Xanthine dehydrogenase explained

xanthine dehydrogenase
Ec Number:	1.17.1.4
Cas Number:	9054-84-6
Go Code:	0004854
Width:	320

Xanthine dehydrogenase, also known as XDH, is a protein that, in humans, is encoded by the XDH gene.^{[1] [2]}

Function

Xanthine dehydrogenase belongs to the group of molybdenum-containing hydroxylases involved in the oxidative metabolism of purines. The enzyme is a homodimer. Xanthine dehydrogenase can be converted to xanthine oxidase by reversible sulfhydryl oxidation or by irreversible proteolytic modification.

Xanthine dehydrogenase catalyzes the following chemical reaction:

xanthine + NAD⁺ + H₂O

\rightleftharpoons urate + NADH + H⁺

The three substrates of this enzyme are xanthine, NAD⁺, and H₂O, whereas its three products are urate, NADH, and H⁺.

This enzyme participates in purine metabolism.

Nomenclature

This enzyme belongs to the family of oxidoreductases, to be specific, those acting on CH or CH₂ groups with NAD⁺ or NADP⁺ as acceptor. The systematic name of this enzyme class is xanthine:NAD⁺ oxidoreductase. Other names in common use include NAD⁺-xanthine dehydrogenase, xanthine-NAD⁺ oxidoreductase, xanthine/NAD⁺ oxidoreductase, and xanthine oxidoreductase.

Clinical significance

Defects in xanthine dehydrogenase cause xanthinuria, may contribute to adult respiratory stress syndrome, and may potentiate influenza infection through an oxygen metabolite-dependent mechanism. It has been shown that patients with lung adenocarcinoma tumors which have high levels of XDH gene expression have lower survivals.^{[3] [4]} Addiction to XDH protein has been used to target NSCLC tumors and cell lines in a precision oncology manner.^[4]

See also

• Aldehyde oxidase and xanthine dehydrogenase, a/b hammerhead domain
• MOCOS
• Xanthine oxidase

