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Xanthine dehydrogenase

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Line 28: Line 28:
**[[3on5]] – XDH – ''Bacillus halodurans''<br />
**[[3on5]] – XDH – ''Bacillus halodurans''<br />
**[[1wyg]] – rXDH (mutant) – rat<br />
**[[1wyg]] – rXDH (mutant) – rat<br />
 +
**[[4yrw]], [[4ytz]] - rXDH <br />
 +
**[[2ckj]] – hXDH – human<br />
 +
**[[2e1q]] – hXDH (mutant) <br />
*Xanthine dehydrogenase binary complexes
*Xanthine dehydrogenase binary complexes
-
**[[1vdv]], [[3am9]], [[1n5x]], [[1v97]], [[3bdj]] – bXDH + inhibitor
+
**[[1vdv]], [[3am9]], [[1n5x]], [[1v97]], [[3bdj]] – bXDH + inhibitor <br />
-
 
+
**[[3uni]], [[3una]] – bXDH +NADH<br />
**[[3b9j]], [[3ns1]] – bXDH + purine derivative
**[[3b9j]], [[3ns1]] – bXDH + purine derivative
Line 47: Line 50:
**[[3nvy]] – bXDH + quercetin
**[[3nvy]] – bXDH + quercetin
-
**[[3nvz]] – bXDH + indole-aldehyde
+
**[[3nvz]] – bXDH + indole-aldehyde<br />
-
 
+
**[[4ysw]] – rXDH +NADH<br />
 +
**[[4yty]] – rXDH (mutant) +NADH<br />
**[[3an1]], [[2e3t]] – rXDH (mutant) + urate <br />
**[[3an1]], [[2e3t]] – rXDH (mutant) + urate <br />
**[[1jrp]], [[2w3r]], [[2w3s]] - RcXDH + xanthine derivative<br />
**[[1jrp]], [[2w3r]], [[2w3s]] - RcXDH + xanthine derivative<br />

Revision as of 08:56, 25 June 2015

Template:STRUCTURE 1fo4

Xanthine dehydrogenase (XDH) is a molybdenum-containing hydroxylase involved in oxidative metabolism of purines. It catalyzes the conversion of xanthine to urea using NAD as hydrogen acceptor. Several co-crystal structures of xanthine oxidase and xanthine dehydrogenase (which do not differ in conformation of active site) were studied to understand key interactions for enzyme inhibition. Docking of novel hits and inactive compounds was performed (to in PDB with ID 1vdv) to understand the ligand-protein interactions and hence, for structure-based design of more potent molecules.[1] The paper reports the directions for modification of the hit compound derived from these considerations, which are reported below. The mechanism of action of the novel hits are like and (“pure inhibitors”) and not like & FYX-051 (“substrate inhibitors”).

Xanthine oxidoreductase (XOR), is an oxidoreductive enzyme that is synthesized as xanthine dehydrogenase (XDH) and can be converted reversibly or irreversibly to xanthine oxidase (XO) form. It catalyzes the such as and which is excreted by kidneys.[2] The reaction occurs at the center from where the in case of XDH (PDB code 2w3s)[3] or to molecular oxygen in XO leading to the formation of superoxide anion and H2O2. Excessive production and/or inadequate excretion of uric acid results in hyperuricemia and is associated with conditions like gout, cardiovascular mortality and metabolic syndrome including hyperinsulinemia and hypertriglyceridemia. Alleviating hyperuricemia, therefore, has therapeutic significance, and XO is a key target towards this end.

Piraxostat (PDB code 1vdv) [4] and febuxostat (PDB code 1n5x)[5], show several interactions with the active site residues of the protein. The carboxyl group of piraxostat is involved in and as well. The ring nitrogen is involved in . The cyano group of the ligand forms another . Besides these polar interactions, a number of hydrophobic interactions are observed as well. The heteroaromatic ring is . The phenyl ring has hydrophobic interactions with . The alkoxy side chain extends towards the solvent accessible region and is engaged in hydrophobic interactions with various residues at the entrance of the pocket such as . Piraxostat is in green, Mo-Pt is in deep-sky-blue, residues are colored according to the type of interaction with ligand – salmon for pi-stack, magenta for other hydrophobic and cyan for polar interactions. have been observed by docking our isocytosine series of compounds. The pyrimidine ring (compound 1 is shown). Highly polar groups such as –OH on pyrimidine ring correspond to carboxylate of piraxostat and retain . The –NH2 group in the same ring , which seems to play the role of anchoring the molecule in appropriate pose in the active site. The methoxy group shows a few of the several observed for piraxostat and febuxostat. in the interactions of Compound 1 and piraxostat can help in structure-based design to improve activity of isocytosine series.

