Ergothioneine is a histidine-derived thiol of bacterial and fungal origin that has also been isolated from animal and human tissue. Recent findings point to critical functions of ergothioneine in ...human physiology, but its role in microbial life is poorly understood. This report describes the identification of the ergothioneine biosynthetic gene cluster from mycobacteria and in vitro reconstitution of this process using recombinant proteins from Mycobacterium smegmatis. The key reactions are catalyzed by a methyltransferase that transfers three methyl groups to the α-amino moiety of histidine and an iron(II)-dependent enzyme that catalyzes oxidative sulfurization of trimethylhistidine. A search for homologous genes indicated that ergothioneine production is a frequent trait among fungi, actinobacteria, and cyanobacteria but also occurs in numerous bacteroidetes and proteobacteria.
This report describes a modular enzyme‐catalyzed cascade reaction that transforms l‐ or d‐α‐amino acids to β‐methyl‐α‐amino acids. In this process an α‐amino acid transaminase, an α‐keto acid ...methyltransferase, and a halide methyltransferase cooperate in two orthogonal reaction cycles that mediate product formation and regeneration of the cofactor pyridoxal‐5′‐phosphate and the co‐substrate S‐adenosylmethionine. The only stoichiometric reagents consumed in this process are the unprotected l‐ or d‐α‐amino acid and methyl iodide.
A modular enzyme‐catalyzed one‐pot reaction that produces l‐ and d‐β‐methyl‐α‐amino acids from unprotected l‐ or d‐α‐amino acids is described. In this system an α‐amino acid transaminase (TA), an α‐keto acid methyltransferase (MT), and a halide methyltransferase (HMT) cooperate in two orthogonal reaction cycles that mediate product formation and regeneration of the cofactor pyridoxal‐5′‐phosphate and the co‐substrate S‐adenosylmethionine.
Anaerobic Origin of Ergothioneine Burn, Reto; Misson, Laëtitia; Meury, Marcel ...
Angewandte Chemie International Edition,
October 2, 2017, Letnik:
56, Številka:
41
Journal Article
Recenzirano
Ergothioneine is a sulfur metabolite that occurs in microorganisms, fungi, plants, and animals. The physiological function of ergothioneine is not clear. In recent years broad scientific consensus ...has formed around the idea that cellular ergothioneine primarily protects against reactive oxygen species. Herein we provide evidence that this focus on oxygen chemistry may be too narrow. We describe two enzymes from the strictly anaerobic green sulfur bacterium Chlorobium limicola that mediate oxygen‐independent biosynthesis of ergothioneine. This anoxic origin suggests that ergothioneine is also important for oxygen‐independent life. Furthermore, one of the discovered ergothioneine biosynthetic enzymes provides the first example of a rhodanese‐like enzyme that transfers sulfur to non‐activated carbon.
Without oxygen: The sulfur metabolite ergothioneine is a ubiquitous scavenger of reactive oxygen species. Discovery of ergothioneine production in strictly anaerobic bacteria and archaea suggests that ergothioneine is also important for anoxic life.
Biosynthesis of N‐α‐trimethyl‐2‐thiohistidine (ergothioneine) is a frequent trait in cyanobacteria. This sulfur compound may provide essential relief from oxidative stress related to oxygenic ...photosynthesis. The central steps in ergothioneine biosynthesis are catalyzed by a histidine methyltransferase and an iron‐dependent sulfoxide synthase. In this report, we present evidence that some cyanobacteria recruited and adapted a sulfoxide synthase from a different biosynthetic pathway to make ergothioneine. The discovery of a second origin of ergothioneine production underscores the physiological importance of this metabolite and highlights the evolutionary malleability of the thiohistidine biosynthetic machinery.
Two paths, one destination: Biosynthesis of N‐α‐trimethyl‐2‐thiohistidine (ergothioneine) is a frequent trait in cyanobacteria. Evidence is presented of convergent evolution of ergothioneine biosynthesis. Ancient cyanobacteria may have adapted an ovothiol biosynthetic enzyme to produce ergothioneine as a response to changing environmental conditions.
Late‐stage methylation is a key technology in the development of pharmaceutical compounds. Methyltransferase biocatalysis may provide powerful options to insert methyl groups into complex molecules ...with high regio‐ and chemoselectivity. The challenge of a large‐scale application of methyltransferases is their dependence on S‐adenosylmethionine (SAM) as a stoichiometric, and thus exceedingly expensive co‐substrate. As a solution to this problem, we and others have explored the use of methyl halides as reagents for the in situ regeneration of SAM. However, the need to handle volatile electrophiles, such as methyl iodide (MeI), may also hamper applications at scale. As a more practical solution, we have now developed an enzyme‐catalyzed process for the regeneration of SAM with methyl toluene sulfonate. Herein, we describe enzymes from the thiopurine methyltransferase family that accept sulfate‐ and sulfonate‐based methyl donors to convert S‐adenosylhomocysteine into SAM with efficiencies that rival MeI‐based reactions.