References

Further reading

• Battelli MG, Lorenzoni E . Purification and properties of a new glutathione-dependent thiol:disulphide oxidoreductase from rat liver . The Biochemical Journal . 207 . 1 . 133–8 . October 1982 . 6960894 . 1153833 . 10.1042/bj2070133 .
• Corte ED, Stirpe F . The regulation of rat liver xanthine oxidase. Involvement of thiol groups in the conversion of the enzyme activity from dehydrogenase (type D) into oxidase (type O) and purification of the enzyme . The Biochemical Journal . 126 . 3 . 739–45 . February 1972 . 4342395 . 1178433 . 10.1042/bj1260739 .
• Parzen SD, Fox AS . Purification of xanthine dehydrogenase from Drosophila melanogaster . Biochimica et Biophysica Acta (BBA) - Specialized Section on Enzymological Subjects . 92 . 3 . 465–71 . December 1964 . 14264879 . 10.1016/0926-6569(64)90006-9 .
• Rajagopalan KV, Handler P . Purification and properties of chicken liver xanthine dehydrogenase . The Journal of Biological Chemistry . 242 . 18 . 4097–107 . September 1967 . 10.1016/S0021-9258(18)95784-4 . 4294045 . free .
• Smith ST, Rajagopalan KV, Handler P . Purification and properties of xanthine dehydroganase from Micrococcus lactilyticus . The Journal of Biological Chemistry . 242 . 18 . 4108–17 . September 1967 . 10.1016/S0021-9258(18)95785-6 . 6061702 . free .
• Parschat K, Canne C, Hüttermann J, Kappl R, Fetzner S . Xanthine dehydrogenase from Pseudomonas putida 86: specificity, oxidation-reduction potentials of its redox-active centers, and first EPR characterization . Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology . 1544 . 1–2 . 151–65 . January 2001 . 11341925 . 10.1016/S0167-4838(00)00214-4 .
• Ichida K, Amaya Y, Noda K, Minoshima S, Hosoya T, Sakai O, Shimizu N, Nishino T . Cloning of the cDNA encoding human xanthine dehydrogenase (oxidase): structural analysis of the protein and chromosomal location of the gene . Gene . 133 . 2 . 279–84 . November 1993 . 8224915 . 10.1016/0378-1119(93)90652-J .
• Enroth C, Eger BT, Okamoto K, Nishino T, Nishino T, Pai EF . Crystal structures of bovine milk xanthine dehydrogenase and xanthine oxidase: structure-based mechanism of conversion . Proceedings of the National Academy of Sciences of the United States of America . 97 . 20 . 10723–8 . September 2000 . 11005854 . 27090 . 10.1073/pnas.97.20.10723 . 2000PNAS...9710723E . free .
• Truglio JJ, Theis K, Leimkühler S, Rappa R, Rajagopalan KV, Kisker C . Crystal structures of the active and alloxanthine-inhibited forms of xanthine dehydrogenase from Rhodobacter capsulatus . Structure . 10 . 1 . 115–25 . January 2002 . 11796116 . 10.1016/S0969-2126(01)00697-9 . free .
• Hille R . The Mononuclear Molybdenum Enzymes . Chemical Reviews . 96 . 7 . 2757–2816 . November 1996 . 11848841 . 10.1021/cr950061t .
• Meneshian A, Bulkley GB . The physiology of endothelial xanthine oxidase: from urate catabolism to reperfusion injury to inflammatory signal transduction . Microcirculation . 9 . 3 . 161–75 . July 2002 . 12080414 . 10.1038/sj.mn.7800136 . 40739497 .
• Xu P, Huecksteadt TP, Harrison R, Hoidal JR . Molecular cloning, tissue expression of human xanthine dehydrogenase . Biochemical and Biophysical Research Communications . 215 . 1 . 429 . October 1995 . 7575623 . 10.1006/bbrc.1995.2482 . free .
• Xu P, Zhu XL, Huecksteadt TP, Brothman AR, Hoidal JR . Assignment of human xanthine dehydrogenase gene to chromosome 2p22 . Genomics . 23 . 1 . 289–91 . September 1994 . 7829092 . 10.1006/geno.1994.1498 .
• Minoshima S, Wang Y, Ichida K, Nishino T, Shimizu N . Mapping of the gene for human xanthine dehydrogenase (oxidase) (XDH) to band p23 of chromosome 2 . Cytogenetics and Cell Genetics . 68 . 1–2 . 52–3 . 1994 . 7956358 . 10.1159/000133887 .
• Rytkönen EM, Halila R, Laan M, Saksela M, Kallioniemi OP, Palotie A, Raivio KO . The human gene for xanthine dehydrogenase (XDH) is localized on chromosome band 2q22 . Cytogenetics and Cell Genetics . 68 . 1–2 . 61–3 . 1994 . 7956361 . 10.1159/000133890 .
• Xu P, Huecksteadt TP, Harrison R, Hoidal JR . Molecular cloning, tissue expression of human xanthine dehydrogenase . Biochemical and Biophysical Research Communications . 199 . 2 . 998–1004 . March 1994 . 8135849 . 10.1006/bbrc.1994.1328 .
• Ichida K, Amaya Y, Noda K, Minoshima S, Hosoya T, Sakai O, Shimizu N, Nishino T . Cloning of the cDNA encoding human xanthine dehydrogenase (oxidase): structural analysis of the protein and chromosomal location of the gene . Gene . 133 . 2 . 279–84 . November 1993 . 8224915 . 10.1016/0378-1119(93)90652-J .
• Satoh A, Sasago S, Takahashi S, Kato N . Regulation of xanthine dehydrogenase in rat liver in response to peroxisome proliferators . Biochemical and Biophysical Research Communications . 195 . 2 . 751–7 . September 1993 . 8373410 . 10.1006/bbrc.1993.2109 .
• Xu P, Huecksteadt TP, Hoidal JR . Molecular cloning and characterization of the human xanthine dehydrogenase gene (XDH) . Genomics . 34 . 2 . 173–80 . June 1996 . 8661045 . 10.1006/geno.1996.0262 .
• Saksela M, Raivio KO . Cloning and expression in vitro of human xanthine dehydrogenase/oxidase . The Biochemical Journal . 315 . Pt 1 . 235–9 . April 1996 . 8670112 . 1217176 . 10.1042/bj3150235 .
• Many A, Westerhausen-Larson A, Kanbour-Shakir A, Roberts JM . Xanthine oxidase/dehydrogenase is present in human placenta . Placenta . 17 . 5–6 . 361–5 . 1996 . 8829220 . 10.1016/S0143-4004(96)90061-2 .
• Hellsten Y, Frandsen U, Orthenblad N, Sjødin B, Richter EA . Xanthine oxidase in human skeletal muscle following eccentric exercise: a role in inflammation . The Journal of Physiology . 498 . Pt 1 . 239–48 . January 1997 . 9023782 . 1159248 . 10.1113/jphysiol.1997.sp021855 .
• Ichida K, Amaya Y, Kamatani N, Nishino T, Hosoya T, Sakai O . Identification of two mutations in human xanthine dehydrogenase gene responsible for classical type I xanthinuria . The Journal of Clinical Investigation . 99 . 10 . 2391–7 . May 1997 . 9153281 . 508078 . 10.1172/JCI119421 .
• Rouquette M, Stevens C, Blake DR, Harrison R, Whish J, Whish WD . Expression of xanthine oxidase activity in human endothelial cells as a function of cell density . Biochemical Society Transactions . 25 . 3 . 532S . August 1997 . 9388748 . 10.1042/bst025532s .
• Newaz MA, Adeeb NN . Detection of xanthine oxidase in human plasma . The Medical Journal of Malaysia . 53 . 1 . 70–5 . March 1998 . 10968141 .
• Martelin E, Palvimo JJ, Lapatto R, Raivio KO . Nuclear factor Y activates the human xanthine oxidoreductase gene promoter . FEBS Letters . 480 . 2–3 . 84–8 . September 2000 . 11034305 . 10.1016/S0014-5793(00)01909-8 . 34293318 .
• Stiborová M, Frei E, Sopko B, Wiessler M, Schmeiser HH . Carcinogenic aristolochic acids upon activation by DT-diaphorase form adducts found in DNA of patients with Chinese herbs nephropathy . Carcinogenesis . 23 . 4 . 617–25 . April 2002 . 11960915 . 10.1093/carcin/23.4.617 . free .
• Frederiks WM, Vreeling-Sindelárová H . Ultrastructural localization of xanthine oxidoreductase activity in isolated rat liver cells . Acta Histochemica . 104 . 1 . 29–37 . 2002 . 11993848 . 10.1078/0065-1281-00629 .
• Cejková J, Ardan T, Filipec M, Midelfart A . Xanthine oxidoreductase and xanthine oxidase in human cornea . Histology and Histopathology . 17 . 3 . 755–60 . 2003 . 12168784 . 10.14670/HH-17.755 .

