3zyv
From Proteopedia
Crystal structure of the mouse liver Aldehyde Oxidase 3 (mAOX3)
Structural highlights
FunctionAOXC_MOUSE Oxidase with broad substrate specificity, oxidizing aromatic azaheterocycles, such as N1-methylnicotinamide and phthalazine, as well as aldehydes, such as benzaldehyde, retinal and pyridoxal. Plays a key role in the metabolism of xenobiotics and drugs containing aromatic azaheterocyclic substituents. Is probably involved in the regulation of reactive oxygen species homeostasis. May be a prominent source of superoxide generation via the one-electron reduction of molecular oxygen. May also catalyze nitric oxide (NO) production via the reduction of nitrite to NO with NADH or aldehyde as electron donor.[1] [2] [3] [4] Publication Abstract from PubMedBACKGROUND: Aldehyde oxidases have pharmacological relevance, and AOX3 is the major drug-metabolizing enzyme in rodents. RESULTS: The crystal structure of mouse AOX3 with kinetics and molecular docking studies provides insights into its enzymatic characteristics. CONCLUSION: Differences in substrate and inhibitor specificities can be rationalized by comparing the AOX3 and xanthine oxidase structures. SIGNIFICANCE: The first aldehyde oxidase structure represents a major advance for drug design and mechanistic studies. Aldehyde oxidases (AOXs) are homodimeric proteins belonging to the xanthine oxidase family of molybdenum-containing enzymes. Each 150-kDa monomer contains a FAD redox cofactor, two spectroscopically distinct [2Fe-2S] clusters, and a molybdenum cofactor located within the protein active site. AOXs are characterized by broad range substrate specificity, oxidizing different aldehydes and aromatic N-heterocycles. Despite increasing recognition of its role in the metabolism of drugs and xenobiotics, the physiological function of the protein is still largely unknown. We have crystallized and solved the crystal structure of mouse liver aldehyde oxidase 3 to 2.9 A. This is the first mammalian AOX whose structure has been solved. The structure provides important insights into the protein active center and further evidence on the catalytic differences characterizing AOX and xanthine oxidoreductase. The mouse liver aldehyde oxidase 3 three-dimensional structure combined with kinetic, mutagenesis data, molecular docking, and molecular dynamics studies make a decisive contribution to understand the molecular basis of its rather broad substrate specificity. The first mammalian aldehyde oxidase crystal structure: insights into substrate specificity.,Coelho C, Mahro M, Trincao J, Carvalho AT, Ramos MJ, Terao M, Garattini E, Leimkuhler S, Romao MJ J Biol Chem. 2012 Nov 23;287(48):40690-702. doi: 10.1074/jbc.M112.390419. Epub, 2012 Sep 27. PMID:23019336[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
Categories: Large Structures | Mus musculus | Coelho C | Garattini E | Leimkuehler S | Mahro M | Rodrigues D | Romao MJ | Terao M | Trincao J
