Regioselectivity in the cytochromes P-450: Control by protein constraints and by chemical reactivities☆
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2018, Biochimica et Biophysica Acta - Proteins and ProteomicsBiocatalytic production of 5-hydroxy-2-adamantanone by P450cam coupled with NADH regeneration
2013, Journal of Molecular Catalysis B: EnzymaticCitation Excerpt :We succeeded in producing 36 mM (5.9 g/l) 5-hydroxy-2-adamantanone using wet cells expressing only the P450cam multicomponent system (Fig. 6A) and 21 mM (3.5 g/l) of the product using freeze-dried cells co-expressing this P450cam system with Gdh (Fig. 6B). The oxidation activities of the whole cells towards 2-adamantanone were almost the same as that of the purified P450cam system previously reported (52 mol (mol P450)−1 min−1) [28], whereas our experimental setup using whole cells achieved gram-per-liter-scale production of 5-hydroxy-2-adamantanone. Through the experiments, we found that wet cells were able to effectively oxidize 2-adamantanone without co-expression of Gdh, whereas freeze-dried cells required co-expression of Gdh for the oxidation activity (Figs. 3 and 5).
The many faces of the adamantyl group in drug design
2011, European Journal of Medicinal ChemistryCitation Excerpt :Mono- and dihydroxylation of the adamantyl group is a common metabolite of adamantyl-based compounds, as catalysed by cytochrome P450s. The pattern of adamantyl hydroxylation has been shown to occur first at the bridgehead carbon atom and second at the secondary carbon atom [170,178]. During the drug discovery process of oral DPP-IV inhibitors, monohydroxylation at the adamantyl bridgehead of a precursor produced 7, which relative to the unsubstituted adamantyl analogue, showed a 30-fold improved oral availability [21].
Simultaneous measurement of CYP1A2 activity, regioselectivity, and coupling: Implications for environmental sensitivity of enzyme-substrate binding
2011, Archives of Biochemistry and BiophysicsCitation Excerpt :An improved understanding of these interactions could lead to more accurate in vitro – in vivo metabolic correlations facilitating drug development [3], and assist in the development and optimization of synthetic schemes in the biotechnology sector [2,9]. P450 regioselectivity is thought to be controlled by a combination of substrate positioning with respect to the active oxidant and the relative reactivity of different potential oxidation sites on the substrate [10]. Regioselectivity of a very mobile substrate, one able to bind in many orientations, is likely governed primarily by the relative reactivity of the different chemical moieties in proximity to the heme.
Bioconversion of 1-adamantanol to 1,3-adamantanediol using Streptomyces sp. SA8 oxidation system
2010, Journal of Bioscience and Bioengineering
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This work was supported by United States Public Health Service Research Grants GM 28737 (R.E.W.) and GM 31756 (S.G.S.).