The Chemistry of Gut Microbial Metabolism of Polyphenols

Abstract

Gut microbiota contribute to the metabolism of dietary polyphenols and affect the bioavailability of both the parent polyphenols and their metabolites. Although there is a large number of reports of specific polyphenol metabolites, relatively little is known regarding the chemistry and enzymology of the metabolic pathways utilized by specific microbial species and taxa, which is the focus of this review. Major classes of dietary polyphenols include monomeric and oligomeric catechins (proanthocyanidins), flavonols, flavanones, ellagitannins, and isoflavones. Gut microbial metabolism of representatives of these polyphenol classes can be classified as A- and C-ring cleavage (retro Claisen reactions), C-ring cleavage mediated by dioxygenases, dehydroxylations (decarboxylation or reduction reactions followed by release of H₂O molecules), and hydrogenations of alkene moieties in polyphenols, such as resveratrol, curcumin, and isoflavones (mediated by NADPH-dependent reductases). The qualitative and quantitative metabolic output of the gut microbiota depends to a large extent on the metabolic capacity of individual taxa, which emphasizes the need for assessment of functional analysis in conjunction with determinations of gut microbiota compositions.

Keywords: Catabolism; flavonoid; gut microbiota; mechanism; metabolic pathway.

Figure 1

Proposed mechanism for the conversion of cyanidin into protocatechuic acid (1.6) and 2-(2,4,6-trihydroxyphenyl)acetic acid (1.7). Steps: i) hydrolytic attack of the flavylium carbon at position 2, ii) conversion of the hemi-ketal into the keto form followed by keto-enol tautomerism of the neighboring enol yields an α-diketo species, iii) microbial enzyme-mediated nucleophilic attack of one of the keto carbons by a peroxyl anion species, iv) insertion of the alkoxy oxygen results in an acyl anhydride, v) hydrolysis of anhydride releases two phenolic acids.

Figure 2

a) A mechanism for quercetinase-mediated conversion of quercetin (2.1) into 2-protocatechuoylphloroglucinolcarboxylic acid (2.5) adapted from (Schaab, Barney, Francisco, 2006). Decarboxylation of 1,3,5-trihydroxybenzoic acid (2.7) into phloroglucinol (2.8) is not mediated by quercetinase. b) The co-crystal structure of Aspergillus japonicus quercetinase 2,3 dioxygenase complexed with the natural substrate quercetin under anaerobic condition is available (pdb 1H1I). The X-ray structure shows that the flavonol coordinates to the copper ion through the C-ring OH group at position 3 (Steiner, Kalk, Dijkstra, 2002).

Figure 3

Gut microbial conversion of (epi)catechin (3.1) into 3-hydroxyphenyl-γ-valerolactone (3.13) by reverse Claisen-driven degradation of the A-ring (steps iv–viii). D = hydride donor, B = basic amino acid residue.

Figure 4

Proposed mechanism for gut microbial conversion of (epi)catechin into 2-(3,4-dihydroxyphenyl)acetic acid (4.4). Iron is linked to a dioxygenase via one or more amino acids, indicated as L_n.

Figure 5

Reverse Claisen mechanism for the conversion of phloretin (5.1) into 3-(4-hydroxyphenyl)propanoic acid (5.3) and phloroglucinol (5.4).

Figure 6

Mechanism for the dehydroxylation of 4-hydroxybenzoic acid according to (Carmona, Zamarro, Blazquez et al., 2009; McInerney, Gieg, 2004).

Figure 7

Gut microbial conversion of ellagic acid into urolithins A, B, and C. In this metabolic pathway, dehydration reactions (ii, v, x) are driven by decarboxylation (ii) and reduction reactions (vii, ix). Other steps: hydrolysis (i) and keto-enol tautomerism (i, iv, vi, viii). D = hydride donor, B = basic amino acid residue.

Figure 8

Stepwise reduction of curcumin by the E. coli enzyme, CurA (Hassaninasab, Hashimoto, Tomita-Yokotani et al., 2011).

Figure 9

Gut microbial metabolism of resveratrol (Bode, Bunzel, Huch et al., 2013).

Figure 10

Gut microbial biotransformation of daidzein into the phytoestrogens equol and O-desmethylangolensin (O-DMA).

Figure 11

Gene organization maps of the gene cluster encoding enzymes involved in the metabolic conversation of daidzein to S-equol in three equol-producing bacterial strains: a, S. isoflavoniconvertens (Schroder, Matthies, Engst et al., 2013), b, Slackia sp. strain NATTS (Tsuji, Moriyama, Nomoto et al., 2012), and c, Lactococcus strain 20-92 (Shimada, Takahashi, Miyazawa et al., 2012; Shimada, Takahashi, Miyazawa et al., 2011).

Figure 12

a) Stereospecific conversion of (3S,4R)-tetrahydrodaidzein (THD) to (S)-equol and b) the proposed mechanistic pathway of (3S,4R)-THD to (S)-equol catalyzed by tetrahydrodaidzein reductase (THDR) according to Kim et al. 2010 (Kim, Marsh, Kim et al., 2010).

Figure 13

Racemization of dihydrodaidzein catalyzed by dihydrodaidzein racemase.

Figure 14

a) Intestinal microbial transformation of daidzein to O-desmethylangolensin (O-DMA) according to Joannou et al. 1995 (Joannou, Kelly, Reeder et al., 1995). b) Structure of (−)-(R)-O-desmethylangolensin.