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. 2022 Aug 26:18:1107-1115.
doi: 10.3762/bjoc.18.113. eCollection 2022.

A Streptomyces P450 enzyme dimerizes isoflavones from plants

Run-Zhou Liu  1   2   3 , Shanchong Chen  2   3 , Lihan Zhang  2   3
Affiliations

A Streptomyces P450 enzyme dimerizes isoflavones from plants

Run-Zhou Liu et al. Beilstein J Org Chem. .

Abstract

Dimerization is a widespread natural strategy that enables rapid structural diversification of natural products. However, our understanding of the dimerization enzymes involved in this biotransformation is still limited compared to the numerous reported dimeric natural products. Here, we report the characterization of three new isoflavone dimers from Streptomyces cattleya cultured on an isoflavone-containing agar plate. We further identified a cytochrome P450 monooxygenase, CYP158C1, which is able to catalyze the dimerization of isoflavones. CYP158C1 can also dimerize plant-derived polyketides, such as flavonoids and stilbenes. Our work represents a unique bacterial P450 that can dimerize plant polyphenols, which extends the insights into P450-mediated biaryl coupling reactions in biosynthesis.

Keywords: biaryl coupling; cytochrome P450; dimerization; isoflavone; natural product.

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Figures

Figure 1
Figure 1
Structures of cattleyaisoflavones A (1), B (2), C (3), and daidzein (4).
Figure 2
Figure 2
a) The culture in ISP-2 liquid did not produce 1–3, while feeding with 4 restored the production (analytical method A according to Experimental section, 254 nm). b) Chemical genetics experiments indicated three P450 inhibitors could reduce the production of dimers derived from 4 (analytical method B to better analyze the isoflavone region, 254 nm). CTA: clotrimazole (2.5 µM), FCA: fluconazole (1000 µM), RVT: resveratrol (100 µM).
Figure 3
Figure 3
CYP158C1 dimerizes 4 to form dimers 2 and 5 in vitro (analytical method B, 254 nm). Control conditions (green): 4 (0.4 mM), NADPH (1 mM), and ferredoxin–NADP+ reductase SelFdR0978/ferredoxin SelFdx1499 (FdR/Fdx, 5 µM) in buffer (50 mM PBS, 0.2 mM DTT, 1 mM EDTA, pH 7.4) were incubated at 37 °C for 1 h. Red: the conditions above with the addition of CYP158C1 (3 µM). Blue: the conditions above with the addition of CYP158C1 (3 µM) and RVT (0.5 mM).
Scheme 1
Scheme 1
a) Compatible and b) incompatible substrates of CYP158C1. Products were identified using analytical method D.
Scheme 2
Scheme 2
Proposed mechanism of CYP158C1-mediated dimerization of isoflavones.
See this image and copyright information in PMC

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