Discovery and structural analysis of a phloretin hydrolase from the opportunistic human pathogen <i>Mycobacterium abscessus</i>

Han, Jianting; Zhang, Siping; Jia, Wenhao; Zhang, Zhang; Wang, Yong; He, Yong‐Xing

doi:10.1111/febs.14792

Cited by 8 publications

(8 citation statements)

References 35 publications

(41 reference statements)

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“…Both corresponding enzyme complexes include at least one glycosyltransferase and an oxidoreductase. Phloretin hydrolysis as carried out by phloretin hydrolase [ 28 , 29 ] and the three-step conversion of daidzein to equol [ 30 , 31 , 32 ] are relatively well studied, while the gut bacterial enzymes involved in dehydroxylation and O -demethylation of flavonoids are not yet described. However, an O -demethylase from Eubacterium limosum ZL-II demethylates polyphenolic lignans, [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

“…Phloretin hydrolase (Phy) hydrolytically cleaves the C-C bond adjacent to the aromatic A-ring of phloretin and thereby produces phloroglucinol and 3-(4-hydroxyphenyl)propionic acid. The first Phy was discovered in E. ramulus [ 28 , 44 ]. The only other Phy has been found in the intestinal pathogenic Mycobacterium abscessis , showing a 30% amino acid sequence identity to that of E. ramulus [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

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Flavonoid-Modifying Capabilities of the Human Gut Microbiome—An In Silico Study

2021

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Flavonoids are a major group of dietary plant polyphenols and have a positive health impact, but their modification and degradation in the human gut is still widely unknown. Due to the rise of metagenome data of the human gut microbiome and the assembly of hundreds of thousands of bacterial metagenome-assembled genomes (MAGs), large-scale screening for potential flavonoid-modifying enzymes of human gut bacteria is now feasible. With sequences of characterized flavonoid-transforming enzymes as queries, the Unified Human Gastrointestinal Protein catalog was analyzed and genes encoding putative flavonoid-modifying enzymes were quantified. The results revealed that flavonoid-modifying enzymes are often encoded in gut bacteria hitherto not considered to modify flavonoids. The enzymes for the physiologically important daidzein-to-equol conversion, well studied in Slackiaisoflavoniconvertens, were encoded only to a minor extent in Slackia MAGs, but were more abundant in Adlercreutzia equolifaciens and an uncharacterized Eggerthellaceae species. In addition, enzymes with a sequence identity of about 35% were encoded in highly abundant MAGs of uncultivated Collinsella species, which suggests a hitherto uncharacterized daidzein-to-equol potential in these bacteria. Of all potential flavonoid modification steps, O-deglycosylation (including derhamnosylation) was by far the most abundant in this analysis. In contrast, enzymes putatively involved in C-deglycosylation were detected less often in human gut bacteria and mainly found in Agathobacter faecis (formerly Roseburia faecis). Homologs to phloretin hydrolase, flavanonol/flavanone-cleaving reductase and flavone reductase were of intermediate abundance (several hundred MAGs) and mainly prevalent in Flavonifractor plautii. This first comprehensive insight into the black box of flavonoid modification in the human gut highlights many hitherto overlooked and uncultured bacterial genera and species as potential key organisms in flavonoid modification. This could lead to a significant contribution to future biochemical-microbiological investigations on gut bacterial flavonoid transformation. In addition, our results are important for individual nutritional recommendations and for biotechnological applications that rely on novel enzymes catalyzing potentially useful flavonoid modification reactions.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Flavonoid-Modifying Capabilities of the Human Gut Microbiome—An In Silico Study

2021

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“…All annotations were programmatically collated into an updated H37Rv reference genome annotation. homologs, color-annotated with conserved residues essential for phloroglucol moiety recognition and for phloretin substrate specificity in MaPhlG (47). The structural similarity and conserved Zinc-coordinating and catalytic residues affirm Rv1775 as a bona fide C-C hydrolase, potentially with a substrate that includes a phloroglucol moiety, but likely not phloretin.…”

Section: Figuresmentioning

confidence: 99%

Structure-aware M. tuberculosis functional annotation uncloaks resistance, metabolic, and virulence genes

