Recent structures, evolution and mechanisms of glycosyltransferases

Breton, C.; Fournel‐Gigleux, Sylvie; Palcic, Monica M.

doi:10.1016/j.sbi.2012.06.007

Cited by 204 publications

(180 citation statements)

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“…3d), suggesting that Ct3GT-A adopts a catalytic mechanism similar to that proposed for VvGT1: the conserved histidine residue acts as a general base to help deprotonation of the 3-hydroxyl group of the acceptor substrate, after which the generated nucleophile attacks the anomeric carbon of the glucose moiety (Breton et al, 2012). The carboxyl side chain of Asp119 is thought to increase the proton-accepting ability of the imidazole ring as seen in the catalytic mechanism of serine proteases, which have a catalytic triad of Ser-His-Asp with a similar geometry (Wharton, 1998).…”

Section: Structural Characteristics For the Function Of Ct3gt-amentioning

confidence: 94%

“…2a), which are conserved in plant UGTs (Breton et al, 2012) (C-domain) is composed of a twisted -sheet with six strands accompanied by ten -helices on its two sides. There is a cleft located between the N-and C-domains (Fig.…”

Section: Overall Structure Of Ct3gt-amentioning

confidence: 99%

“…In addition, the crystal structures of these four plant UGTs have been reported so far: Medicago truncatula UGT71G1, a triterpene/flavonoid glycosyltransferase involved in saponin biosynthesis (Shao et al, 2005), UGT85H2, an (iso)flavonoid glycosyltransferase involved in the biosynthesis of secondary metabolites (Li et al, 2007), UGT78G1, an (iso)flavonoid glycosyltransferase that functions in anthocyanin biosynthesis (Modolo et al, 2009) and Arabidopsis thaliana UGT72B1, a chloroaniline/chlorophenol glucosyltransferase in the metabolism of xenobiotics (Brazier-Hicks et al, 2007). These plant UGTs all have the GT-B fold, one of two general folds found in the UGT superfamily of enzymes (Coutinho et al, 2003;Breton et al, 2012), and they possess two N-and C-terminal domains with similar Rossmann-like folds (Wang, 2009). They also have in common a signature motif known as putative secondary plant glycosyltransferase (PSPG) box near the C-terminus, which is thought to be involved in binding to the UDP moiety of the sugardonor substrate (Lairson et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Crystal structure of UDP-glucose:anthocyanidin 3-O-glucosyltransferase fromClitoria ternatea

Hiromoto

Honjo

Tamada

et al. 2013

J Synchrotron Radiat

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Flowers of the butterfly pea (Clitoria ternatea) accumulate a group of polyacylated anthocyanins, named ternatins, in their petals. The first step in ternatin biosynthesis is the transfer of glucose from UDP‐glucose to anthocyanidins such as delphinidin, a reaction catalyzed in C. ternatea by UDP‐glucose:anthocyanidin 3‐O‐glucosyltransferase (Ct3GT‐A; AB185904). To elucidate the structure–function relationship of Ct3GT‐A, recombinant Ct3GT‐A was expressed in Escherichia coli and its tertiary structure was determined to 1.85 Å resolution by using X‐ray crystallography. The structure of Ct3GT‐A shows a common folding topology, the GT‐B fold, comprised of two Rossmann‐like β/α/β domains and a cleft located between the N‐ and C‐domains containing two cavities that are used as binding sites for the donor (UDP‐Glc) and acceptor substrates. By comparing the structure of Ct3GT‐A with that of the flavonoid glycosyltransferase VvGT1 from red grape (Vitis vinifera) in complex with UDP‐2‐deoxy‐2‐fluoro glucose and kaempferol, locations of the catalytic His‐Asp dyad and the residues involved in recognizing UDP‐2‐deoxy‐2‐fluoro glucose were essentially identical in Ct3GT‐A, but certain residues of VvGT1 involved in binding kaempferol were found to be substituted in Ct3GT‐A. These findings are important for understanding the differentiation of acceptor‐substrate recognition in these two enzymes.

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Section: Structural Characteristics For the Function Of Ct3gt-amentioning

confidence: 94%

Section: Overall Structure Of Ct3gt-amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Crystal structure of UDP-glucose:anthocyanidin 3-O-glucosyltransferase fromClitoria ternatea

Hiromoto

Honjo

Tamada

et al. 2013

J Synchrotron Radiat

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“…Glycosyltransferases are the enzymes shaping glycans through the formation of glycosidic linkages. The majority of these glycosyltransferases are transmembrane proteins anchored in the endoplasmic reticulum (ER) and Golgi membranes [13]. Defects of ER glycosyltransferases involved in the assembly of the lipid-linked oligosaccharide GlcNAc 2 Man 9 Glc 3 limit the availability of this substrate for transfer to N-glycosylation sites on acceptor proteins during translation (Figure 2).…”

