{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T23:20:40Z","timestamp":1787613640272,"version":"build-2736575974"},"reference-count":35,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["FEBS Letters"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:label\/>\n                    <jats:p>Glycosaminoglycan assembly on proteoglycans involves a common tetrasaccharide linker that starts with xylose attached to a serine on the protein. Defective linker biosynthesis caused by a missense mutation of human UDP\u2010xylose synthase (hUXS1) is associated with connective tissue disorders characterized by skeletal abnormality and short stature. The Ile181Asn variant of hUXS1 was reported as inactive in releasing UDP\u2010xylose from UDP\u2010glucuronic acid. Here, we show that Ile181Asn\u2010hUXS1 exhibited catalytic properties similar to the wild\u2010type enzyme but featured a significant decrease in stability, expressed in melting temperature lowered from 48.2\u2009\u00b0C to 35.2\u2009\u00b0C. At 37\u2009\u00b0C, Ile181Asn\u2010hUXS1 was ~10\u2010fold less stable and more prone to precipitation than wild\u2010type hUXS1. The loss of function in Ile181Asn\u2010hUXS1 is thus explained by instability, consistent with molecular dynamics simulations predicting structural destabilization.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"box\" position=\"anchor\">\n                        <jats:caption>\n                          <jats:title>Impact statement<\/jats:title>\n                        <\/jats:caption>\n                        <jats:p>The Ile181Asn variant of human UDP\u2010xylose synthase (hUXS1), associated with a short\u2010stature genetic syndrome, has previously been reported as inactive. We show here with experiments and molecular simulations that hUXS1 malfunction arises from structural instability rather than from a catalytic defect.<\/jats:p>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/1873-3468.70277","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T07:19:01Z","timestamp":1768375141000},"page":"2063-2076","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Structural instability impairs function of the\n                    <scp>UDP<\/scp>\n                    \u2010xylose synthase 1\n                    <scp>Ile181Asn<\/scp>\n                    variant associated with short\u2010stature genetic syndrome in humans"],"prefix":"10.1002","volume":"600","author":[{"given":"Tuo","family":"Li","sequence":"first","affiliation":[{"name":"Institute of Biotechnology and Biochemical Engineering Graz University of Technology  Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro A.","family":"S\u00e1nchez\u2010Murcia","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry, Otto\u2010Loewi Research Center Medical University of Graz  Austria"},{"name":"BioTechMed\u2010Graz  Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5030-2643","authenticated-orcid":false,"given":"Bernd","family":"Nidetzky","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology and Biochemical Engineering Graz University of Technology  Austria"},{"name":"Austrian Centre of Industrial Biotechnology (acib)  Graz Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph11010027"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.745372"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2015.02.003"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00442.2021"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1877-1173(10)93001-9"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.17107"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.386706"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2018.03.014"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109316200"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2010.02.035"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.066803"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-008-8588-y"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi301135b"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-019-1110-9"},{"key":"e_1_2_8_16_1","article-title":"Mutations 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