scholarly journals Discovering and harnessing oxidative enzymes for chemoenzymatic synthesis and diversification of anticancer camptothecin analogues

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Tuan-Anh M. Nguyen ◽  
Trinh-Don Nguyen ◽  
Yuen Yee Leung ◽  
Matthew McConnachie ◽  
Oleg Sannikov ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Anticancer Agents ◽  
Chemoenzymatic Synthesis ◽  
Oxidative Enzymes ◽  
Cytochrome P450 Monooxygenases ◽  
P450 Monooxygenases ◽  
Quinoline Alkaloid ◽  
Synthetic Derivatives ◽  
Derivatives Of ◽  
Camptothecin Analogues

AbstractSemi-synthetic derivatives of camptothecin, a quinoline alkaloid found in the Camptotheca acuminata tree, are potent anticancer agents. Here we discovered two C. acuminata cytochrome P450 monooxygenases that catalyze regio-specific 10- and 11-oxidations of camptothecin, and demonstrated combinatorial chemoenzymatic C-H functionalizations of the camptothecin scaffold using the new enzymes to produce a suite of anticancer drugs, including topotecan (Hycamtin®) and irinotecan (Camptosar®). This work sheds new light into camptothecin metabolism, and represents greener approaches for accessing clinically relevant camptothecin derivatives.

Characterization of cytochrome P450-monooxygenases of Chinese hamsters with respect to aflatoxin B1 activation

Toxicology ◽  
1994 ◽  
Vol 93 (2-3) ◽  
pp. 165-173 ◽  
Author(s):  
Morio Fukuhara ◽  
Eric Antignac ◽  
Naomi Fukusen ◽  
Kazue Kato ◽  
Masanobu Kimura
Keyword(s):  
Cytochrome P450 ◽  
Aflatoxin B1 ◽  
Cytochrome P450 Monooxygenases ◽  
P450 Monooxygenases ◽  
Chinese Hamsters

scholarly journals Specificity and mechanism of carbohydrate demethylation by cytochrome P450 monooxygenases

2018 ◽  
Vol 475 (23) ◽  
pp. 3875-3886 ◽  
Author(s):  
Craig S. Robb ◽  
Lukas Reisky ◽  
Uwe T. Bornscheuer ◽  
Jan-Hendrik Hehemann
Keyword(s):  
Cytochrome P450 ◽  
Active Site ◽  
Substrate Recognition ◽  
High Energy ◽  
Cytochrome P450 Monooxygenases ◽  
P450 Monooxygenases ◽  
High Energy Barrier ◽  
Molecular Determinants ◽  
Cytochrome P450 Family ◽  
Carbohydrate Ligand

Degradation of carbohydrates by bacteria represents a key step in energy metabolism that can be inhibited by methylated sugars. Removal of methyl groups, which is critical for further processing, poses a biocatalytic challenge because enzymes need to overcome a high energy barrier. Our structural and computational analysis revealed how a member of the cytochrome P450 family evolved to oxidize a carbohydrate ligand. Using structural biology, we ascertained the molecular determinants of substrate specificity and revealed a highly specialized active site complementary to the substrate chemistry. Invariance of the residues involved in substrate recognition across the subfamily suggests that they are critical for enzyme function and when mutated, the enzyme lost substrate recognition. The structure of a carbohydrate-active P450 adds mechanistic insight into monooxygenase action on a methylated monosaccharide and reveals the broad conservation of the active site machinery across the subfamily.

scholarly journals Biotechnological Methods of Sulfoxidation: Yesterday, Today, Tomorrow

Catalysts ◽  
2018 ◽  
Vol 8 (12) ◽  
pp. 624 ◽  
Author(s):  
Wanda Mączka ◽  
Katarzyna Wińska ◽  
Małgorzata Grabarczyk
Keyword(s):  
Cytochrome P450 ◽  
Chemical Industry ◽  
Functional Materials ◽  
Cytochrome P450 Monooxygenases ◽  
Whole Cells ◽  
Historical Significance ◽  
P450 Monooxygenases ◽  
Bacteria And Fungi ◽  
Positive Results ◽  
Huge Variety

The production of chiral sulphoxides is an important part of the chemical industry since they have been used not only as pharmaceuticals and pesticides, but also as catalysts or functional materials. The main purpose of this review is to present biotechnological methods for the oxidation of sulfides. The work consists of two parts. In the first part, examples of biosyntransformation of prochiral sulfides using whole cells of bacteria and fungi are discussed. They have more historical significance due to the low predictability of positive results in relation to the workload. In the second part, the main enzymes responsible for sulfoxidation have been characterized such as chloroperoxidase, dioxygenases, cytochrome flavin-dependent monooxygenases, and P450 monooxygenases. Particular emphasis has been placed on the huge variety of cytochrome P450 monooxygenases, and flavin-dependent monooxygenases, which allows for pure sulfoxides enantiomers effectively to be obtained. In the summary, further directions of research on the optimization of enzymatic sulfoxidation are indicated.

scholarly journals Knock-Down of Gossypol-Inducing Cytochrome P450 Genes Reduced Deltamethrin Sensitivity in Spodoptera exigua (Hübner)

2019 ◽  
Vol 20 (9) ◽  
pp. 2248 ◽  
Author(s):  
Muhammad Hafeez ◽  
Sisi Liu ◽  
Saad Jan ◽  
Le Shi ◽  
G. Mandela Fernández-Grandon ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Secondary Metabolites ◽  
Molecular Mechanisms ◽  
Spodoptera Exigua ◽  
Plant Secondary Metabolites ◽  
Detoxification Enzymes ◽  
Beet Armyworm ◽  
Cytochrome P450 Monooxygenases ◽  
Control Group ◽  
P450 Monooxygenases

Plants employ an intricate and dynamic defense system that includes physiological, biochemical, and molecular mechanisms to counteract the effects of herbivorous attacks. In addition to their tolerance to phytotoxins, beet armyworm has quickly developed resistance to deltamethrin; a widely used pyrethroid insecticide in cotton fields. The lethal concentration (LC50) required to kill 50% of the population of deltamethrin to gossypol-fed Spodoptera exigua larvae was 2.34-fold higher than the control group, suggesting a reduced sensitivity as a consequence of the gossypol diet. Piperonyl butoxide (PBO) treatment was found to synergize with deltamethrin in gossypol-fed S. exigua larvae. To counteract these defensive plant secondary metabolites, beet armyworm elevates their production of detoxification enzymes, including cytochrome P450 monooxygenases (P450s). Gossypol-fed beet armyworm larvae showed higher 7-ethoxycoumarin-O-deethylase (ECOD) activities and exhibited enhanced tolerance to deltamethrin after 48 and 72 h when compared to the control. Moreover, gossypol pretreated S. exigua larvae showed faster weight gain than the control group after transferring to a deltamethrin-supplemented diet. Meanwhile, gossypol-induced P450s exhibited high divergence in the expression level of two P450 genes: CYP6AB14 and CYP9A98 in the midgut and fat bodies contributed to beet armyworm tolerance to deltamethrin. Knocking down of CYP6AB14 and CYP9A98, via double-stranded RNAs (dsRNA) in a controlled diet, rendered the larvae more sensitive to the insecticide. These data demonstrate that generalist insects can exploit secondary metabolites from host plants to enhance their defense systems against other toxic chemicals. Impairing this defense pathway by RNA interference (RNAi) holds a potential to eliminate the pest’s tolerance to insecticides and, therefore, reduce the required dosages of agrochemicals in pest control.

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