Section: Glycosyltransferasesmentioning

confidence: 99%

Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction

Hennet

Cabalzar

2015

Trends in Biochemical Sciences

112

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Glycosylation is a ubiquitous modification of lipids and proteins. Despite the essential contribution of glycoconjugates to the viability of all living organisms, diseases of glycosylation in humans have only been identified over the past few decades. The recent development of next-generation DNA sequencing techniques has accelerated the pace of discovery of novel glycosylation defects. The description of multiple mutations across glycosylation pathways not only revealed tremendous diversity in functional impairments, but also pointed to phenotypic similarities, emphasizing the interconnected flow of substrates underlying glycan assembly. The current list of 100 known glycosylation disorders provides an overview of the significance of glycosylation in human development and physiology. Congenital disorders of glycosylation -a consice chart of glycocalyx dysfunctionThierry Hennet, Jürg Cabalzar Institute of Physiology, University of Zurich, CH-8057 Zurich, Switzerland AbstractGlycosylation is a ubiquitous modification of lipids and proteins. Despite the essential contribution of glycoconjugates to the viability of all living organisms, diseases of glycosylation in humans have only been identified over the past few decades. The recent development of next-generation DNA sequencing techniques has accelerated the pace of discovery of novel glycosylation defects. The description of multiple mutations across glycosylation pathways has revealed a tremendous diversity of functional impairments bus also pointed to phenotypic similarities emphasizing the interconnected flow of substrates underlying glycan assembly. The current list of 100 known glycosylation disorders provides an overview on the significance of glycosylation in human development and physiology. Highlights Congenital disorders underline the role of glycosylation in human development.  Next-gen sequencing techniques expanded the discovery of glycosylation gene defects.  The clinical variability of glycosylation disorders implies they are underdiagnosed. Glycosylation disordersGlycosylation is by far the most complex form of protein [1,2] and lipid modification [3,4] in all domains of life. The tremendous diversity of glycoconjugate structures resulting from intricate biosynthetic pathways is a major factor hampering the assignment of functions to glycans chains. Much has been learnt from the study of disrupted glycosylation genes in model organisms, thereby establishing numerous essential contributions of glycans in regulating cell and organ functions [5]. The study of human diseases of glycosylation brings additional insights by providing a more differentiated view on glycan functions. Indeed, most human mutations are hypomorphic, thus causing partial loss of glycosylation reactions that lead to variable clinical manifestations.Diseases of glycosylation are also referred to as congenital disorders of glycosylation (CDG). Given the heterogeneity of glycans, the clinical scope of CDG is considerable, ranging from nearly normal phenotypes to sever...

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“…HS are composed of uronic acid and N-acetylglucosamine repeating disaccharide units covalently attached to the core protein of PG through a tetrasaccharide linkage region. 2 During biosynthesis, HS are subjected to marked structural modifications -mainly epimerization, Ndeacetylation, N-and O-sulfation, catalyzed by numerous enzymes, including HS-Osulfotransferases. 3,4 The range of biological functions of HS ultimately depends on the fine structure of their polysaccharide chain.…”

Section: Introductionmentioning

confidence: 99%

The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer

et al. 2016

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The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer Mao, X.; Gauche, C.; Coughtrie, M. W. H.; Bui, C.; Gulberti, S.; Merhi-Soussi, F. Citation for published version (APA):Mao, X., Gauche, C., Coughtrie, M. W. H., Bui, C., Gulberti, S., Merhi-Soussi, F., ... Fournel-Gigleux, S. (2016). The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer. Oncogene, 35, 5043-5055. DOI: 10.1038/onc.2016 General rights Copyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain.• You may freely distribute the URL identifying the publication in the public portal. Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Heparan sulfate (HS) proteoglycan chains are key components of the breast tumor microenvironment that critically influence the behavior of cancer cells. It is established that abnormal synthesis and processing of HS play a prominent role in tumorigenesis albeit mechanisms remain mostly obscure. HS function is mainly controlled by sulfotransferases, and here we report a novel cellular and pathophysiological significance for the 3--O--sulfotransferase 3--OST3A (HS3ST3A), catalyzing the final maturation step of HS, in breast cancer. We show that 3--OST3A is epigenetically repressed in all breast cancer cell lines of a panel representative of distinct molecular subgroups, except in HER2--positive (HER2+) SKBR3 cells. Epigenetic mechanisms involved both DNA methylation and histone modifications, producing different repressive chromatin environments depending on the cell molecular signature. Gain and loss of function experiments by cDNA and siRNA transfection revealed profound effects of 3--OST3A expression on cell behavior including apoptosis, proliferation, response to trastuzumab in vitro and tumor growth in xenografted mice. 3--OST3A exerted dual activities acting as tumor--suppressor in lumA--MCF--7 and triple negative--MDA--MB--231 cells, or as an oncogenic factor in HER2+--SKBR3 cells. Mechanistically, fluorescence--resonance energy transfer (FRET)--fluorescence--lifetime imaging microscopy (FLIM) experiments indicated that the effects of 3--OST3A in MCF--7 cells were mediated by altered interactions between HS and fibroblast growth factor--7 (FGF--7). Further, this interplay between HS and FGF--7 modulated downstream ERK, AKT and p38 cascades, suggesting that altering 3--O--sulfation affects FGFR...

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Recent structures, evolution and mechanisms of glycosyltransferases

Cited by 204 publications

References 54 publications

Crystal structure of UDP-glucose:anthocyanidin 3-O-glucosyltransferase fromClitoria ternatea

Crystal structure of UDP-glucose:anthocyanidin 3-O-glucosyltransferase fromClitoria ternatea

Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction

The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer

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