Nucleotide Sugars in Chemistry and Biology

Mikkola, Satu

doi:10.3390/molecules25235755

Cited by 47 publications

(39 citation statements)

References 201 publications

(453 reference statements)

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“…UDP-linked amino sugars are difficult to synthesize, however, chemical, enzymatic and chemoenzymatic approaches have been explored ( Koizumi et al, 1998 ; Ahmadipour and Miller 2017 ; Zamora et al, 2017 ; Ahmadipour et al, 2018 ; Ahmadipour et al, 2019 ; Mikkola, 2020 ). Chemical synthesis of activated carbohydrates is demanding and relies on specialized expertise in carbohydrate chemistry; however, due to the lack of alternative routes, it remains a popular choice to synthesize non-natural sugar nucleotides (e.g., fluorinated nucleotide sugars) ( Wagner et al, 2009 ; Tedaldi et al, 2012 ), which may serve for the synthesis of modified oligosaccharides, as enzyme inhibitors and/or in diagnostics ( Mikkola, 2020 ). In general, sugar nucleotides generated from chemical routes are often quite expensive due to low extraction yield, and attempts made to scale up the production proved to be non-economical or impractical ( Heidlas et al, 1992 ; Timmons and Jakeman, 2007 ; Wagner et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

“…Efficient enzymatic synthesis of UDP-GlcNAc and other nucleotide sugars has recently been described in an up to 200 ml lab scale via enzyme cascades in repetitive batch mode ( Fischöder et al, 2019 ). Compared to the chemical synthesis, this enzymatic process seems to be quite competitive, however, all these processes often require expensive starting materials (e.g., ATP, UDP and UTP), purified enzymes and complex operations for scaling up ( Mikkola, 2020 ; Zhao et al, 2021 ), and therefore, are expensive and difficult to be used for industrial production.…”

Section: Discussionmentioning

confidence: 99%

“…Depending on the nucleoside phosphate attached, these sugar nucleotides are classified as nucleoside monophosphate sugars (such as cytidine monophospho-N-acetylneuraminic acid) or nucleoside diphosphate sugars, such as adenine- or uridine-diphosphate glucose, guanosine-diphosphate mannose or the activated amino sugar uridine-diphosphate-N-acetylglucosamine (UDP-GlcNAc) ( Wagner et al, 2009 ). UDP-linked amino sugars have attracted a great deal of attention because of their indispensable role in cell wall biosynthesis and in the synthesis of natural glycoproteins, glycolipids, oligosaccharides, and glycosides by providing the sugar moieties ( Barreteau et al, 2008 ; Thibodeaux et al, 2008 ; De Bruyn et al, 2015 ; Mikkola, 2020 ). UDP-GlcNAc plays a pivotal role in several metabolic processes in both prokaryotes as well as eukaryotes.…”

Section: Introductionmentioning

confidence: 99%

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Metabolic Engineering of Corynebacterium glutamicum for Production of UDP-N-Acetylglucosamine

Gauttam

Desiderato

Radoš

et al. 2021

Front. Bioeng. Biotechnol.

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Uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) is an acetylated amino sugar nucleotide that naturally serves as precursor in bacterial cell wall synthesis and is involved in prokaryotic and eukaryotic glycosylation reactions. UDP-GlcNAc finds application in various fields including the production of oligosaccharides and glycoproteins with therapeutic benefits. At present, nucleotide sugars are produced either chemically or in vitro by enzyme cascades. However, chemical synthesis is complex and non-economical, and in vitro synthesis requires costly substrates and often purified enzymes. A promising alternative is the microbial production of nucleotide sugars from cheap substrates. In this study, we aimed to engineer the non-pathogenic, Gram-positive soil bacterium Corynebacterium glutamicum as a host for UDP-GlcNAc production. The native glmS, glmU, and glmM genes and glmM of Escherichia coli, encoding the enzymes for UDP-GlcNAc synthesis from fructose-6-phosphate, were over-expressed in different combinations and from different plasmids in C. glutamicum GRS43, which lacks the glucosamine-6-phosphate deaminase gene (nagB) for glucosamine degradation. Over-expression of glmS, glmU and glmM, encoding glucosamine-6-phosphate synthase, the bifunctional glucosamine-1-phosphate acetyltransferase/N-acetyl glucosamine-1-phosphate uridyltransferase and phosphoglucosamine mutase, respectively, was confirmed using activity assays or immunoblot analysis. While the reference strain C. glutamicum GlcNCg1 with an empty plasmid in the exponential growth phase contained intracellularly only about 0.25 mM UDP-GlcNAc, the best engineered strain GlcNCg4 accumulated about 14 mM UDP-GlcNAc. The extracellular UDP-GlcNAc concentrations in the exponential growth phase did not exceed 2 mg/L. In the stationary phase, about 60 mg UDP-GlcNAc/L was observed extracellularly with strain GlcNCg4, indicating the potential of C. glutamicum to produce and to release the activated sugar into the culture medium. To our knowledge, the observed UDP-GlcNAc levels are the highest obtained with microbial hosts, emphasizing the potential of C. glutamicum as a suitable platform for activated sugar production.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metabolic Engineering of Corynebacterium glutamicum for Production of UDP-N-Acetylglucosamine

