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Dermatan sulfate epimerase

Nadège Gouignard, Marco Maccarana, Ina Strate, Kristoffer von Stedingk, Anders Malmström, Edgar M Pera
Of all live births with congenital anomalies, approximately one-third exhibit deformities of the head and face. Most craniofacial disorders are associated with defects in a migratory stem and progenitor cell population, which is designated the neural crest (NC). Musculocontractural Ehlers-Danlos syndrome (MCEDS) is a heritable connective tissue disorder with distinct craniofacial features; this syndrome comprises multiple congenital malformations that are caused by dysfunction of dermatan sulfate (DS) biosynthetic enzymes, including DS epimerase-1 (DS-epi1; also known as DSE)...
June 1, 2016: Disease Models & Mechanisms
Emil Tykesson, Yang Mao, Marco Maccarana, Yi Pu, Jinshan Gao, Cheng Lin, Joseph Zaia, Gunilla Westergren-Thorsson, Ulf Ellervik, Lars Malmström, Anders Malmström
Distinct from template-directed biosynthesis of nucleic acids and proteins, the enzymatic synthesis of heterogeneous polysaccharides is a complex process that is difficult to study using common analytical tools. Therefore, the mode of action and processivity of those enzymes are largely unknown. Dermatan sulfate epimerase 1 (DS-epi1) is the predominant enzyme during the formation of iduronic acid residues in the glycosaminoglycan dermatan sulfate. Using recombinant DS-epi1 as a model enzyme, we describe a tandem mass spectrometry-based method to study the mode of action of polysaccharide processing enzymes...
February 1, 2016: Chemical Science
Florin Sasarman, Catalina Maftei, Philippe M Campeau, Catherine Brunel-Guitton, Grant A Mitchell, Pierre Allard
Glycosaminoglycans (GAG) are long, unbranched heteropolymers with repeating disaccharide units that make up the carbohydrate moiety of proteoglycans. Six distinct classes of GAGs are recognized. Their synthesis follows one of three biosynthetic pathways, depending on the type of oligosaccharide linker they contain. Chondroitin sulfate, dermatan sulfate, heparan sulfate, and heparin sulfate contain a common tetrasaccharide linker that is O-linked to specific serine residues in core proteins. Keratan sulfate can contain three different linkers, either N-linked to asparagine or O-linked to serine/threonine residues in core proteins...
March 2016: Journal of Inherited Metabolic Disease
Xanthi N Stachtea, Emil Tykesson, Toin H van Kuppevelt, Ricardo Feinstein, Anders Malmström, Rogier M Reijmers, Marco Maccarana
The epimerization of glucuronic acid into iduronic acid adds structural variability to chondroitin/dermatan sulfate polysaccharides. Iduronic acid-containing domains play essential roles in processes such as coagulation, chemokine and morphogen modulation, collagen maturation, and neurite sprouting. Therefore, we generated and characterized, for the first time, mice deficient in dermatan sulfate epimerase 1 and 2, two enzymes uniquely involved in dermatan sulfate biosynthesis. The resulting mice, termed DKO mice, were completely devoid of iduronic acid, and the resulting chondroitin sulfate chains were structurally different from the wild type chains, from which a different protein binding specificity can be expected...
2015: PloS One
Judith Habicher, Tatjana Haitina, Inger Eriksson, Katarina Holmborn, Tabea Dierker, Per E Ahlberg, Johan Ledin
Chondroitin/dermatan sulfate (CS/DS) proteoglycans consist of unbranched sulfated polysaccharide chains of repeating GalNAc-GlcA/IdoA disaccharide units, attached to serine residues on specific proteins. The CS/DS proteoglycans are abundant in the extracellular matrix where they have essential functions in tissue development and homeostasis. In this report a phylogenetic analysis of vertebrate genes coding for the enzymes that modify CS/DS is presented. We identify single orthologous genes in the zebrafish genome for the sulfotransferases chst7, chst11, chst13, chst14, chst15 and ust and the epimerase dse...