Currently approved drugs for xanthine oxidase inhibition are allopurinol and febuxostat. Although both bind to the xanthine-binding site of XO, they work by different molecular mechanisms of action. Allopurinol acts as a substrate that is metabolized via hydroxylation to oxypurinol by Mo-Pt in the active site. Oxypurinol further inhibits the binding of xanthine by co-ordinating with Mo-Pt.[6] Febuxostat binds tightly in the active site and blocks the binding of xanthine, without interacting with Mo-Pt.[5] FYX-051 or topiroxostat currently in Phase II clinical trials also interacts with Mo-Pt just like allopurinol whereas piraxostat is akin to febuxostat.[7] The mechanism of metabolism of substrate by XO requires that an electrophilic carbon next to a ring nitrogen of the substrate be positioned adjacent to Mo-Pt, with nitrogen towards Glu1261. Glu1261 acts as a general base and abstracts a proton from Mo-Pt hydroxyl group. The ionized Mo-Pt facilitates nucleophilic attack on the electrophilic carbon center. This type of motif is seen in the substrate inhibitors, allopurinol and FYX-051.[7] Febuxostat and piraxostat do not possess this motif and do not get metabolized by Mo-Pt. Our hit has a novel isocytosine scaffold that has a nitrogen in the desired position, but the carbon is substituted with –NH2, and is not available for attack by Mo-Pt. Hence our compounds are "pure inhibitors" and not "substrate inhibitors".

3D structures of xanthine dehydrogenase

Updated on 25-June-2015

References

  1. ↑ B-Rao C, Kulkarni-Almeida A, Katkar KV, Khanna S, Ghosh U, Keche A, Shah P, Srivastava A, Korde V, Nemmani KV, Deshmukh NJ, Dixit A, Brahma MK, Bahirat U, Doshi L, Sharma R, Sivaramakrishnan H. Identification of novel isocytosine derivatives as xanthine oxidase inhibitors from a set of virtual screening hits. Bioorg Med Chem. 2012 May 1;20(9):2930-9. Epub 2012 Mar 14. PMID:22483591 doi:10.1016/j.bmc.2012.03.019
  2. ↑ Pauff JM, Cao H, Hille R. Substrate Orientation and Catalysis at the Molybdenum Site in Xanthine Oxidase: CRYSTAL STRUCTURES IN COMPLEX WITH XANTHINE AND LUMAZINE. J Biol Chem. 2009 Mar 27;284(13):8760-7. Epub 2008 Dec 24. PMID:19109252 doi:10.1074/jbc.M804517200
  3. ↑ Dietzel U, Kuper J, Doebbler JA, Schulte A, Truglio JJ, Leimkuhler S, Kisker C. Mechanism of Substrate and Inhibitor Binding of Rhodobacter capsulatus Xanthine Dehydrogenase. J Biol Chem. 2009 Mar 27;284(13):8768-76. Epub 2008 Dec 24. PMID:19109249 doi:http://dx.doi.org/10.1074/jbc.M808114200
  4. ↑ Fukunari A, Okamoto K, Nishino T, Eger BT, Pai EF, Kamezawa M, Yamada I, Kato N. Y-700 [1-[3-Cyano-4-(2,2-dimethylpropoxy)phenyl]-1H-pyrazole-4-carboxylic acid]: a potent xanthine oxidoreductase inhibitor with hepatic excretion. J Pharmacol Exp Ther. 2004 Nov;311(2):519-28. Epub 2004 Jun 9. PMID:15190124 doi:10.1124/jpet.104.070433
  5. ↑ 5.0 5.1 Okamoto K, Eger BT, Nishino T, Kondo S, Pai EF, Nishino T. An extremely potent inhibitor of xanthine oxidoreductase. Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition. J Biol Chem. 2003 Jan 17;278(3):1848-55. Epub 2002 Nov 5. PMID:12421831 doi:10.1074/jbc.M208307200
  6. ↑ Truglio JJ, Theis K, Leimkuhler S, Rappa R, Rajagopalan KV, Kisker C. Crystal structures of the active and alloxanthine-inhibited forms of xanthine dehydrogenase from Rhodobacter capsulatus. Structure. 2002 Jan;10(1):115-25. PMID:11796116
  7. ↑ 7.0 7.1 Okamoto K, Matsumoto K, Hille R, Eger BT, Pai EF, Nishino T. The crystal structure of xanthine oxidoreductase during catalysis: implications for reaction mechanism and enzyme inhibition. Proc Natl Acad Sci U S A. 2004 May 25;101(21):7931-6. Epub 2004 May 17. PMID:15148401 doi:10.1073/pnas.0400973101

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