David Lim
@unibe.ch
Advanced Postdoctoral Researcher
Universität Bern
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
David Lim and Francesca Paradisi
Wiley
AbstractGlycosylation of bioactive molecules has been found to improve the pharmacokinetic properties of the parent molecule. However, their syntheses often require tedious protecting group manipulations. The development of methodologies which allow direct aqueous conversion of unprotected sugars into glycosides is therefore an ambitious goal. Herein, we present a broadly applicable method for the synthesis of selenoglycosides in water. We show the ease of direct conjugation of unprotected glycosyl diselenides with various biomolecules, including resorcinol, resveratrol, and the antitumor agent, gimeracil, furnishing the corresponding selenoglycoconjugates in up to 96 % yield. We also demonstrate the oxidatively‐triggered release of the bioactive drug from the sugar, priming these molecules for medicinal applications. The generality and broad substrate scope of this novel transformation will provide access to various selenium‐containing glycomimetics and glycoconjugates.
Sabrina de Lorenzo, Lauriane Pillet, David Lim, and Francesca Paradisi
Royal Society of Chemistry (RSC)
An engineered glycosidase from H. orenii showcases for the first time that glycosyl benzoates are better donors than p-nitrophenyl glucoside in enzyme-catalysed thioglucosylations. The thioglycoside products were formed with conversions up to 94%.
Lauriane Pillet, David Lim, Nourah Almulhim, Ana I. Benítez-Mateos, and Francesca Paradisi
Royal Society of Chemistry (RSC)
A novel triple mutant of an extremophilic glycosyl hydrolase allowed the stereoselective, efficient, and sustainable synthesis of still elusive thioglycosides.
Mariia A. Beliaeva, Reto Burn, David Lim, and Florian P. Seebeck
Wiley
Ergothioneine is an emerging component of the redox homeostasis system in human cells and in microbial pathogens, such as Mycobacterium tuberculosis or Burkholderia pseudomallei. Synthesis of stable isotope labelled ergothioneine derivatives may provide important tools for deciphering the distribution, function and metabolism of this compound in vivo. We describe a general protocol for the production of ergothioneine isotopologues with programmable 2H, 15N 13C, 34S and 33S isotope labelling patterns. This enzyme-based approach makes efficient use of commercial isotope reagents and is also directly applicable for the synthesis of radio-isotopologues.
David Lim, Xiaojin Wen, and Florian P. Seebeck
Wiley
Se‐benzyl selenoimidazolium salts are characterized by remarkable alkyl‐transfer potential under physiological conditions. Structure‐activity relationship studies show that selective monoalkylation of primary amines depends on supramolecular interactions between the selenoimidazole leaving group and the target nucleophile. We demonstrate that these reagents can be used for site‐selective and nearly quantitative modification of the model protein lysozyme on Lys13, bypassing the higher intrinsic reactivities of Lys1 and Lys33. These observations introduce selenoimidazolium salts as novel class of electrophiles for selective N‐alkylation of native proteins.
Kristina V. Goncharenko, Sebastian Flückiger, Cangsong Liao, David Lim, Anja R. Stampfli, and Florian P. Seebeck
Wiley
Sulfoxide synthases are non-heme iron enzymes that participate in the biosynthesis of thiohistidines such as ergothioneine and ovothiol A. The sulfoxide synthase EgtB from Chloracidobacterium thermophilum ( Cth EgtB) catalyzes oxidative coupling between the side chains of N-α-trimethyl histidine (TMH) and cysteine (Cys) in a reaction that entails complete reduction of molecular oxygen, carbon-sulfur (C-S) and sulfur-oxygen (S-O) bond formation and carbon-hydrogen (C-H) bond cleavage. In this report we show that bacterial sulfoxide synthases cannot efficiently turnover selenocysteine (SeCys) as an alternative substrate because the sulfur-to-selenium substitution. In contrast, the sulfoxide synthase from the filamentous fungus Chaetomium thermophilum ( Cth Egt1) catalyzes C-S and C-Se bond formation at almost equal efficiency. We discuss evidence suggesting that this difference emerges from different modes of oxygen-activation.
David Lim, Dirk Gründemann, and Florian P. Seebeck
Wiley
The N- α-trimethyl 2-selenohistidine selenoneine is the selenium isolog of the natural antioxidant ergothioneine. Sulfur-to-selenium substitutions are known to endow proteins and nucleic acids with special activities. In contrast, secondary metabolites that exploit selenium-specific chemistry are rare. Selenoneine therefore provides a unique opportunity to study how natural organoselenides interact with cellular processes. In this report we describe the chemical synthesis of selenoneine and other 2-selenoimidazoles. With synthetic selenoneine at hand we discovered a set of reactivities that distinguish selenoneine from ergothioneine, showing that the two compounds can fill distinct functional niches. Synthetic access to 2-selenoimidazoles should pave the way to explore the pharmaceutical potential and physiological function of this heretofore inaccessible class of compounds.