Notes and References

1. Web site: Entrez Gene: XDH xanthine dehydrogenase. October 25, 2012 .
2. Ichida K, Amaya Y, Noda K, Minoshima S, Hosoya T, Sakai O, Shimizu N, Nishino T . Cloning of the cDNA encoding human xanthine dehydrogenase (oxidase): structural analysis of the protein and chromosomal location of the gene . Gene . 133 . 2 . 279–84 . November 1993 . 8224915 . 10.1016/0378-1119(93)90652-J .
3. Konno H, Minamiya Y, Saito H, Imai K, Kawaharada Y, Motoyama S, Ogawa J . Acquired xanthine dehydrogenase expression shortens survival in patients with resected adenocarcinoma of lung . Tumour Biology . 33 . 5 . 1727–32 . October 2012 . 22678977 . 10.1007/s13277-012-0431-2 . 13495397 .
4. Tavassoly I, Hu Y, Zhao S, Mariottini C, Boran A, Chen Y, Li L, Tolentino RE, Jayaraman G, Goldfarb J, Gallo J, Iyengar R . Genomic signatures defining responsiveness to allopurinol and combination therapy for lung cancer identified by systems therapeutics analyses . Molecular Oncology . May 2019 . 31116490 . 10.1002/1878-0261.12521 . 13 . 8 . 1725–1743 . 6670022.