Mutational and functional analyses of xylosyltransferases and their implication in osteoarthritis

Schön, Sylvia; Huep, Gunnar; Prante, Christian; Müller, Sandra; Christ, R. M.; Hagena, F.-W.; Kühn, Joachim; Kleesiek, Knut; Götting, Christian

doi:10.1016/j.joca.2005.11.004

Cited by 27 publications

(23 citation statements)

References 28 publications

(28 reference statements)

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“…Although the biological role of xylosyltransferase secretion has not been solved, this feature offers new diagnostic opportunities to measure the proteoglycan biosynthesis rate. The simultaneous secretion of xylosyltransferase and large proteoglycans makes the quantification of xylosyltransferase activity in body fluids a valuable tool for non-invasive determination of the actual proteoglycan synthesis rate, which is of importance in pathological tissue remodeling processes [28,32,87,96,97,103,104].…”

Section: Secretion Of Xt-i and Xt-ii Into Extracellular Spacementioning

confidence: 99%

“…Degenerative joint diseases are characterized by a progressive erosion of the cartilage, including degradation and release of proteoglycans. Elevated xylosyltransferase levels were found in rheumatoid arthritis and osteoarthritis, reflecting the progressive damage of the articular cartilage and the cellular proteoglycan re-synthesis mechanism [32,98]. Pulmonary fibrosis rat lung tissue › high XT activity after bleomycin-induced lung fibrosis [139] Menstrual cycle human blood serum !…”

Section: Xylosyltransferases Biochemical Markers Of Fibrosis and Tismentioning

confidence: 99%

“…In osteoarthritis, higher serum xylosyltransferase levels were found in patients with a longer disease course [32]. Human xylosyltransferases are subjected to hormonal regulation, with serum xylosyltransferase activities changing in women during the menstrual cycle and correlating with b-estradiol levels [41].…”

Section: Review Articlementioning

confidence: 99%

“…These results and the absence of nonsense mutations, frame-shift alterations and splice-site mutations point to the important role of the xylosyltransferases for human life. However, some sequence variations in xylosyltransferase genes that serve as major risk factors for proteoglycan-associated diseases could be identified ( Table 2, Table 3) [31,32,163]. Proteoglycans are important components of the glomerular basement membrane and are responsible for the size-and charge-dependent permeability of the basement membrane [1,165].…”

Section: Sequence Variations In the Xylosyltransferase Genesmentioning

confidence: 99%

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Human xylosyltransferases in health and disease

Götting

Kühn

Kleesiek

2007

Cell. Mol. Life Sci.

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The xylosyltransferases I and II (XT-I, XT-II, EC 2.4.2.26) catalyze the transfer of xylose from UDP-xylose to selected serine residues in the proteoglycan core protein, which is the initial and ratelimiting step in glycosaminoglycan biosynthesis. Both xylosyltransferases are Golgi-resident enzymes and transfer xylose to similar core proteins acceptors. XT-I and XT-II are differentially expressed in cell types and tissues, although the reason for the existence of two xylosyltransferase isoforms in all higher organisms remains elusive. Serum xylosyltransferase activity was found to be a biochemical marker for the assessment of disease activity in systemic sclerosis and for the diagnosis of fibrotic remodeling processes. Furthermore, sequence variations in the XT-I and XT-II coding genes were identified as risk factors for diabetic nephropathy, osteoarthritis or pseudoxanthoma elasticum. These findings point to the important role of the xylosyltransferases as disease modifiers in pathologies which are characterized by an altered proteoglycan metabolism. The present review discusses recent advances in mammalian xylosyltransferases and the impact of xylosyltransferases in proteoglycan-associated diseases.

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Section: Secretion Of Xt-i and Xt-ii Into Extracellular Spacementioning

confidence: 99%

Section: Xylosyltransferases Biochemical Markers Of Fibrosis and Tismentioning

confidence: 99%

Section: Review Articlementioning

confidence: 99%

Section: Sequence Variations In the Xylosyltransferase Genesmentioning

confidence: 99%

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Human xylosyltransferases in health and disease

Götting

Kühn

Kleesiek

2007

Cell. Mol. Life Sci.