Alice Maurer, Florian Leisinger, David Lim, and Florian P. Seebeck
Wiley
Ergothioneine is a sulfur-containing histidine derivative that emerges from microbial biosynthesis and enters the human body via intestinal uptake and regulated distribution into specific tissues. While the proteins involved in biosynthesis and uptake are well characterized, less is known about the degradative pathways of ergothioneine. In this report we describe the crystal structure of the active form of ergothionase from the oral pathogen Treponema denticola in complex with the substrate analog desmethyl-ergothioneine sulfonic acid. This enzyme catalyzes 1,2-elimination of trimethylamine from ergothioneine and its oxidation product ergothioneine sulfonic acid using a unique mode of substrate activation combined with acid/base catalysis. This structural and mechanistic investigation revealed four essential catalytic residues that are strictly conserved in homologous proteins from common gastrointestinal bacteria and numerous pathogenic bacteria, suggesting that bacterial activity may play an important role in determining the availability of ergothioneine in healthy and diseased human tissue.
David Lim and Antony J. Fairbanks
Springer International Publishing
2-Chloro-1,3-dimethylimidazolinium chloride (DMC) and its derivatives are useful for numerous synthetic transformations, which involve selective activation of the anomeric centre of unprotected reducing sugars in water. This chapter summarises research reported to date using DMC and derivatives, such as 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP). DMC has been successfully employed for the synthesis of glycosyl oxazolines, 1,6-anhydro-, 1-azido-, and a variety of thioglycosides. The use of ADMP allows the one-pot synthesis of glycosyl triazoles in water via the Cu-catalysed azide-alkyne Huisgen cycloaddition reaction. This latter methodology can be applied to a wide variety of carbohydrates and is also amenable to convergent glycopeptide synthesis in which oligosaccharides are directly conjugated to peptides that contain propargyl glycine residues. Such protecting group free methodologies, particularly when applied to complex oligosaccharides isolated from natural sources, may allow ready access to a wide variety of biologically interesting glycoconjugates.
S. R. Alexander, D. Lim, Z. Amso, M. A. Brimble, and A. J. Fairbanks
Royal Society of Chemistry (RSC)
Un-protected 2-acetamido terminated reducing sugars may be converted into the corresponding glycosyl thiols in water, and conjugated to peptides using the thiol–ene click reaction without recourse to any protecting groups.
David Lim and Antony J. Fairbanks
Royal Society of Chemistry (RSC)
Selective acetylation of only the anomeric hydroxyl group of unprotected sugars is possible in aqueous solution. This new one step route to glycosyl acetates may facilitate their use as donors for enzyme catalysed glycosylation.
David Lim and Ian C. Shaw
Wiley
Summary
The human health implications of exposure to environmental pollutants and food components (e.g. phytoestrogens) that mimic the female hormone 17β-estradiol (xenoestrogens) are a subject of significant debate. In this study, we use published data on human dietary phytoestrogen intake and sperm concentrations in the USA and China to assess effects on sperm concentration as a marker of male reproductive health. Comparison of the phytoestrogen intake and sperm concentration trends shows that in the USA phytoestrogen intake has increased from 0.8 mg day−1 in 1993 to 13.7 mg day−1 in 2005 and sperm concentration is trending down (not statistically significant), whereas in China phytoestrogen intake has decreased from 64.7 mg day−1 in 1991 to 15.6 mg day−1 in 2008, and the sperm concentration has increased from 55 × 106 mL−1 in 1999 to 74 × 106 mL−1 in 2008. We present this as evidence that phytoestrogen intake via food might, at least in part, be responsible for sperm concentration trends.
David Lim, Margaret A. Brimble, Renata Kowalczyk, Andrew J. A. Watson, and Antony John Fairbanks
Wiley
The conversion of sugars into glycomimetics typically involves multiple protecting-group manipulations. The development of methodology allowing the direct aqueous conversion of free sugars into glycosides, and mimics of oligosaccharides and glycoconjugates in a high-yielding and stereoselective process is highly desirable. The combined use of 2-azido-1,3-dimethylimidazolinium hexafluorophosphate and the Cu-catalyzed Huisgen cycloaddition allowed the synthesis of a range of glycoconjugates in a one-step reaction directly from reducing sugars under aqueous conditions. The reaction, which is completely stereoselective, may be applied to the convergent synthesis of triazole-linked glycosides, oligosaccharides, and glycopeptides. The procedure provides a method for the one-pot aqueous ligation of oligosaccharides and peptides bearing alkyne side chains.