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At least 73 records · Page 4Linked to original sources
PubMed2004

New metabolic pathways for flavanones catalyzed by rat liver microsomes.

Flavonoids represent a diverse group of natural pigments widely distributed in the plant kingdom and are an important component of human diet due to their high content in fruits and vegetables. Since many flavonoids have been shown to be potent inhibitors, substrates, and even inducers of various cytochrome P450 isoforms, there is considerable interest in studying interactions of this class of molecules with the cytochrome P450 enzyme system. In this study, the metabolism of several simple flavanones by rat liver microsomes was investigated and compared. In addition to the expected aromatic hydroxylation products, several novel metabolic pathways were observed including C-ring desaturation to form the corresponding flavones, oxidation of the B-ring to generate an unusual quinol oxidation product, B-ring cleavage with the formation of chromone derivatives, and reduction of carbonyl group to form flavan-4-ol derivatives. The metabolites were characterized and identified primarily by using liquid chromatographytandem mass spectrometry with comparison to authentic standards. Formation of flavones from dietary flavanones might have biological significance since flavones often exhibit pharmacological activities that are different from those of flavanones. However, little is known about the pharmacological activities of the other types of flavonone metabolites.

Animals↗
PubMed2005

Biosynthesis of natural flavanones in Saccharomyces cerevisiae.

A four-step flavanone biosynthetic pathway was constructed and introduced into Saccharomyces cerevisiae. The recombinant yeast strain was fed with phenylpropanoid acids and produced the flavanones naringenin and pinocembrin 62 and 22 times more efficiently compared to previously reported recombinant prokaryotic strains. Microbial biosynthesis of the flavanone eriodictyol was also achieved.

Flavanones↗
PubMed2003

New potent antioxidative hydroxyflavanones produced with Aspergillus saitoi from flavanone glycoside in citrus fruit.

Potent antioxidative hydroxyflavanones were produced with Aspergillus saitoi from hesperidin or naringin, which are flavanone glycosides in citrus fruit with weak antioxidative activity. The hydroxyflavanone produced from hesperidin was identified as 8-hydroxyhesperetin (8-HHE), a novel substance, and those from naringin were identified as carthamidin (6-hydroxynaringenin) and isocarthamidin (8-hydroxynaringenin) by FAB-MS, 1H-NMR and 13C-NMR analyses. The antioxidative activity of these hydroxyflavanones was examined by using the free radical-scavenging system of 1,1-diphenyl-2-picrylhydrazyl (DPPH) and the methyl linoleate oxidation system. The hydroxyflavanones (8-HHE, carthamidin, and isocarthamidin) exhibited stronger activity than the flavanone glycosides (hesperidin or naringin) and their aglycones (hesperetin or naringenin). The activity of 8-HHE and isocarthamidin was comparable to that of alpha-tocopherol, and that of carthamidin was weaker than that of isocarthamidin. The hydroxyflavanones, which were hydroxylated on A ring of flavanone by Aspergillus saitoi, were obtained as potent antioxidants.

Antioxidants↗
PubMed1979

Identification of urinary metabolites of flavanone in the rat.

The urinary metabolites of flavanone in the rate were investigated using a gas chromatographic mass spectrometric method employing an OV-1 capillary column. Forty-three metabolites were detected and the most prominent of these were identified. The most common metabolic reactions were reduction of the keto group and hydroxylation at the 3- or 6-positions. Little hydroxylation occurred in ring B. The major metabolites were flavan-4 alpha-ol, trans-3-hydroxyflavan-4 beta-ol, 6-hydroxyflavanone and 6-hydroxyflavan-4 beta-ol. Gas chromatography analysis of underivatized flavanone metabolites, especially with stainless steel columns, results in the formation of dehydrated products including flavone, flav-3-ene and flavanone itself.

Animals↗
PubMed1998

Minor Flavanones from Erythrina abyssinica

Four new prenylated flavanones, abyssinone-V 4'-methyl ether (1) and abyssinoflavanones IV (2), V (3), and VI (4), have been isolated as minor flavanones from the African medicinal plant, Erythrina abyssinica, together with a known flavanone, sigmoidin D. The structure elucidation of compounds 1-4 by spectroscopic studies is described.