2015: PloS One
Delfien Syx, Tim Van Damme, Sofie Symoens, Merel C Maiburg, Ingrid van de Laar, Jenny Morton, Mohnish Suri, Miguel Del Campo, Ingrid Hausser, Trinh Hermanns-Lê, Anne De Paepe, Fransiska Malfait
Bi-allelic variants in CHST14, encoding dermatan 4-O-sulfotransferase-1 (D4ST1), cause musculocontractural Ehlers-Danlos syndrome (MC-EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies. Recently, the identification of bi-allelic variants in DSE, encoding dermatan sulfate epimerase-1 (DS-epi1), in a child with MC-EDS features, suggested locus heterogeneity for this condition. DS-epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondroitin sulfate (CS)/DS glycosaminoglycans (GAGs)...
May 2015: Human Mutation
Renata Gustafsson, Xanthi Stachtea, Marco Maccarana, Emma Grottling, Erik Eklund, Anders Malmström, Ake Oldberg
BACKGROUND: Dermatan sulfate (DS) is a highly sulfated polysaccharide with a variety of biological functions in extracellular matrix organization and processes such as tumorigenesis and wound healing. A distinct feature of DS is the presence of iduronic acid, produced by the two enzymes, DS-epimerase 1 and 2, which are encoded by Dse and Dsel, respectively. METHODS: We have previously shown that Dse knockout (KO) mice in a mixed C57BL/6-129/SvJ background have an altered collagen matrix structure in skin...
September 2014: Birth Defects Research. Part A, Clinical and Molecular Teratology
Subhash C Juneja, Christian Veillette
This review summarizes the genetic alterations and knockdown approaches published in the literature to assess the role of key proteoglycans and glycoproteins in the structural development, function, and repair of tendon, ligament, and enthesis. The information was collected from (i) genetically altered mice, (ii) in vitro knockdown studies, (iii) genetic variants predisposition to injury, and (iv) human genetic diseases. The genes reviewed are for small leucine-rich proteoglycans (lumican, fibromodulin, biglycan, decorin, and asporin); dermatan sulfate epimerase (Dse) that alters structure of glycosaminoglycan and hence the function of small leucine-rich proteoglycans by converting glucuronic to iduronic acid; matricellular proteins (thrombospondin 2, secreted phosphoprotein 1 (Spp1), secreted protein acidic and rich in cysteine (Sparc), periostin, and tenascin X) including human tenascin C variants; and others, such as tenomodulin, leukocyte cell derived chemotaxin 1 (chondromodulin-I, ChM-I), CD44 antigen (Cd44), lubricin (Prg4), and aggrecan degrading gene, a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 5 (Adamts5)...
2013: Arthritis
Barbara Bartolini, Martin A Thelin, Lena Svensson, Giancarlo Ghiselli, Toin H van Kuppevelt, Anders Malmström, Marco Maccarana
Aortic smooth muscle cells produce chondroitin/dermatan sulfate (CS/DS) proteoglycans that regulate extracellular matrix organization and cell behavior in normal and pathological conditions. A unique feature of CS/DS proteoglycans is the presence of iduronic acid (IdoA), catalyzed by two DS epimerases. Functional ablation of DS-epi1, the main epimerase in these cells, resulted in a major reduction of IdoA both on cell surface and in secreted CS/DS proteoglycans. Downregulation of IdoA led to delayed ability to re-populate wounded areas due to loss of directional persistence of migration...
2013: PloS One
Thomas Müller, Shuji Mizumoto, Indrajit Suresh, Yoshie Komatsu, Julia Vodopiutz, Munis Dundar, Volker Straub, Arno Lingenhel, Andreas Melmer, Silvia Lechner, Johannes Zschocke, Kazuyuki Sugahara, Andreas R Janecke
The sulfated polysaccharide dermatan sulfate (DS) forms proteoglycans with a number of distinct core proteins. Iduronic acid-containing domains in DS have a key role in mediating the functions of DS proteoglycans. Two tissue-specific DS epimerases, encoded by DSE and DSEL, and a GalNAc-4-O-sulfotransferase encoded by CHST14 are necessary for the formation of these domains. CHST14 mutations were previously identified for patients with the musculocontractural type of Ehlers-Danlos syndrome (MCEDS). We now identified a homozygous DSE missense mutation (c...
