Structure and Mechanism of Ergothionase from Treponema denticola

Abstract

Ergothioneine is asulfur-containing histidine derivative that emerges from microbial biosynthesis and enters the human body through intestinal uptake and regulated distribution into specific tissues.A lthough the proteins involved in biosynthesis and uptake are well characterized,l ess is known aboutt he degradative pathways of ergothioneine. This report describes the crystal structure of the active form of ergothionasef rom the oral pathogen Treponemad enticola complexed with the substrate analogued esmethyl-ergothioneine sulfonica cid. This enzyme catalyzes the 1,2-elimination of trimethylamine from ergothioneine and ergothioneine sulfonic acid by using au nique mode of substrate activation combined with acid/base catalysis. This structural and mechanistic investigation revealed four essential catalytic residues, which are strictly conserved in homologous proteins from common gastrointestinal bacteria and numerous pathogenic bacteria, suggesting that bacterial activity mayp lay an important role in determining the availability of ergothioneine in healthy and diseased human tissue. Figure 3.To p: Proposed substrate binding mode and mechanism for substrate activationbyTdETL wt .Bottom:Chargec omplementary enzyme:ligand complexes that stabilize ap ositivec harge on the imidazole ring (green)a re more active that complexes with unbalanced chargeo ran eutral imidazole ring (red). Bold letters indicate the corresponding entries in Ta ble 1.

The biology of ergothioneine, an antioxidant nutraceutical

“…There was also quite some variation in uptake between individuals, presumably reflecting variation in their expression of SLC22A4. Agrobacterium radiobacter (403) and other bacteria (404)(405)(406)(407)(408)(409) contain an ergothionase that degrades ERG to thiolurocanic acid (3-(1H-imidazol-5-yl)prop-2-enethioic S-acid) and trimethylamine, also implying that such cells possess one or more transporters for ERG. The thiolurocanic acid can be further degraded to glutamate (410) .…”

Elucidation of an anaerobic pathway for metabolism of l -carnitine–derived γ-butyrobetaine to trimethylamine in human gut bacteria

“…The key step in TMA production from γbb is breaking an unactivated C–N bond. None of the bbu genes is predicted to encode homologs of known enzymes that catalyze C–N bond cleavage and release TMA [e.g., choline TMA-lyase ( 28 ), glycine betaine reductase ( 29 ), ergothionase ( 30 )], indicating that this pathway uses a distinct enzyme for this critical step. We identified the predicted acyl-CoA dehydrogenase-like enzyme BbuA as the most likely candidate for this reaction.…”

Ergothioneine, recent developments

“…Some other microorganisms including Burkholderia sp. [ 155 ], Treponema denticola [ 156 ], and Alcaligenes faecalis [ 157 , 158 ], also possess ergothionase. Further studies are needed to evaluate if other commensal bacteria can degrade ET and if this contributes to decreased absorption of ET from the gut.…”

“…As mentioned earlier, while most microorganisms are incapable of ET biosynthesis, some can accumulate and utilize ET from their surrounding environment [ 4 ], especially some opportunistic pathogens e.g. E. coli [ 154 ] and the oral pathogen Treponema denticola [ 156 ]. Drugs targeting the uptake mechanisms may thus be useful in limiting their pathogenicity.…”