ArticleThe Journal of biological chemistry2012
Structure and mechanism of human UDP-xylose synthase: evidence for a promoting role of sugar ring distortion in a three-step catalytic conversion of UDP-glucuronic acid.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 46 citations in OpenAlex.
- The phospholipase PlcP mediates membrane lipid remodeling required for the intracellular survival of Burkholderia cenocepacia.The Journal of biological chemistry · 2026Article
- UDP-glucuronate decarboxylase 1 promotes tumor immune evasion by accelerating KMT2D loss in hepatocellular carcinoma.Journal for immunotherapy of cancer · 2026Article
- Structural instability impairs function of the UDP-xylose synthase 1 Ile181Asn variant associated with short-stature genetic syndrome in humans.FEBS letters · 2026Article
- Multi-platform evidence of GSDMD-dependent pyroptosis in malaria with a potential role for TLR7.Frontiers in immunology · 2026Article
- Article
- Kinetic Dissection of the Reaction of Human GDP-l-Fucose Synthase.ACS catalysis · 2025Article
- The carboxylate "gripper" of the substrate is critical for C-4 stereo-inversion by UDP-glucuronic acid 4-epimerase.FEBS letters · 2025Article
- One-Pot Hetero-Di-C-Glycosylation of the Natural Polyphenol Phloretin by a Single C-Glycosyltransferase With Broad Sugar Substrate Specificity.Biotechnology and bioengineering · 2025Article
- Decarboxylation in Natural Products Biosynthesis.JACS Au · 2024Review
- HiChIP-Based Epigenomic Footprinting Identifies a Promoter Variant of UXS1 That Confers Genetic Susceptibility to Gastroesophageal Cancer.Cancer research · 2024Article
- A monoallelic UXS1 variant associated with short-limbed short stature.Molecular genetics & genomic medicine · 2024Article
- Article
- Enzymatic C4-Epimerization of UDP-Glucuronic Acid: Precisely Steered Rotation of a Transient 4-Keto Intermediate for an Inverted Reaction without Decarboxylation.Angewandte Chemie (International ed. in English) · 2023Article
- Enzymatische C4-Epimerisierung von UDP-Glucuronsäure: präzise gesteuerte Rotation eines transienten 4-Ketointermediats für eine invertierende Reaktion ohne Decarboxylierung.Angewandte Chemie (Weinheim an der Bergstrasse, Germany) · 2023Article
- Comparative Transcriptome Analysis on the Regulatory Mechanism of Thoracic Ganglia inLife (Basel, Switzerland) · 2022Article
- Mechanistic characterization of UDP-glucuronic acid 4-epimerase.The FEBS journal · 2021Article
- Crystallographic snapshots of UDP-glucuronic acid 4-epimerase ligand binding, rotation, and reduction.The Journal of biological chemistry · 2020Article
- Deciphering the enzymatic mechanism of sugar ring contraction in UDP-apiose biosynthesis.Nature catalysis · 2019Article
- Structural basis for broad substrate specificity of UDP-glucose 4-epimerase in the human milk oligosaccharide catabolic pathway of Bifidobacterium longum.Scientific reports · 2019Article
- Isotope Probing of the UDP-Apiose/UDP-Xylose Synthase Reaction: Evidence of a Mechanism via a Coupled Oxidation and Aldol Cleavage.Angewandte Chemie (International ed. in English) · 2017Article
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Authors and funding
8 authors at 6 institutions in 2 countries.
Funding
Abstract
UDP-xylose synthase (UXS) catalyzes decarboxylation of UDP-D-glucuronic acid to UDP-xylose. In mammals, UDP-xylose serves to initiate glycosaminoglycan synthesis on the protein core of extracellular matrix proteoglycans. Lack of UXS activity leads to a defective extracellular matrix, resulting in strong interference with cell signaling pathways. We present comprehensive structural and mechanistic characterization of the human form of UXS. The 1.26-Å crystal structure of the enzyme bound with NAD(+) and UDP reveals a homodimeric short-chain dehydrogenase/reductase (SDR), belonging to the NDP-sugar epimerases/dehydratases subclass. We show that enzymatic reaction proceeds in three chemical steps via UDP-4-keto-D-glucuronic acid and UDP-4-keto-pentose intermediates. Molecular dynamics simulations reveal that the D-glucuronyl ring accommodated by UXS features a marked (4)C(1) chair to B(O,3) boat distortion that facilitates catalysis in two different ways. It promotes oxidation at C(4) (step 1) by aligning the enzymatic base Tyr(147) with the reactive substrate hydroxyl and it brings the carboxylate group at C(5) into an almost fully axial position, ideal for decarboxylation of UDP-4-keto-D-glucuronic acid in the second chemical step. The protonated side chain of Tyr(147) stabilizes the enolate of decarboxylated C(4) keto species ((2)H(1) half-chair) that is then protonated from the Si face at C(5), involving water coordinated by Glu(120). Arg(277), which is positioned by a salt-link interaction with Glu(120), closes up the catalytic site and prevents release of the UDP-4-keto-pentose and NADH intermediates. Hydrogenation of the C(4) keto group by NADH, assisted by Tyr(147) as catalytic proton donor, yields UDP-xylose adopting the relaxed (4)C(1) chair conformation (step 3).
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