September 15, 2013: Human Molecular Genetics
Martin A Thelin, Barbara Bartolini, Jakob Axelsson, Renata Gustafsson, Emil Tykesson, Edgar Pera, Åke Oldberg, Marco Maccarana, Anders Malmstrom
The presence of iduronic acid in chondroitin/dermatan sulfate changes the properties of the polysaccharides because it generates a more flexible chain with increased binding potentials. Iduronic acid in chondroitin/dermatan sulfate influences multiple cellular properties, such as migration, proliferation, differentiation, angiogenesis and the regulation of cytokine/growth factor activities. Under pathological conditions such as wound healing, inflammation and cancer, iduronic acid has diverse regulatory functions...
May 2013: FEBS Journal
Anders Malmström, Barbara Bartolini, Martin A Thelin, Benny Pacheco, Marco Maccarana
The ability of chondroitin/dermatan sulfate (CS/DS) to convey biological information is enriched by the presence of iduronic acid. DS-epimerases 1 and 2 (DS-epi1 and 2), in conjunction with DS-4-O-sulfotransferase 1, are the enzymes responsible for iduronic acid biosynthesis and will be the major focus of this review. CS/DS proteoglycans (CS/DS-PGs) are ubiquitously found in connective tissues, basement membranes, and cell surfaces or are stored intracellularly. Such wide distribution reflects the variety of biological roles in which they are involved, from extracellular matrix organization to regulation of processes such as proliferation, migration, adhesion, and differentiation...
December 2012: Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society
Lifan Zhang, Jennifer J Michal, James V O'Fallon, Zengxiang Pan, Charles T Gaskins, Jerry J Reeves, Jan R Busboom, Xiang Zhou, Bo Ding, Michael V Dodson, Zhihua Jiang
In the present study, a total of 91 genes involved in various pathways were investigated for their associations with six carcass traits and twenty-four fatty acid composition phenotypes in a Wagyu×Angus reference population, including 43 Wagyu bulls and their potential 791 F(1) progeny. Of the 182 SNPs evaluated, 102 SNPs that were in Hardy-Weinberg equilibrium with minor allele frequencies (MAF>0.15) were selected for parentage assignment and association studies with these quantitative traits. The parentage assignment revealed that 40 of 43 Wagyu sires produced over 96...
2012: International Journal of Biological Sciences
Anne K Bergfeld, Oliver M T Pearce, Sandra L Diaz, Roger Lawrence, David J Vocadlo, Biswa Choudhury, Jeffrey D Esko, Ajit Varki
The outermost positions of mammalian cell-surface glycans are predominantly occupied by the sialic acids N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc). To date, hydroxylation of CMP-Neu5Ac resulting in the conversion into CMP-Neu5Gc is the only known enzymatic reaction in mammals to synthesize a monosaccharide carrying an N-glycolyl group. In our accompanying paper (Bergfeld, A. K., Pearce, O. M., Diaz, S. L., Pham, T., and Varki, A. (2012) J. Biol. Chem. 287, jbc.M112.363549), we report a metabolic pathway for degradation of Neu5Gc, demonstrating that N-acetylhexosamine pathways are tolerant toward the N-glycolyl substituent of Neu5Gc breakdown products...
August 17, 2012: Journal of Biological Chemistry
Barbara Bartolini, Martin A Thelin, Uwe Rauch, Ricardo Feinstein, Ake Oldberg, Anders Malmström, Marco Maccarana
Dermatan sulfate epimerase 2 (DS-epi2), together with its homolog DS-epi1, transform glucuronic acid into iduronic acid in DS polysaccharide chains. Iduronic acid gives DS increased chain flexibility and promotes protein binding. DS-epi2 is ubiquitously expressed and is the predominant epimerase in the brain. Here, we report the generation and initial characterization of DS-epi2 null mice. DS-epi2-deficient mice showed no anatomical, histological or morphological abnormalities. The body weights and lengths of mutated and wild-type littermates were indistinguishable...