Journal Article↗
PubMed2000

Site-directed mutagenesis of the active site serine290 in flavanone 3beta-hydroxylase from Petunia hybrida.

Flavanone 3beta-hydroxylase (FHT) catalyzes a pivotal reaction in the formation of flavonoids, catechins, proanthocyanidins and anthocyanidins. In the presence of oxygen and ferrous ions the enzyme couples the oxidative decarboxylation of 2-oxoglutarate, releasing carbon dioxide and succinate, with the oxidation of flavanones to produce dihydroflavonols. The hydroxylase had been cloned from Petunia hybrida and expressed in Escherichia coli, and a rapid isolation method for the highly active, recombinant enzyme had been developed. Sequence alignments of the Petunia hydroxylase with various hydroxylating 2-oxoglutarate-dependent dioxygenases revealed few conserved amino acids, including a strictly conserved serine residue (Ser290). This serine was mutated to threonine, alanine or valine, which represent amino acids found at the corresponding sequence position in other 2-oxoglutarate-dependent enzymes. The mutant enzymes were expressed in E. coli and purified to homogeneity. The catalytic activities of [Thr290]FHT and [Ala290]FHT were still significant, albeit greatly reduced to 20 and 8%, respectively, in comparison to the wild-type enzyme, whereas the activity of [Val290]FHT was negligible (about 1%). Kinetic analyses of purified wild-type and mutant enzymes revealed the functional significance of Ser290 for 2-oxoglutarate-binding. The spatial configurations of the related Fe(II)-dependent isopenicillin N and deacetoxycephalosporin C synthases have been reported recently and provide the lead structures for the conformation of other dioxygenases. Circular dichroism spectroscopy was employed to compare the conformation of pure flavanone 3beta-hydroxylase with that of isopenicillin N synthase. A double minimum in the far ultraviolet region at 222 nm and 208-210 nm and a maximum at 191-193 nm which are characteristic for alpha-helical regions were observed, and the spectra of the two dioxygenases fully matched revealing their close structural relationship. Furthermore, the spectrum remained unchanged after addition of either ferrous ions, 2-oxoglutarate or both of these cofactors, ruling out a significant conformational change of the enzyme on cofactor-binding.

Amino Acid Sequence↗
PubMed1993

Molecular characterization of flavanone 3 beta-hydroxylases. Consensus sequence, comparison with related enzymes and the role of conserved histidine residues.

A heterologous cDNA probe from Petunia hybrida was used to isolate flavanone-3 beta-hydroxylase-encoding cDNA clones from carnation (Dianthus caryophyllus), china aster (Callistephus chinensis) and stock (Matthiola incana). The deduced protein sequences together with the known sequences of the enzyme from P. hybrida, barley (Hordeum vulgare) and snapdragon (Antirrhinum majus) enabled the determination of a consensus sequence which revealed an overall 84% similarity (53% identity) of flavanone 3 beta-hydroxylases from the different sources. Alignment with the sequences of other known enzymes of the same class and to related non-heme iron-(II) enzymes demonstrated the strict genetic conservation of 14 amino acids, in particular, of three histidines and an aspartic acid. The conservation of the histidine motifs provides strong support for the possible conservation of structurally similar iron-binding sites in these enzymes. The putative role of histidines as chelators of ferrous ions in the active site of flavanone 3 beta-hydroxylases was corroborated by diethyl-pyrocarbonate modification of the partially purified recombinant Petunia enzyme.

Amino Acid Sequence↗
PubMed1997

Identification of strictly conserved histidine and arginine residues as part of the active site in Petunia hybrida flavanone 3beta-hydroxylase.