Gauttam

Desiderato

Radoš

et al. 2021

Front. Bioeng. Biotechnol.

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“…Enzymatic production processes would likely provide tighter control over the product composition while also eliminating the need for organic solvents. Although certain glycosyltransferases are specialized in the synthesis of β-Gs (Douglas 2001), the high cost of their nucleotide-activated donor sugars is a serious limitation for their commercial exploitation (Mikkola 2020). Due to their ability to use the easily accessible donor α-G1P, β-glucan phosphorylases seem better suited for cost-effective industrial use.…”

Section: Discovery Of β-Glucan and β-Glucobiose Phosphorylasesmentioning

confidence: 99%

β-Glucan phosphorylases in carbohydrate synthesis

Ubiparip

Doncker

Beerens

et al. 2021

Appl Microbiol Biotechnol

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β-Glucan phosphorylases are carbohydrate-active enzymes that catalyze the reversible degradation of β-linked glucose polymers, with outstanding potential for the biocatalytic bottom-up synthesis of β-glucans as major bioactive compounds. Their preference for sugar phosphates (rather than nucleotide sugars) as donor substrates further underlines their significance for the carbohydrate industry. Presently, they are classified in the glycoside hydrolase families 94, 149, and 161 (www.cazy.org). Since the discovery of β-1,3-oligoglucan phosphorylase in 1963, several other specificities have been reported that differ in linkage type and/or degree of polymerization. Here, we present an overview of the progress that has been made in our understanding of β-glucan and associated β-glucobiose phosphorylases, with a special focus on their application in the synthesis of carbohydrates and related molecules. Key points • Discovery, characteristics, and applications of β-glucan phosphorylases. • β-Glucan phosphorylases in the production of functional carbohydrates.

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“…Nucleotide sugars (i.e. NDP- d -glucose) are activated forms of monosaccharides and are key intermediates in carbohydrate metabolism [34]. In mycobacteria, NDP- d -glucose is the precursor of trehalose, a critical component of mycobacterial cell envelope glycolipids such as trehalose dimycolate (TDM), or ‘cord factor’ [35].…”

Section: Ironmentioning

confidence: 99%

Interplay between central carbon metabolism and metal homeostasis in mycobacteria and other human pathogens

Serafini¹

2021

Microbiology

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Bacterial nutrition is a fundamental aspect of pathogenesis. While the host environment is in principle nutrient-rich, hosts have evolved strategies to interfere with nutrient acquisition by pathogens. In turn, pathogens have developed mechanisms to circumvent these restrictions. Changing the availability of bioavailable metal ions is a common strategy used by hosts to limit bacterial replication. Macrophages and neutrophils withhold iron, manganese, and zinc ions to starve bacteria. Alternatively, they can release manganese, zinc, and copper ions to intoxicate microorganisms. Metals are essential micronutrients and participate in catalysis, macromolecular structure, and signalling. This review summarises our current understanding of how central carbon metabolism in pathogens adapts to local fluctuations in free metal ion concentrations. We focus on the transcriptomics and proteomics data produced in studies of the iron-sparing response in Mycobacterium tuberculosis , the etiological agent of tuberculosis, and consequently generate a hypothetical model linking trehalose accumulation, succinate secretion and substrate-level phosphorylation in iron-starved M. tuberculosis . This review also aims to highlight a large gap in our knowledge of pathogen physiology: the interplay between metal homeostasis and central carbon metabolism, two cellular processes which are usually studied separately. Integrating metabolism and metal biology would allow the discovery of new weaknesses in bacterial physiology, leading to the development of novel and improved antibacterial therapies.

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Nucleotide Sugars in Chemistry and Biology

Cited by 47 publications

References 201 publications

Metabolic Engineering of Corynebacterium glutamicum for Production of UDP-N-Acetylglucosamine

Metabolic Engineering of Corynebacterium glutamicum for Production of UDP-N-Acetylglucosamine

β-Glucan phosphorylases in carbohydrate synthesis

Interplay between central carbon metabolism and metal homeostasis in mycobacteria and other human pathogens

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