Modlin

Gunasekaran

et al. 2018

Preprint

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Each decade, billions are invested in Tuberculosis (TB) research to further characterize M. tuberculosis pathogenesis. Despite this investment, nearly half of the 4,031 M. tuberculosis protein-coding genes lack descriptive annotation in community databases, due largely to incomplete reconciliation with the literature and a lack of structure-based methods for functional inference. We coin the term "hypotheticome" as the set of genes in an organism without known function. For M. tuberculosis' hypotheticome, we compiled the set of genes lacking functional assignment in the most frequently used Mycobacteria annotation database through systematic, exhaustive manual literature curation and 3Dprotein structure-based inference, and reconciled these annotations with frequented functional databases, creating a comprehensive M. tuberculosis functional knowledge-base. In doing so, we also introduce standard usage of qualifying adjectives based on quantitative measures of certainty with the hope that this approach is adopted in choosing qualifiers for future functional assignments.Through these methods we functionally annotated 41.3% of the M. tuberculosis hypotheticome, and provide insight into its pathogenesis, antibiotic-resistance, and virulence. Processes implicated in the unique lifestyle of M. tuberculosis of long-term persistence and obligate pathogenesis in genotoxic host microenvironmentslipid metabolism, polyketide biosynthesis, and membrane transport and effluxwere overrepresented in our annotation. Our structural similarity approach unturned proteins that appear critical in host-interaction through apparent host mimicry, particularly involving the phagosome and vesicle-mediated transport, as well as putative structural analogs for highly mutable protein classes, including dozens of PE/PPE family proteins which are major players at the host-pathogen interface, and sixteen potential efflux pumps which are integral to M. tuberculosis drug tolerance. Hypotheses drawn from these proteins' function may help characterize the onset of latency and identify therapeutic targets. A unified annotation is essential for clear communication about M. tuberculosis. These improvements provide the most comprehensive M. tuberculosis genome annotation to date, and the approach presented can be applied to systematically annotate the genome of other organisms. We provide our novel annotations in General Feature Format with Enzyme Commission and Gene Ontology terms for integration into existing annotation frameworks.

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“…Elucidation of the more complex C-deglycosylation pathway was tackled in Eubacterium cellulosolvens, Catenibacillus scindens and strain PUE (likely a bacterium of the Dorea genus), but not completely resolved [22][23][24]. Phloretin hydrolysis as carried out by phloretin hydrolase [25,26] and the three-step conversion of daidzein to equol [27][28][29] are relatively well studied, while gut bacterial enzymes involved in dehydroxylation and O-demethylation of avonoids were not yet described in the literature. However, an O-demethylase from Eubacterium limosum ZL-II demethylates secoisolariciresinol, a polyphenolic lignan, to 4,4′-dihydroxyenterodiol [30].…”

Section: Introductionmentioning

confidence: 99%

“…The rst puri ed and characterized Phy was that of Eubacterium ramulus [26] in the apigenin and naringenin degradation pathway [44]. Only one other Phy sequence from the intestinal pathogenic Mycobacterium abscessis showing a 30% amino acid sequence identity to that of E. ramulus was published [25].…”

Section: Introductionmentioning

confidence: 99%

Flavonoid-modifying capabilities of the gut microbiome – an in silico study

Goris

Cuadrat

Braune

2021

Preprint

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Flavonoids are a major group of dietary plant polyphenols and have a positive health impact, but their modification and degradation in the human gut is still widely unknown. Due to the rise of human gut metagenome data and the assembly of hundreds of thousands of bacterial metagenome-assembled genomes (MAGs), large-scale screening for potential flavonoid-modifying enzymes is now feasible. With sequences from characterized flavonoid-transforming enzymes as queries, the Unified Human Gastrointestinal Protein catalog was analyzed and quantification of putative flavonoid-modifying enzymes was carried out. The results revealed that flavonoid-modifying enzymes are often highly abundant in bacteria hitherto not considered as flavonoid-modifying gut bacteria. The enzymes for the physiologically important daidzein to equol conversion, well studied in Slackia isoflavoniconvertens, were encoded only to a low extent in Slackia MAGs, but more abundant in Adlercreutzia equolifaciens and an uncharacterizedEggerthellaceae species. In addition, a high abundance of genes with a similarity of only about 35% in uncultivated Collinsella species suggest a hitherto uncharacterized Daidzein-to-equol potential in these bacteria. Of all potential flavonoid modification steps, O-deglycosylation (including derhamnosylation) was by far the most abundant in this analysis. In contrast, enzymes putatively involved in C-deglycosylation were detected less often in human gut bacteria and mainly found in Agathobacter faecis (formerly Roseburia faecis). Phloretin hydrolase, flavanonol/flavanone-cleaving reductase and flavone reductase (all three most abundant in Flavonifractor plautii) and O-demethylase (Intestinibacter bartlettii) homologs were of intermediate prevalence (several hundreds of MAGs). This first comprehensive insight into the black box of flavonoid modification in the human gut highlights many hitherto overlooked and uncultured bacterial genera and species as key organisms in flavonoid modification by the human gut microbiota. This could lead to a significant contribution to future biochemical-microbiological investigations on gut bacterial flavonoid transformation. In addition, our results are important for individual nutritional recommendations and for biotechnological applications which rely on novel enzymes catalyzing potentially useful flavonoid modification reactions.

show abstract

Discovery and structural analysis of a phloretin hydrolase from the opportunistic human pathogen Mycobacterium abscessus

Cited by 8 publications

References 35 publications

Flavonoid-Modifying Capabilities of the Human Gut Microbiome—An In Silico Study

Flavonoid-Modifying Capabilities of the Human Gut Microbiome—An In Silico Study

Structure-aware M. tuberculosis functional annotation uncloaks resistance, metabolic, and virulence genes

Flavonoid-modifying capabilities of the gut microbiome – an in silico study

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