July 2012: Glycobiology
Martin A Thelin, Katrin J Svensson, Xiaofeng Shi, Mariam Bagher, Jakob Axelsson, Anna Isinger-Ekstrand, Toin H van Kuppevelt, Jan Johansson, Mef Nilbert, Joseph Zaia, Mattias Belting, Marco Maccarana, Anders Malmström
Extracellular matrix, either produced by cancer cells or by cancer-associated fibroblasts, influences angiogenesis, invasion, and metastasis. Chondroitin/dermatan sulfate (CS/DS) proteoglycans, which occur both in the matrix and at the cell surface, play important roles in these processes. The unique feature that distinguishes DS from CS is the presence of iduronic acid (IdoA) in DS. Here, we report that CS/DS is increased five-fold in human biopsies of esophagus squamous cell carcinoma (ESCC), an aggressive tumor with poor prognosis, as compared with normal tissue...
April 15, 2012: Cancer Research
Christine Herzog, Ines Lippmann, Kay Grobe, Alina D Zamfir, Frank Echtermeyer, Daniela G Seidler
An important part of the biosynthesis of proteoglycans is the epimerization of glycosaminoglycan chains. As a consequence of the conversion of chondroitin sulfate (CS) to dermatan sulfate (DS), the glycosaminoglycans become more flexible and enable DS to perform more sophisticated signaling functions. In a recent study, we generated a chimera (S222A) composed of a truncated form of a DS (decorin) and CS (CSF-1) containing proteoglycan and analyzed the influence of the core protein on the extent of epimerization...
October 2011: Molecular BioSystems
Zhihua Jiang, Jennifer J Michal, Xiao-Lin Wu, Zengxiang Pan, Michael D MacNeil
Six genes involved in the heparan sulfate and heparin metabolism pathway, DSEL (dermatan sulfate epimerase-like), EXTL1 (exostoses (multiple)-like 1), HS6ST1 (heparan sulfate 6-O-sulfotransferase 1), HS6ST3 (heparan sulfate 6-O-sulfotransferase 3), NDST3 (N-deacetylase/N-sulfotransferase (heparan glucosaminyl) 3), and SULT1A1 (sulfotransferase family, cytosolic, 1A, phenol-preferring, member 1), were investigated for their associations with muscle lipid composition using cattle as a model organism. Nineteen single nucleotide polymorphisms (SNPs)/multiple nucleotide length polymorphisms (MNLPs) were identified in five of these six genes...
2011: International Journal of Biological Sciences
Shinobu Yamauchi, Akira Kurosu, Masahito Hitosugi, Toshiaki Nagai, Atsuhiko Oohira, Shogo Tokudome
Chondroitin sulfate/dermatan sulfate (CS/DS) polysaccharides have been reported to play a crucial role in the proliferation and maintenance of neural stem cells (NSCs). However, little is known about the structural changes and functional role of CS/DS chains in the differentiation of NSCs. Western blots of NSCs, neurons and astrocytes in culture, with three CS-polysaccharide antibodies of different specificities, revealed marked differences in CS structure among the three cell types. To confirm this finding, we measured gene expression levels of CS sulfotransferases and C5-epimerase in these cell types, as these are responsible for producing the high structural diversity of CS/DS...
April 15, 2011: Neuroscience Letters
Chizuru Akatsu, Shuji Mizumoto, Tomoyuki Kaneiwa, Marco Maccarana, Anders Malmström, Shuhei Yamada, Kazuyuki Sugahara
Chondroitin sulfate (CS) and dermatan sulfate (DS) are expressed in significant amounts in the brain and play important roles in the development of the central nervous system in mammals. CS and DS structures are often found in a single CS/DS hybrid chain. The l-iduronic acid (IdoA)-containing domain, which defines a DS-type domain, appears key to the biological functions of the CS/DS hybrid chain. In this study, to clarify the distribution of the DS-type structure in the brain during development, the expression patterns of DS epimerase 1 (DS-epi1) and DS-epi2, both of which convert d-glucuronic acid into IdoA, were investigated by in situ hybridization...
May 2011: Glycobiology
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