Xanthine oxidase structure

A set of 4-amino-3-aryltriazoles, each one further substituted by a 5-amide, -ester, or -nitrile group, inhibited these enzymes adenosine deaminase, guanine deaminase, and xanthine oxidase. Structure-action relationships were discussed (79MI1 85FES73). 

Enroth, C., Eger, B. T, Okamoto, K., Nishino, T, Nishino, T., Pai, E. F. (2000). Crystal structures of bovine miUc xanthine dehydrogenase and xanthine oxidase structure-based mechanism of conversion. Proceedings of the National Academy of Sciences of the United States of... 

Xanthine anions structure, 5, 509 Xanthine-8-carboxylic acid synthesis, 3, 308, 322 Xanthine oxidase... 

At the present time, the greatest importance of covalent hydration in biology seems to lie in the direction of understanding the action of enzymes. In this connection, the enzyme known as xanthine oxidase has been extensively investigated.This enzyme catalyzes the oxidation of aldehydes to acids, purines to hydroxypurines, and pteridines to hydroxypteridines. The only structural feature which these three substituents have in common is a secondary alcoholic group present in the covalently hydrated forms. Therefore it was logical to conceive of this group as the point of attack by the enzyme. 

Romao MJ, Huber R (1998) Structure and Function of the Xanthine-Oxidase Family of Molybdenum Enzymes. 90 69-96 Rosenzweig A, see Penneman RA (1973) 13 1-52... 

The three known crystal structures of molybdopterin-containing enzymes are from members of the first two families the aldehyde oxido-reductase from D. gigas (MOP) belongs to the xanthine oxidase family (199, 200), whereas the DMSO reductases from Rhodobacter (R.) cap-sulatus (201) and from/ , sphaeroides (202) and the formate dehydrogenase from E. coli (203) are all members of the second family of enzymes. There is a preliminary report of the X-ray structure for enzymes of the sulfite oxidase family (204). 

The aldehyde oxidoreductase from Desulfovibrio gigas shows 52% sequence identity with xanthine oxidase (199, 212) and is, so far, the single representative of the xanthine oxidase family. The 3D structure of MOP was analyzed at 1.8 A resolution in several states oxidized, reduced, desulfo and sulfo forms, and alcohol-bound (200), which has allowed more precise definition of the metal coordination site and contributed to the understanding of its role in catalysis. The overall structure, composed of a single polypeptide of 907 amino acid residues, is organized into four domains two N-terminus smaller domains, which bind the two types of [2Fe-2S] centers and two much larger domains, which harbor the molybdopterin cofactor, deeply buried in the molecule (Fig. 10). The pterin cofactor is present as a cytosine dinucleotide (MCD) and is 15 A away from the molecular surface,... 

These structural data are in agreement and support EXAFS data for MOP (214) as well as for xanthine oxidase (in both oxidized and reduced forms) (198, 215), but the coordinated water ligand was iden-... 

Molybdopterin is a component of four enzyme families all of which contain Mo(VI) the xanthine oxidase and the sulfite oxidase families with one molybdopterin and the DMSO family with two molybdopterins. There are a number of tungsten-containing enzymes with structures analogous... 

In addition to these more-or-less well characterized proteins, iron is known to be bound to certain flavoproteins such as succinic dehydrogenase (20), aldehyde oxidase (27), xanthine oxidase (22) and dihydrooro-tate dehydrogenase (23). Iron is present and functional in non-heme segments of the electron transport chain but again no real structural information is at hand (24). 

Most in vitro studies of xanthines have centered around the enzyme xanthine oxidase. Bergmann and co-workers 40-4)) have examined the main oxidative pathways in the xanthine oxidase catalyzed oxidation of purines. The mechanism proposed by these workers 41 > is that the enzyme binds a specific tautomeric form of the substrate, regardless of whether or not that form represents the major structure present in solution. It is then proposed that the purine, e.g., xanthine, undergoes hydration at the N7=C8 double bond either prior to or simultaneously with dehydrogenation of the same position. Accordingly, the process would involve either pathway a or b. Fig. 15. Route a would give a lactim form of the oxidized purine, while b would give the cor-... 

