UDP-glucose 6-dehydrogenase explained

UDP-glucose 6-dehydrogenase is a cytosolic enzyme that in humans is encoded by the UGDH gene.^{[1] [2] [3]}

The protein encoded by this gene converts UDP-glucose to UDP-glucuronate and thereby participates in the biosynthesis of glycosaminoglycans such as hyaluronan, chondroitin sulfate, and heparan sulfate. These glycosylated compounds are common components of the extracellular matrix and likely play roles in signal transduction, cell migration, and cancer growth and metastasis. The expression of this gene is up-regulated by transforming growth factor beta and down-regulated by hypoxia.

This enzyme participates in 4 metabolic pathways: pentose and glucuronate interconversions, ascorbate and aldarate metabolism, starch and sucrose metabolism, and nucleotide sugars metabolism.

Loss of UGDH has recently been implicated in epileptic encephalopathy in humans^[4]

Nomenclature

This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with NAD⁺ or NADP⁺ as acceptor. The systematic name of this enzyme class is UDP-glucose:NAD⁺ 6-oxidoreductase.

Other names in common use include:

• UDP-glucose dehydrogenase,
• uridine diphosphoglucose dehydrogenase,
• UDPG dehydrogenase,
• UDPG:NAD oxidoreductase,
• UDP-alpha-D-glucose:NAD oxidoreductase,
• UDP-glucose:NAD⁺ oxidoreductase,
• uridine diphosphate glucose dehydrogenase,
• UDP-D-glucose dehydrogenase, and
• uridine diphosphate D-glucose dehydrogenase.

Biochemistry

In enzymology, a UDP-glucose 6-dehydrogenase is an enzyme that catalyzes the chemical reaction

UDP-glucose + 2 NAD⁺ + H₂O

UDP-glucuronate + 2 NADH + 2 H⁺

The 3 substrates of this enzyme are UDP-glucose, NAD⁺, and H₂O, whereas its 3 products are UDP-glucuronate, NADH, and H⁺

References:^{[5] [6] [7] [8]}

Further reading

• Peng HL, Lou MD, Chang ML, Chang HY. Howard Y. Chang . cDNA cloning and expression analysis of the human UDPglucose dehydrogenase . Proceedings of the National Science Council, Republic of China. Part B, Life Sciences . 22 . 4 . 166–72 . Oct 1998 . 9850599 .
• Bontemps Y, Maquart FX, Wegrowski Y . Human UDP-glucose dehydrogenase gene: complete cloning and transcription start mapping . Biochemical and Biophysical Research Communications . 275 . 3 . 981–5 . Sep 2000 . 10973831 . 10.1006/bbrc.2000.3389 .
• Bontemps Y, Vuillermoz B, Antonicelli F, Perreau C, Danan JL, Maquart FX, Wegrowski Y . Specific protein-1 is a universal regulator of UDP-glucose dehydrogenase expression: its positive involvement in transforming growth factor-beta signaling and inhibition in hypoxia . The Journal of Biological Chemistry . 278 . 24 . 21566–75 . Jun 2003 . 12682078 . 10.1074/jbc.M209366200 . free .
• Sommer BJ, Barycki JJ, Simpson MA . Characterization of human UDP-glucose dehydrogenase. CYS-276 is required for the second of two successive oxidations . The Journal of Biological Chemistry . 279 . 22 . 23590–6 . May 2004 . 15044486 . 10.1074/jbc.M401928200 . free .
• Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk GJ, Li Y, Xu C, Fang R, Guegler K, Rao MS, Mandalam R, Lebkowski J, Stanton LW . Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation . Nature Biotechnology . 22 . 6 . 707–16 . Jun 2004 . 15146197 . 10.1038/nbt971 . 27764390 .
• Huh JW, Yoon HY, Lee HJ, Choi WB, Yang SJ, Cho SW . Importance of Gly-13 for the coenzyme binding of human UDP-glucose dehydrogenase . The Journal of Biological Chemistry . 279 . 36 . 37491–8 . Sep 2004 . 15247292 . 10.1074/jbc.M404234200 . free .
• Huh JW, Lee HJ, Choi MM, Yang SJ, Yoon SY, Kim DW, Kim SY, Choi SY, Cho SW . Identification of a UDP-glucose-binding site of human UDP-glucose dehydrogenase by photoaffinity labeling and cassette mutagenesis . Bioconjugate Chemistry . 16 . 3 . 710–6 . 2005 . 15898741 . 10.1021/bc0500387 .
• Vatsyayan J, Peng HL, Chang HY . Analysis of human UDP-glucose dehydrogenase gene promoter: identification of an Sp1 binding site crucial for the expression of the large transcript . Journal of Biochemistry . 137 . 6 . 703–9 . Jun 2005 . 16002992 . 10.1093/jb/mvi082 .
• Wang L, Zhu YF, Guo XJ, Huo R, Ma X, Lin M, Zhou ZM, Sha JH . A two-dimensional electrophoresis reference map of human ovary . Journal of Molecular Medicine . 83 . 10 . 812–21 . Oct 2005 . 16021519 . 10.1007/s00109-005-0676-y . 6644433 .
• Vatsyayan J, Lin CT, Peng HL, Chang HY . Identification of a cis-acting element responsible for negative regulation of the human UDP-glucose dehydrogenase gene expression . Bioscience, Biotechnology, and Biochemistry . 70 . 2 . 401–10 . Feb 2006 . 16495656 . 10.1271/bbb.70.401 . 25853385 . free .
• Huh JW, Robinson RC, Lee HS, Lee JI, Heo YS, Kim HT, Lee HJ, Cho SW, Choe H . Expression, purification, crystallization, and preliminary X-Ray analysis of the human UDP-glucose dehydrogenase . Protein and Peptide Letters . 13 . 8 . 859–62 . 2006 . 17073734 . 10.2174/092986606777841253 . 28298102 .
• Easley KE, Sommer BJ, Boanca G, Barycki JJ, Simpson MA . Characterization of human UDP-glucose dehydrogenase reveals critical catalytic roles for lysine 220 and aspartate 280 . Biochemistry . 46 . 2 . 369–78 . Jan 2007 . 17209547 . 10.1021/bi061537d .

