Cytochrome P450 monooxygenase-mediated tailoring of triterpenoids and steroids in plants

• Karan Malhotra and
• Jakob Franke

Beilstein J. Org. Chem. 2022, 18, 1289–1310, doi:10.3762/bjoc.18.135

• (CYP) superfamily comprises hemethiolate enzymes that perform remarkable regio- and stereospecific oxidative chemistry. As such, CYPs are key agents for the structural and functional tailoring of triterpenoids, one of the largest classes of plant natural products with widespread applications in

• pharmaceuticals, food, cosmetics, and agricultural industries. In this review, we provide a full overview of 149 functionally characterised CYPs involved in the biosynthesis of triterpenoids and steroids in primary as well as in specialised metabolism. We describe the phylogenetic distribution of triterpenoid

• - and steroid-modifying CYPs across the plant CYPome, present a structure-based summary of their reactions, and highlight recent examples of particular interest to the field. Our review therefore provides a comprehensive up-to-date picture of CYPs involved in the biosynthesis of triterpenoids and

Bacterial terpene biosynthesis: challenges and opportunities for pathway engineering

• Eric J. N. Helfrich,
• Geng-Min Lin,
• Christopher A. Voigt and
• Jon Clardy

Beilstein J. Org. Chem. 2019, 15, 2889–2906, doi:10.3762/bjoc.15.283

• ], vanadium-dependent bromoperoxidases [61][62], or methyltransferases [63]). In addition, enzymes typically classified as tailoring enzymes, such as flavin-dependent monooxygenases [64] and cytochrome P450s (CYPs) [65], were reported to be involved in noncanonical terpene cyclization. Furthermore, both

• ., phenalinolactone (42 kb) [81] and platensimycin/platencin (47/41 kb) [82]) while most are less than 10 kb in size and harbor only one or two putative tailoring enzymes. Among them, oxidoreductases, especially CYPs, are the most abundant tailoring enzymes involved in the diversification process (Supporting

• Information File 1, Table S2). CYPs are heme-dependent iron proteins that catalyze a wide range of reactions [83][84]. The reactions typically involve substrate radical generation by the activated iron species and subsequent hydroxylation. Terpenes are mainly composed of nonactivated hydrocarbons that are

Active site diversification of P450cam with indole generates catalysts for benzylic oxidation reactions

• Paul P. Kelly,
• Anja Eichler,
• Susanne Herter,
• David C. Kranz,
• Nicholas J. Turner and
• Sabine L. Flitsch

Beilstein J. Org. Chem. 2015, 11, 1713–1720, doi:10.3762/bjoc.11.186

• low cost starting materials [1]. One of the most attractive reagents in terms of cost and environmental impact for hydrocarbon oxidation is oxygen in the presence of a catalyst. In this context enzymatic oxidations are attractive, in particular cytochrome P450 monooxygenases (P450s or CYPs) due to

• hydroxylation by P450cam [10][11] and various other P450s, including the bacterial P450 BM3 [12][13] and human CYPs 2A6, 2C19 and 2E1 [14][15] has been previously identified to translate well to mutants activities toward structurally distinct and more demanding substrates such as diphenylmethane [10

Chemical–biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target

• Jonathan W. Choy,
• Clifford Bryant,
• Claudia M. Calvet,
• Patricia S. Doyle,
• Shamila S. Gunatilleke,
• Siegfried S. F. Leung,
• Kenny K. H. Ang,
• Steven Chen,
• Jiri Gut,
• Juan A. Oses-Prieto,
• Jonathan B. Johnston,
• Michelle R. Arkin,
• Alma L. Burlingame,
• Jack Taunton,
• Matthew P. Jacobson,
• James M. McKerrow,
• Larissa M. Podust and
• Adam R. Renslo

Beilstein J. Org. Chem. 2013, 9, 15–25, doi:10.3762/bjoc.9.3

• (TcCYP51), a cytochrome P450 enzyme involved in the biosynthesis of ergosterol in the parasite. Compound 4 also inhibits mammalian CYP isoforms but is trypanocidal at concentrations below those required to significantly inhibit mammalian CYPs in vitro. A chemical-proteomics approach employing an activity

• , producing new lead compounds with compelling properties [37][38][39]. Inhibition of mammalian CYPs A concern with any inhibitor of TcCYP51 is the potential for cross reactivity with mammalian cytochrome P450 (CYP) enzymes, especially those CYPs involved in drug metabolism, like CYP3A4. To assess this risk

• , we evaluated the inhibitory activities of 4 and 1 across a panel of relevant mammalian CYP enzymes (Table 2). Both 4 and 1 inhibited all CYPs in the panel, with IC50 values generally in the low micromolar range. Although compound 4 did inhibit CYP3A4, the potency of inhibition (IC50 = 0.8 μM) was