for a smaller aromatic side chain revealed a distinct role for the residue in regulating MSR and CPR catalysis. MSR W697F and W697Y showed enhanced catalysis, noted by increases in kcat and k(cat)/K(m)(NADPH) for steady-state cytochrome c(3+) reduction and a 10-fold increase in the rate constant (k(obs1)) associated with hydride transfer. Elevated primary kinetic isotope effects on k(obs1) for W697F and W697Y suggest that preceding isotopically insensitive steps like displacement of W697 are less rate determining. MSR W697Y, but not MSR W697F, showed detectable formation of the disemiquinone intermediate, indicating that the polarity of the aromatic side chain influences the rate of interflavin electron transfer. By contrast, the CPR variants (W676F and W676Y) displayed modest decreases in cytochrome c(3+) reduction, a 30- and 3.5-fold decrease in the rate of FAD reduction, accumulation of a FADH2 -NADP(+) charge-transfer complex and dramatically suppressed rates of interflavin electron transfer. We conclude for MSR that hydride transfer is 'gated' by the free energy required to disrupt dispersion forces between the FAD isoalloxazine ring and W697. By contrast, the bulky indole ring of W676 accelerates catalysis in CPR by lowering the energy barrier for displacement of the oxidized nicotinamide ring coplanar with the FAD." @default.
• W2073659765 created "2016-06-24" @default.
• W2073659765 creator A5009331019 @default.
• W2073659765 creator A5051683772 @default.
• W2073659765 creator A5089558139 @default.
• W2073659765 date "2013-02-15" @default.
• W2073659765 modified "2023-10-02" @default.
• W2073659765 title "Aromatic substitution of the FAD-shielding tryptophan reveals its differential role in regulating electron flux in methionine synthase reductase and cytochrome P450 reductase" @default.
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• W2073659765 doi "https://doi.org/10.1111/febs.12141" @default.
• W2073659765 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23332101" @default.
• W2073659765 hasPublicationYear "2013" @default.
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