Oxetane ring formation in taxol biosynthesis is catalyzed by a bifunctional cytochrome P450 enzyme
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Oxetane ring formation in taxol biosynthesis is catalyzed by a bifunctional cytochrome P450 enzyme. / Zhao, Yong; Liang, Feiyan; Xie, Yuman; Duan, Yao Tao; Andeadelli, Aggeliki; Pateraki, Irini; Makris, Antonios M.; Pomorski, Thomas G.; Staerk, Dan; Kampranis, Sotirios C.
In: Journal of the American Chemical Society, Vol. 146, 2024, p. 801-810.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Oxetane ring formation in taxol biosynthesis is catalyzed by a bifunctional cytochrome P450 enzyme
AU - Zhao, Yong
AU - Liang, Feiyan
AU - Xie, Yuman
AU - Duan, Yao Tao
AU - Andeadelli, Aggeliki
AU - Pateraki, Irini
AU - Makris, Antonios M.
AU - Pomorski, Thomas G.
AU - Staerk, Dan
AU - Kampranis, Sotirios C.
N1 - Publisher Copyright: © 2023 American Chemical Society.
PY - 2024
Y1 - 2024
N2 - Taxol is a potent drug used in various cancer treatments. Its complex structure has prompted extensive research into its biosynthesis. However, certain critical steps, such as the formation of the oxetane ring, which is essential for its activity, have remained unclear. Previous proposals suggested that oxetane formation follows the acetylation of taxadien-5α-ol. Here, we proposed that the oxetane ring is formed by cytochrome P450-mediated oxidation events that occur prior to C5 acetylation. To test this hypothesis, we analyzed the genomic and transcriptomic information for Taxus species to identify cytochrome P450 candidates and employed two independent systems, yeast (Saccharomyces cerevisiae) and plant (Nicotiana benthamiana), for their characterization. We revealed that a single enzyme, CYP725A4, catalyzes two successive epoxidation events, leading to the formation of the oxetane ring. We further showed that both taxa-4(5)-11(12)-diene (endotaxadiene) and taxa-4(20)-11(12)-diene (exotaxadiene) are precursors to the key intermediate, taxologenic oxetane, indicating the potential existence of multiple routes in the Taxol pathway. Thus, we unveiled a long-elusive step in Taxol biosynthesis.
AB - Taxol is a potent drug used in various cancer treatments. Its complex structure has prompted extensive research into its biosynthesis. However, certain critical steps, such as the formation of the oxetane ring, which is essential for its activity, have remained unclear. Previous proposals suggested that oxetane formation follows the acetylation of taxadien-5α-ol. Here, we proposed that the oxetane ring is formed by cytochrome P450-mediated oxidation events that occur prior to C5 acetylation. To test this hypothesis, we analyzed the genomic and transcriptomic information for Taxus species to identify cytochrome P450 candidates and employed two independent systems, yeast (Saccharomyces cerevisiae) and plant (Nicotiana benthamiana), for their characterization. We revealed that a single enzyme, CYP725A4, catalyzes two successive epoxidation events, leading to the formation of the oxetane ring. We further showed that both taxa-4(5)-11(12)-diene (endotaxadiene) and taxa-4(20)-11(12)-diene (exotaxadiene) are precursors to the key intermediate, taxologenic oxetane, indicating the potential existence of multiple routes in the Taxol pathway. Thus, we unveiled a long-elusive step in Taxol biosynthesis.
U2 - 10.1021/jacs.3c10864
DO - 10.1021/jacs.3c10864
M3 - Journal article
C2 - 38129385
AN - SCOPUS:85180563523
VL - 146
SP - 801
EP - 810
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
ER -
ID: 378767114