Notes and References

1. Spicer AP, Kaback LA, Smith TJ, Seldin MF . Molecular cloning and characterization of the human and mouse UDP-glucose dehydrogenase genes . The Journal of Biological Chemistry . 273 . 39 . 25117–24 . Sep 1998 . 9737970 . 10.1074/jbc.273.39.25117 . free.
2. Marcu O, Stathakis DG, Marsh JL . Assignment of the UGDH locus encoding UDP-glucose dehydrogenase to human chromosome band 4p15.1 by radiation hybrid mapping . Cytogenetics and Cell Genetics . 86 . 3–4 . 244–5 . Jan 2000 . 10575217 . 10.1159/000015350 . 25740995 .
3. Web site: Entrez Gene: UGDH UDP-glucose dehydrogenase.
4. Hengel, H., Bosso-Lefèvre, C., Grady, G. et al. Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy. Nat Commun 11, 595 (2020). https://doi.org/10.1038/s41467-020-14360-7
5. Druzhinina TN, Kusov YY, Shibaev VN, Kochetkov NK, Bielý P, Kucár S, Bauer S . Uridine diphosphate 2-deoxyglucose. Chemical synthesis, enzymic oxidation and epimerization . Biochimica et Biophysica Acta . 381 . 2 . 301–7 . Feb 1975 . 1091296 . 10.1016/0304-4165(75)90236-6 .
6. Kalckar HM, Maxwell ES, Strominger JL . Some properties of uridine diphosphoglucose dehydrogenase . Archives of Biochemistry and Biophysics . 65 . 1 . 2–10 . Nov 1956 . 13373402 . 10.1016/0003-9861(56)90171-0 .
7. Strominger JL, Mapson LW . Uridine diphosphoglucose dehydrogenase of pea seedlings . The Biochemical Journal . 66 . 4 . 567–72 . Aug 1957 . 13459898 . 1200063 . 10.1042/bj0660567.
8. Axelrod J, Kalckar HM, Maxwell ES, Strominger JL . Enzymatic formation of uridine diphosphoglucuronic acid . The Journal of Biological Chemistry . 224 . 1 . 79–90 . Jan 1957 . 10.1016/S0021-9258(18)65012-4 . 13398389 . free .