Flavanone 3beta-hydroxylase, involved in the biosynthesis of flavonoids, catechins, and anthocyanidins, is a non-heme iron enzyme, dependent on Fe2+, molecular oxygen, 2-oxoglutarate, and ascorbate, the typical cofactors of the class of 2-oxoglutarate-dependent dioxygenases. Sequence alignment analysis of various 2-oxoglutarate-dependent dioxygenases and related enzymes revealed eight amino acid residues that seem to be strictly conserved within this group of enzymes. Among these residues, two histidines (His220 and His278) and one aspartic acid (Asp222) were identified as part of the putative iron-binding site and an arginine residue (Arg288) as part of the 2-oxoglutarate binding site, by site-directed mutagenesis and functional analysis of the mutated recombinant enzyme. The mutant genes were expressed in Escherichia coli to give soluble proteins whose molecular masses were in excellent agreement with the wild-type enzyme. Four out of nine mutant enzymes, [Gln78]FHT, [Gln121]FHT, [Gln264]FHT and [Gln266]FHT, were enzymatically active with activities reduced to 26-57%, implying that the mutated amino acid residues are not essential for catalysis. Replacement of His220 by glutamine and Asp222 by asparagine remarkably reduced the catalytic activity to about 0.15% and 0.4%, respectively. The [Gln220]FHT and [Asn222]FHT enzymes showed a slightly increased Km value with respect to iron binding, as compared to the wild-type enzyme. The most drastic effect on the reaction rate of flavanone 3beta-hydroxylase was achieved by mutating His278 to glutamine. The mutant had no detectable enzyme activity, indicating that His278 was essential for the catalytic reaction. The observed protection of purified enzyme from inactivation by diethylpyrocarbonate after the addition of cofactors provided further independent confirmation for the involvement of histidine residues in the active site. The substitution of Arg288 by lysine or glutamine induced a precipitous decrease in catalytic activity and a fivefold and 160-fold increase in the Michaelis constants for 2-oxoglutarate, respectively. In addition, the enzymatic activities of the latter two mutant enzymes showed a strong pH dependence in the weakly acidic as well as in the neutral pH range, unlike the wild-type enzyme. These results clearly indicate that Arg288 probably contributes to the specific binding of 2-oxoglutarate at the active site of the enzyme, most likely by providing a positive charge, properly located in order to interact with the delta-carboxyl function of 2-oxoglutarate. Furthermore, we conclude that His220, His278 and Asp222 constitute three of the possible ligands for iron binding in the active site of flavanone 3beta-hydroxylase.

Adipates↗
PubMed1992

Molecular cloning, sequence analysis, and in vitro expression of flavanone 3 beta-hydroxylase from Petunia hybrida.

A cDNA encoding flavanone 3 beta-hydroxylase was isolated from petals of Petunia hybrida. The open reading frame of the nearly full length cDNA coded for a 369-amino acid polypeptide with a calculated Mr of 41,466. The function of this nucleotide sequence was verified by comparison with amino acid sequence of the amino terminus and tryptic peptides from purified plant enzyme, by Northern blotting with RNA from wild type and mutant plants, and by prokaryotic expression yielding an enzymatically active hydroxylase. Computer-aided sequence analysis revealed high similarity (73.5%) to flavanone 3 beta-hydroxylase from barley. Genomic Southern blot analysis showed the presence of only one gene for flavanone 3 beta-hydroxylase in P. hybrida.

Amino Acid Sequence↗
PubMed1979

Concomitant induction of phenylalanine ammonia-lyase and flavanone synthase mRNAs in irradiated plant cells.

