The Mechanism of Enzyme-catalyzed Ergothioneine Degradation

Maurer, Alice. The Mechanism of Enzyme-catalyzed Ergothioneine Degradation. 2020, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: https://edoc.unibas.ch/80474/

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The sulfur containing histidine derivative ergothioneine is a ubiquitous natural product. Research on its biosynthesis and degradation can elucidate the complex biological and molecular function of this small molecular weight compound. The biosynthesis of ergothioneine is well established, yet little is known about its degradation. The first step of ergothioneine degradation is catalyzed by the enzyme ergothionase, which will be the focus of this thesis.
Ergothionase catalyzes the 1,2-elimination of trimethylamine from ergothioneine to yield thiourocanic acid. In this work, kinetic and structural investigations elucidate the mechanism of ergothionase. Based on the identification of catalytic residues, we are able to portray ergothionase producing organisms and found that they are mainly gut bacteria. This finding is in particular interesting because ergothioneine as food-additive is generally regarded as safe, whereas the ergothionase-mediated degrading of ergothioneine yields to trimethylamine, which is toxic.
Furthermore, we characterized two unknown lyases. One of these new lyases employs a similar mechanism as ergothionase but uses an oxidized substrate derivative. Whereas, the other new lyase catalyzes the elimination of trimethylamine from trimethylhistidine (TMH) and has distinctive differences in the active site compared to ergothionase. The function and position of the catalytic acid in the active site of TMH-lyase suggest a mechanistic variation of the thought to be well-known 4-methylideneimidazol-5-one (MIO) dependent aromatic amino acid lyases: maybe the posttranslational formed MIO-moiety does not only serve as electron sink but also as catalytic acid.
Studies on the phylogeny of ergothionase, TMH-lyase, aromatic amino acid lyase and the aspartase/fumarase superfamily propose that ergothionase has evolved prior to the aromatic amino acid lyases. The long evolutionary history of ergothionase underscores ergothioneine as ancient molecule. However, it is questioning that on the one hand an aromatic amino acid lyase represents the first step of the ubiquitous histidine degradation pathway, whereas on the other hand histidine builds the basis for ergothioneine biosynthesis. This finding might suggest the presence of an unknown alternative histidine degradation pathway.
In addition, we have not only studied the degradation but also the biosynthesis of ergothioneine. Thereby, we focused on the regulation of EgtD, the methyltransferase of ergothioneine biosynthesis, and showed that this enzyme is not subject of phosphorylation in vitro.
Advisors:Seebeck, Florian Peter and Müller, Michael
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Molecular Bionics (Seebeck)
UniBasel Contributors:Maurer, Alice and Seebeck, Florian Peter
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:13988
Thesis status:Complete
Number of Pages:iv, 162
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss139885
edoc DOI:
Last Modified:05 Mar 2021 05:30
Deposited On:04 Mar 2021 08:08

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