Microbial transformation of (+)-nootkatone and the antiproliferative activity of its metabolites

Gliszczyńska, Anna; Łysek, Agnieszka; Janeczko, Tomasz; Świtalska, Marta; Wietrzyk, Joanna; Wawrzeńczyk, Czesław

doi:10.1016/j.bmc.2011.01.062

Cited by 49 publications

(36 citation statements)

References 13 publications

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“…In addition, they differ in size and in structural complexity, providing the opportunity to evaluate the effect of UAA substitutions in the context of a small-molecule drug ( 1 ) and a bulkier natural product ( 2 ). In addition to its commercial value as a fragrance compound, interest in the late-stage functionalization of (+)-nootkatone also stems from its promising activity as an antiproliferative agent [25] .…”

Section: Resultsmentioning

confidence: 99%

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Enhancing the Efficiency and Regioselectivity of P450 Oxidation Catalysts by Unnatural Amino Acid Mutagenesis

et al. 2014

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The development of effective strategies for modulating the reactivity and selectivity of cytochrome P450 enzymes represents a key step toward expediting the use of these biocatalysts for synthetic applications. In this work, we investigated the potential of unnatural amino acid mutagenesis to aid efforts in this direction. To this end, four unnatural amino acids comprising a diverse set of aromatic side-chain groups were incorporated into eleven active site positions of a substrate-promiscuous CYP102A1 variant. The resulting ‘uP450s’ were then tested for their catalytic activity and regioselectivity in the oxidation of two representative substrates consisting of a small-molecule drug and a natural product. Large shifts in regioselectivity were obtained as a result of these single mutations and, in particular, via para-acetyl-Phe substitutions at positions in close proximity to the heme cofactor. Notably, screening of this mini library of uP450s enabled the rapid identification of P450 catalysts for the selective hydroxylation of four aliphatic positions in the target substrates, including a C(sp3)—H site not oxidized by the parent enzyme. Furthermore, our studies led to the discovery of a general activity-enhancing effect of active site substitutions involving the unnatural amino acid para-amino-Phe, resulting in P450 catalysts capable of supporting the highest total turnover number reported to date on a complex molecule (34,650 turnovers). The functional changes induced by the unnatural amino acids could not be recapitulated by any of the twenty natural amino acids. This study thus demonstrates that unnatural amino acid mutagenesis constitutes a promising, new strategy for improving the catalytic activity and regioselectivity of P450 oxidation catalysts.

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Section: Resultsmentioning

confidence: 99%

“…The stereochemistry of the C11 carbon atom was assigned via comparison of NMR data with the reported values for the 11( R ) [25] and 11( S ) [31] epimer.…”

Section: Methodsmentioning

confidence: 99%

Enhancing the Efficiency and Regioselectivity of P450 Oxidation Catalysts by Unnatural Amino Acid Mutagenesis

et al. 2014

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“…In this study, the hydroxylation position of nootkatone was identified at C-13, which is considered as an interesting pharmaceutical derivative. It has been shown that 13-hydroxy-nootkatone was able to increase its antiproliferative activity towards a cancer cell line, while such effect was not significant with other hydroxylated products of nootkatone (Gliszczyńska et al 2011). Moreover, the presence of 13-hydroxy-nootkatone in the secretion of diseased wood of Chamaecyparis lawsoniana also suggested a role of this compound in controlling fungal infection (Takahashi et al 2007).…”

Section: Discussionmentioning

confidence: 94%

CYP264B1 from Sorangium cellulosum So ce56: a fascinating norisoprenoid and sesquiterpene hydroxylase