Irradiation of previously dark-grown cell suspension cultures from parsley (Petroselinum hortense Hoffm.) with ultraviolet light caused large, concomitant increases in mRNA activities for two characteristic enzymes of phenylpropanoid metabolism, phenylalanine ammonia-lyase, and flavanone synthase. The rates of enzyme synthesis both in vitro in a reticulocyte lysate and in vivo were quantitated by direct immunoprecipitation of the labeled enzyme subunits. Following a period of about 2 h, during which possible changes were below the limits of detectability, the two mRNA activities increased rapidly in irradiated cells for serveral hours. Phenylalanine ammonia-lyase mRNA reached a peak in activity a few hours earlier than flavanone synthase mRNA. The apparent half-lives of the enzyme activities were about 7 to 10 h for phenylalanine ammonia-lyase and 5 to 7 h for flavanone synthase. These data were used to calculate the expected, light-induced changes in enzyme activity from the measured changes in mRNA activity. The results for both enzymes were in agreement with experimental data, indicating that the light-induced changes in enzyme activity can be explained by changes in the respective mRNA activity. Some data concerning changes in the degree of polyadenylation of the mRNAs and the inhibitory effects of 7-methylguanosine 5'-phosphate are presented.

Acyltransferases↗
PubMedDate not supplied

High-performance liquid chromatography methods for the analysis of adrenergic amines and flavanones in Citrus aurantium L. var. amara.

Reverse-phase HPLC coupled with photodiode array detection was used for the simultaneous separation and determination of naturally occurring adrenergic amines (octopamine, synephrine and tyramine) in fruits and dry extracts of Citrus aurantium L. var. amara and in herbal medicines derived therefrom. Synephrine was the main component in fruits (0.10-0.35%) and in dry extracts (3.00-3.08%) and was present in the range 0.25-0.99% in herbal medicines. Flavanones were analysed in the same samples using a reverse-phase HPLC technique which allowed the identification and quantification of neoeriocitrin, narirutin, naringin, hesperidin, neohesperidin, naringenin and hesperetin. C. aurantium fruits and derivatives contained mainly glycosylated flavanones: in particular, naringin and neohesperidin were found to be the major flavonoids and their concentrations ranged from 1.80 to 26.30 and from 3.90 to 14.71 mg/g, respectively. The levels of aglycones were very low in all samples tested.

Biogenic Amines↗
PubMed1996

A methyltransferase for synthesis of the flavanone phytoalexin sakuranetin in rice leaves.

Rice (Oryza sativa L.) leaves irradiated with short wave UV light accumulated the major rice phytoalexin, flavanone sakuranetin. The extracts from these leaves catalyzed the methylation of the hydroxyl group at position 7 of naringenin to yield sakuranetin, with S-adenosyl-L-methionine as the methyl donor. Activity of the naringenin 7-O-methyltransferase was not found in healthy rice leaves but increased upon irradiation with UV light in parallel with increase in sakuranetin. The autoradiogram of the enzymatic product on 2D-TLC was found to be sakuranetin. The enzyme did not methylate sakuranetin, but methylated other flavanones, but not isoflavanones.

Enzyme Induction↗
PubMed1996

Flavanone absorption after naringin, hesperidin, and citrus administration.

Disposition of citrus flavonoids was evaluated after single oral doses of pure compounds (500 mg naringin and 500 mg hesperidin) and after multiple doses of combined grapefruit juice and orange juice and of once-daily grapefruit. Cumulative urinary recovery indicated low bioavailability ( < 25%) of naringin and hesperidin. The aglycones naringenin and hesperitin were detected in urine and plasma by positive chemical ionization-collisionally activated dissociation tandem mass spectrometry (PCI-CAD MS/MS). After juice administration, PCI-CAD MS/MS detected naringenin, hesperitin, and four related flavanones, tentatively identified as monomethoxy and dimethoxy derivatives. These methoxyflavanones appear to be absorbed from juice. Absorbed citrus flavanones may undergo glucuronidation before urinary excretion.

Adult↗
PubMed2004

Significance of C-terminal sequence elements for Petunia flavanone 3beta-hydroxylase activity.