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“…Section 1734 solely to indicate this fact. biological importance since mutations in the XT-II gene are genetic risk factors for diseases that are characterized by an altered proteoglycan metabolism, such as pseudoxanthoma elasticum (14), osteoarthritis (15), or diabetic nephropathy (16).…”

mentioning

confidence: 99%

Human Xylosyltransferase II Is Involved in the Biosynthesis of the Uniform Tetrasaccharide Linkage Region in Chondroitin Sulfate and Heparan Sulfate Proteoglycans

Pönighaus

Ambrosius

Casanova

et al. 2007

Journal of Biological Chemistry

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Human xylosyltransferase I (XT-I) initiates the biosynthesis of the glycosaminoglycan (GAG) linkage tetrasaccharide in proteoglycans. Xylosyltransferase II (XT-II) is a protein homologous to XT-I but with hitherto unknown activity or physiological function. Here, we report the enzymatic activity of XT-II and provide evidence that XT-II initiates the biosynthesis of both heparan sulfate and chondroitin sulfate GAGs. Transfection of the xylosyltransferase-deficient Chinese hamster ovary mutant pgsA-745 with XT-I or XT-II coding cDNA completely restored GAG biosynthesis. GAG disaccharide analysis revealed that XT-I-and XT-II-transfected pgsA-745 cells produced similar amounts of chondroitin sulfate and heparan sulfate. Furthermore, a high xylosyltransferase activity was measured after transfection with cDNAs encoding either isozyme. Analysis of the enzyme activity revealed that XT-II catalyzes the transfer of xylose to similar peptide acceptors as XT-I but with different efficiency. The optimal XT-II acceptor was observed using a bikunin-related peptide (K m 5.2 M). Analysis of XT-I and XT-II mRNA expression in murine tissues showed a differential expression pattern for both enzymes. In particular, XT-II is highly expressed in liver tissue, where XT-I transcripts were not detected. This is the first report on the enzyme activity of XT-II and its involvement in chondroitin sulfate and heparan sulfate biosynthesis.

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First identification and functional analysis of the human xylosyltransferase II promoter

et al. 2012

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Recently, we demonstrated that the human xylosyltransferase II (XT-II) has enzymatic activity and is able to catalyze the initial and rate-limiting step in the biosynthesis of glycosaminoglycans (GAGs) like chondroitin and dermatan sulfate, as well as heparan sulfate and heparin. Therefore, this enzyme also very likely assumes a crucial regulatory role in the biosynthesis of proteoglycans (PGs). In this study, we identified and characterized for the first time the XYLT2 gene promoter region and transcription factors involved in its regulation. Several binding sites for members of the Sp1 family of transcription factors were identified as being necessary for transcriptional regulation of the XYLT2 gene. This was determined by mithramycin A treatment, electrophoretic mobility shift and supershift assays, as well as numerous site-directed mutagenesis experiments. Different 5' and 3' deletion constructs of the predicted GC rich promoter region, which lacks a canonical TATA and CAAT box, revealed that a 177 nts proximal promoter element is sufficient and indispensable to drive the constitutive transcription in full strength in HepG2 hepatoma cells. In addition, we also detected the transcriptional start site using 5'-RACE (rapid amplification of cDNA ends). Our results provide an insight into transcriptional regulation of the XYLT2 gene and may contribute to understanding the manifold GAG-involving processes in health and disease.

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Mutational and functional analyses of xylosyltransferases and their implication in osteoarthritis

Cited by 27 publications

References 28 publications

Human xylosyltransferases in health and disease

Human xylosyltransferases in health and disease

Human Xylosyltransferase II Is Involved in the Biosynthesis of the Uniform Tetrasaccharide Linkage Region in Chondroitin Sulfate and Heparan Sulfate Proteoglycans

First identification and functional analysis of the human xylosyltransferase II promoter

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