Khatri

Zapp

et al. 2012

Appl Microbiol Biotechnol

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Many terpenes and terpenoid compounds are known as bioactive substances with desirable fragrance and medicinal activities. Modification of such compounds to yield new derivatives with desired properties is particularly attractive. Cytochrome P450 monooxygenases are potential enzymes for these reactions due to their capability of performing different reactions on a variety of substrates. We report here the characterization of CYP264B1 from Sorangium cellulosum So ce56 as a novel sesquiterpene hydroxylase. CYP264B1 was able to convert various sesquiterpenes including nootkatone and norisoprenoids (α-ionone and β-ionone). Nootkatone, an important grapefruit aromatic sesquiterpenoid, was hydroxylated mainly at position C-13. The product has been shown to have the highest antiproliferative activity compared with other nootkatone derivatives. In addition, CYP264B1 was found to hydroxylate α- and β-ionone, important aroma compounds of floral scents, regioselectively at position C-3. The products, 3-hydroxy-β-ionone and 13-hydroxy-nootkatone, were confirmed by (1)H and (13)C NMR. The kinetics of the product formation was analyzed by high-performance liquid chromatography, and the K ( m ) and k (cat) values were calculated. The results of docking α-/β-ionone and nootkatone into a homology model of CYP264B1 revealed insights into the structural basis of these selective hydroxylations.

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“…2). The known compounds 6-37 were identified as cyperenol (6) (Jacobs et al, 1987), cyperenoic acid (7) (Boonyarathanakornkit et al, 1988), cyperotundone (8) (Hikino et al, 1965(Hikino et al, , 1966, sugeonol (9) (Hikino et al, 1968a), scariodione (10) (Hikino et al, 1968a), sugetriol triacetate (11) (Xu et al, 2009), α-cyperone (12) (Naya et al, 1990), (4aS, 7S),-7-hydroxy-1, 4a-dimethyl-7-(prop-1-en-2-yl),-4, 4a, 5, 6, 7, 8-hexahydronaphthalen-2 (3H),-one (13) (Nozaki et al, 1995), (4aS, 7S, 8R),-8-hydroxy-1, 4a-dimethyl-7-(prop-1-en-2-yl), -4, 4a, 5, 6, 7, 8-hexahydronaphtha-len-2 (3H), -one (14) (Nozaki et al, 1995), cyperol (15) (Sun et al, 2000), 1β-hydroxy-α-cyperone (16) (Sanz and Marco, 1990), 10-epieudesm-11-ene-3β, 5α-diol (17) (Huffman et al, 1980), 3β-hydroxyilicic alcohol (11 (13),-eudesmene-3, 4, 12-triol) (18) (Zhang et al, 2007), cyperusol C (19) (Xu et al, 2004), α-corymbolol (20) (Nyasse et al, 1988), 3β, 4α-dihydroxy-7-epieudesm-11 (13), -ene (21) (Ahmed et al, 1998), 2-oxo-α-cyperone (22) (Murai et al, 1982), 7α (H), 10β-eudesm-4-en-3-one-11,12-diol (23) (Hikino et al, 1975), rhombitriol (24) (Rukachaisirikul et al, 2005), 7-epi-teucrenone (25) (Fraga et al, 1995), α-rotunol (26) (Hiking et al, 1971), nootkatone (27) (Gliszczyńska et al, 2011), 12-hydroxynootkatone (28) , oxyphyllol C (29) (Morikawa et al, 2002), 5-hydroxylucinone (30) (Chiu et al, 2001), oplopanone (31) (Carvalho et al, 2003), 10-hydroxyamorph-4-en-3-one (32) (Wu et al, 2007), cyperusol D (33) (Xu et al, 2004), 2-hydroxy-14-calamenenone (34) (Morimoto et al, 2009), 1-isopropyl-2, 7 dimethylnaphthalene (35) (Qin ...…”

Section: Identification Of Compounds 6-37mentioning

confidence: 99%

Bioactivity-guided isolation of anti-hepatitis B virus active sesquiterpenoids from the traditional Chinese medicine: Rhizomes of Cyperus rotundus

Huang

et al. 2015

Journal of Ethnopharmacology

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Microbial transformation of (+)-nootkatone and the antiproliferative activity of its metabolites

Cited by 49 publications

References 13 publications

Enhancing the Efficiency and Regioselectivity of P450 Oxidation Catalysts by Unnatural Amino Acid Mutagenesis

Enhancing the Efficiency and Regioselectivity of P450 Oxidation Catalysts by Unnatural Amino Acid Mutagenesis

CYP264B1 from Sorangium cellulosum So ce56: a fascinating norisoprenoid and sesquiterpene hydroxylase

Bioactivity-guided isolation of anti-hepatitis B virus active sesquiterpenoids from the traditional Chinese medicine: Rhizomes of Cyperus rotundus

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