Flavanone 3beta-hydroxylase (FHT), a 2-oxoglutarate-dependent dioxygenase (2-ODD), catalyzes the hydroxylation of (2S)-flavanones to (2R/3R)-dihydroflavonols in plants as a key step towards the biosynthesis of flavonols, anthocyanins and catechins. Crystallographic studies of 2-ODDs typically revealed a jelly roll in the enzyme core, and the C-terminus of the enzyme polypeptides was proposed to form a lid covering the active site cavity, thereby reducing the chances for oxidative or proteolytic damage and unfolding. Moreover, it has been proposed that in some cases the C-terminus is involved in substrate selectivity of 2-ODDs. In a systematic approach with highly active Petunia FHT, four C-terminally truncated enzyme forms were generated by deletion of five, 11, 24 or 29 amino acids. The recombinant FHTs preserved their substrate selectivity, but the specific activity decreased gradually with the extent of truncation. Then, an enzyme chimera was constructed by domain swapping replacing the C-terminal 52 amino acids of Petunia FHT by the equivalent region of flavonol synthase (FLS) from Citrus unshiu, an enzyme showing ambiguous FLS and FHT activity. The chimeric dioxygenase still revealed exclusively FHT activity, albeit at a moderate level only. The data predict that the selectivity of FHT is not governed by the C-terminal sequence accounting for about 13% of the enzyme polypeptide.

Amino Acid Sequence↗
PubMed2002

A chlorinated monoterpene ketone, acylated beta-sitosterol glycosides and a flavanone glycoside from Mentha longifolia (Lamiaceae).

Mentha longifolia (Lamiaceae), an aromatic herb yielded a new halogenated chloro-derivative of menthone (longifone), two new derivatives of beta-sitosterol glycoside (longiside-A and -B) and a new flavanone-glycoside (longitin). The beta-sitosterol and flavanone glycosides were purified as their acetate derivatives. Structures of all the isolated constituents were elucidated with the aid of HMBC techniques. However, the structure of longifone was also determined through X-ray crystallography.

Acylation↗
PubMed2002

New aromatase inhibitors. Synthesis and inhibitory activity of pyridinyl-substituted flavanone derivatives.

Two (E)-pyridinyl-substituted flavanone derivatives were synthesized and UV irradiation of these compounds afforded a Z-enriched mixture. These products were tested for their ability to inhibit the cytochrome P450 aromatase. It was observed that the introduction of a pyridinylmethylene group at carbon 3 on flavanone nucleus led to a significant increase of aromatase inhibitory effect. Moreover, configuration had a substantial influence on the aromatase inhibitory activity since (E)-isomers were found to be more active than (Z)-isomers.

Androstenedione↗
PubMed2006

Acetylated flavanone glycosides from the rhizomes of Cyclosorus acuminatus.

Six new flavanone glycosides (1-6) were isolated from the methanol extract of the rhizomes of Cyclosorus acuminatus, together with the parent flavanone glycoside 2a. Their structures were established on the basis of spectroscopic and chemical methods. All compounds showed moderate activity against Streptococcus pneumoniae and Haemophilus influenzae.

Anti-Infective Agents↗
PubMedDate not supplied

Microbiological transformation of (+/-)-flavanone and (+/-)-isoflavanone.

The microbiological transformation of flavanone and isoflavanone was explored using a group of 80 microorganisms in the initial screening. Ten metabolites of flavanone were isolated and identified as 4'-hydroxyflavanone [3], 3',4'-dihydroxyflavanone [4], 3-hydroxyflavone [2], flavone [5], 2'-hydroxydihydrochalcone [7], 2',4-dihydroxydihydrochalcone [6], 2',3,4-trihydroxydihydrochalcone [8], 2',5'-dihydroxydihydrochalcone [9], 4'-hydroxyflavan-4 alpha-ol [11], and 2'-hydroxydibenzoylmethane [10]. The isoflavanone metabolites were identified as isoflavone [15], 2-hydroxyisoflavanone [16], 4'-hydroxyisoflavanone [13], 6,4'-dihydroxyisoflavanone [17], and 3',4'-dihydroxyisoflavone [14]. The structures of the metabolites were established using spectroscopic techniques including ir, ms, uv, 1H-nmr, and 13C-nmr spectroscopy. Production of 4'-hydroxyflavanone, 3',4'-dihydroxyflavanone, and 2',4-dihydroxydihydrochalcone by 13 microorganisms was assayed using reversed-phase hplc.

Bacteria↗