The source of free radicals is multiplied under these circumstances, arachidonic acid metabolism, activation of xanthine oxidase, perturbation of electron flow within the respiratory chain, and NOS activation. Structurally, excitotoxicity is generally described as a necrotic process involving initial swelling of the cell and of the endoplasmic reticulum, clumping of chromatin, followed by swelling of the... 

The ability of flavonoids (quercetin and rutin) to react with superoxide has been shown in both aqueous and aprotic media [59,94]. Then, the inhibitory activity of flavonoids in various enzymatic and nonenzymatic superoxide-producing systems has been studied. It was found that flavonoids may inhibit superoxide production by xanthine oxidase by both the scavenging of superoxide and the inhibition of enzyme activity, with the ratio of these two mechanisms depending on the structures of flavonoids (Table 29.4). As seen from Table 29.4, the data obtained by different authors may significantly differ. For example, in recent work [107] it was found that rutin was ineffective in the inhibition of xanthine oxidase that contradicts the previous results [108,109], The origins of such big differences are unknown. 

Huber R, Hof P, Duarte RO, et al. A structure-based catalytic mechanism for the xanthine oxidase family of molybdenum enzymes. Proc Natl Acad Sci USA 1996 93( 17) 8846—8851. 

Figure 17.2 The structure of the pterin cofactor (1) which is common to most molybdenum- and tungsten-containing enzymes and schematic active site structures for members of the xanthine oxidase (2,3), sulfite oxidase (4) and DMSO reductase (5-7) enzyme families. (From Enemark et al., 2004. Copyright (2004) American Chemical Society.)...

The amino groups are replaced with oxygen. Although here a biochemical reaction, the same can be achieved under acid-catalysed hydrolytic conditions, and resembles the nucleophilic substitution on pyrimidines (see Section 11.6.1). The first-formed hydroxy derivative would then tautomerize to the carbonyl structure. In the case of guanine, the product is xanthine, whereas adenine leads to hypoxanthine. The latter compound is also converted into xanthine by an oxidizing enzyme, xanthine oxidase. This enzyme also oxidizes xanthine at C-8, giving uric acid. 

X-ray crystallography, 40 20-21 synthetic models, 40 23-48 xanthane oxidase, 40 21-23 chalcogenide halides, 23 370-377, 413 Chevrel phases, 23 376-377 metal-metal bonding, 23 330, 373 structural data, 23 373-376 as superconductors, 23 376 synthesis, 23 371-372 chloride, 46 4-24, 35-44 heterocations of, 9 290, 291 cluster compounds, 44 45-46 octahedral, 44 47-49, 53-63 electronic structure, 44 55-63 molecular structure, 44 53-54 synthesis, 44 47-49 rhomboidal, 44 75-82 solid-state clusters and, 44 66-72, 74-75, 80-82, 85-87 tetrahedral, 44 72-75 triangular, 44 82-87 cofactor, 40 2, 4-12 anaerobic isolation, 40 5 molybdopterin and, 40 4-8 reduced form, 40 12 synthesis, 40 8-12 xanthine oxidase, 45 60-63 complexes... 

Cos, P. et al., Structure-activity relationship and classification of flavonoids as inhibitors of xanthine oxidase and superoxide scavengers, J. Nat. Prod., 61, 71, 1998. 

The similarity in the pyrimidine ring of pteridines and pterins, especially to the purines adenine and guanosine, undoubtedly makes them good templates for inhibitor design as these examples show. Another enzyme for which inhibition by pteridines has been established is xanthine oxidase <1999BBA387>. In this case, the limitation on structure for inhibitors in the pteridine series was that there should be no substituent on C-7 and that the pteridines should be fully conjugated. The best inhibitors (ICso 0.1 xM) were 6-formylpterin and 6-hydroxylumazine. 

---