20007-87-8Relevant articles and documents
Harnessing the Substrate Promiscuity of Dioxygenase AsqJ and Developing Efficient Chemoenzymatic Synthesis for Quinolones
Tang, Haoyu,Tang, Yijie,Kurnikov, Igor V.,Liao, Hsuan-Jen,Chan, Nei-Li,Kurnikova, Maria G.,Guo, Yisong,Chang, Wei-Chen
, p. 7186 - 7192 (2021/06/30)
Nature has developed complexity-generating reactions within natural product biosynthetic pathways. However, direct utilization of these pathways to prepare compound libraries remains challenging because of limited substrate scopes, involvement of multiple-step reactions, and moderate robustness of these sophisticated enzymatic transformations. Synthetic chemistry offers an alternative approach to prepare natural product analogues. However, because of complex and diverse functional groups appended on the targeted molecules, dedicated design and development of synthetic strategies are typically required. Herein, by leveraging the power of chemoenzymatic synthesis, we report an approach to bridge the gap between biological and synthetic strategies in the preparation of quinolone alkaloid analogues. Leading byin silicoanalysis, the predicted substrate analogues were chemically synthesized. The AsqJ-catalyzed asymmetric epoxidation of these substrate analogues was followed by a Lewis acid-triggered ring contraction to complete the viridicatin formation. We evaluated the robustness of this method in gram-scale reactions. Lastly, through chemoenzymatic cascades, a library of quinolone alkaloids is effectively prepared.
Epoxidation Catalyzed by the Nonheme Iron(II)- A nd 2-Oxoglutarate-Dependent Oxygenase, AsqJ: Mechanistic Elucidation of Oxygen Atom Transfer by a Ferryl Intermediate
Cha, Lide,Chan, Nei-Li,Chang, Wei-Chen,Guo, Yisong,Huang, Jhih-Liang,Kurnikov, Igor V.,Kurnikova, Maria G.,Lee, Justin L.,Li, Jikun,Liao, Hsuan-Jen,Lin, Te-Sheng,Tang, Yijie
, p. 6268 - 6284 (2020/04/27)
Mechanisms of enzymatic epoxidation via oxygen atom transfer (OAT) to an olefin moiety is mainly derived from the studies on thiolate-heme containing epoxidases, such as cytochrome P450 epoxidases. The molecular basis of epoxidation catalyzed by nonheme-iron enzymes is much less explored. Herein, we present a detailed study on epoxidation catalyzed by the nonheme iron(II)- A nd 2-oxoglutarate-dependent (Fe/2OG) oxygenase, AsqJ. The native substrate and analogues with different para substituents ranging from electron-donating groups (e.g., methoxy) to electron-withdrawing groups (e.g., trifluoromethyl) were used to probe the mechanism. The results derived from transient-state enzyme kinetics, M?ssbauer spectroscopy, reaction product analysis, X-ray crystallography, density functional theory calculations, and molecular dynamic simulations collectively revealed the following mechanistic insights: (1) The rapid O2 addition to the AsqJ Fe(II) center occurs with the iron-bound 2OG adopting an online-binding mode in which the C1 carboxylate group of 2OG is trans to the proximal histidine (His134) of the 2-His-1-carboxylate facial triad, instead of assuming the offline-binding mode with the C1 carboxylate group trans to the distal histidine (His211); (2) The decay rate constant of the ferryl intermediate is not strongly affected by the nature of the para substituents of the substrate during the OAT step, a reactivity behavior that is drastically different from nonheme Fe(IV)-oxo synthetic model complexes; (3) The OAT step most likely proceeds through a stepwise process with the initial formation of a C(benzylic)-O bond to generate an Fe-alkoxide species, which is observed in the AsqJ crystal structure. The subsequent C3-O bond formation completes the epoxide installation.
Insights into the Desaturation of Cyclopeptin and its C3 Epimer Catalyzed by a non-Heme Iron Enzyme: Structural Characterization and Mechanism Elucidation
Liao, Hsuan-Jen,Li, Jikun,Huang, Jhih-Liang,Davidson, Madison,Kurnikov, Igor,Lin, Te-Sheng,Lee, Justin L.,Kurnikova, Maria,Guo, Yisong,Chan, Nei-Li,Chang, Wei-Chen
supporting information, p. 1831 - 1835 (2018/01/27)
AsqJ, an iron(II)- and 2-oxoglutarate-dependent enzyme found in viridicatin-type alkaloid biosynthetic pathways, catalyzes sequential desaturation and epoxidation to produce cyclopenins. Crystal structures of AsqJ bound to cyclopeptin and its C3 epimer ar
Mechanistic Investigation of a Non-Heme Iron Enzyme Catalyzed Epoxidation in (-)-4′-Methoxycyclopenin Biosynthesis
Chang, Wei-Chen,Li, Jikun,Lee, Justin L.,Cronican, Andrea A.,Guo, Yisong
supporting information, p. 10390 - 10393 (2016/09/04)
Mechanisms have been proposed for α-KG-dependent non-heme iron enzyme catalyzed oxygen atom insertion into an olefinic moiety in various natural products, but they have not been examined in detail. Using a combination of methods including transient kinetics, M?ssbauer spectroscopy, and mass spectrometry, we demonstrate that AsqJ-catalyzed (-)-4′-methoxycyclopenin formation uses a high-spin Fe(IV)-oxo intermediate to carry out epoxidation. Furthermore, product analysis on 16O/18O isotope incorporation from the reactions using the native substrate, 4′-methoxydehydrocyclopeptin, and a mechanistic probe, dehydrocyclopeptin, reveals evidence supporting oxo? hydroxo tautomerism of the Fe(IV)-oxo species in the non-heme iron enzyme catalysis.