Naturally occurring members of the thiopurine methyltransferase family have been found to accept synthetic methyl sulfates or methyl sulfonates as methyl donors for the stereoselective methylation of S‐adenosylhomocysteine to form S‐adenosylmethionine. This activity can be used for co‐substrate regeneration in methyltransferase biocatalysis.
Dimethylsulfoniopropionate (DMSP) is one of the most abundant sulfur metabolites in marine environments. The biosynthesis of DMSP and its degradation to dimethylsulfide are important links in the ...planetary sulfur cycle. Herein, the first complete description of a DMSP biosynthetic pathway is provided by the in vitro reconstitution of four enzymes from Streptomyces mobaraensis. The isolation of DMSP from S. mobaraensis cells grown at high salinity confirmed that this actinobacterium is indeed is a DMSP‐producing organism. The described DMSP biosynthesis follows the same route as that previously described for angiosperm plants. Despite this chemical congruence, limited sequence similarity between plant and bacterial enzymes suggests that the two biosynthetic activities emerged by convergent evolution.
Nature's way: The first complete description of a DMSP biosynthetic pathway is provided by the in vitro reconstitution of four enzymes from Streptomyces mobaraensis. This pathway follows the same route as that previously described for angiosperm plants; however, this study shows that the two biosynthetic activities emerged by convergent evolution.
Ergothioneine is an emergent factor in cellular redox biochemistry in humans and pathogenic bacteria. Broad consensus has formed around the idea that ergothioneine protects cells against reactive ...oxygen species. The recent discovery that anaerobic microorganisms make the same metabolite using oxygen-independent chemistry indicates that ergothioneine also plays physiological roles under anoxic conditions. In this report, we describe the crystal structure of the anaerobic ergothioneine biosynthetic enzyme EanB from green sulfur bacterium Chlorobium limicola. This enzyme catalyzes the oxidative sulfurization of N-α-trimethyl histidine. On the basis of structural and kinetic evidence, we describe the catalytic mechanism of this unusual C–S bond-forming reaction. Significant active-site conservation among distant EanB homologues suggests that the oxidative sulfurization of heterocyclic substrates may occur in a broad range of bacteria.
Strategic replacement of protons with fluorine atoms or functional groups with fluorine‐containing fragments has proven a powerful strategy to optimize the activity of therapeutic compounds. For this ...reason, the synthetic chemistry of organofluorides has been the subject of intense development and innovation for many years. By comparison, the literature on fluorine biocatalysis still makes for a slim chapter. Herein we introduce S‐adenosylmethionine (SAM) dependent methyltransferases as a new tool for the production of fluorinated compounds. We demonstrate the ability of halide methyltransferases to form fluorinated SAM (S‐adenosyl‐S‐(fluoromethyl)‐L‐homocysteine) from S‐adenosylhomocysteine and fluoromethyliodide. Fluorinated SAM (F‐SAM) is too unstable for isolation, but is accepted as a substrate by C‐, N‐ and O‐specific methyltransferases for enzyme‐catalyzed fluoromethylation of small molecules.
In a biocatalytic approach to the production of fluorinated compounds, halide methyltransferases (HMTs) were found to form fluorinated S‐adenosylmethionine (SAM) from S‐adenosylhomocysteine and fluoromethyliodide. Although too unstable for isolation, fluorinated SAM was accepted as a substrate by C‐, N‐ and O‐specific SAM‐dependent methyltransferases (MTs) to enable the fluoromethylation of small molecules (see scheme).
Structural basis of ergothioneine biosynthesis Stampfli, Anja R; Blankenfeldt, Wulf; Seebeck, Florian P
Current opinion in structural biology,
December 2020, 2020-12-00, 20201201, Letnik:
65
Journal Article
Recenzirano
Odprti dostop
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Ergothioneine is a sulfur-containing histidine derivative synthesized by many bacteria and most fungi but it also finds its way into human tissue by way of specific absorption from ...the diet. The precise role of ergothioneine is not yet known but there is growing evidence that it plays a role as an antioxidant protecting human cells from oxidative stress and pathogenic bacteria from host defenses. In this review we highlight recent advances in understanding the structural basis of ergothioneine biosynthesis. In addition to unusual carbon–sulfur bond forming enzymology this research has revealed that ergothioneine biosynthesis has emerged at least three times by independent molecular evolution.
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