Molybdenum enzymes xanthine oxidase

Of the mammalian enzymes, the sulphite oxidase of bovine liver has only recently been discovered to contain molybdenum (15). The better known molybdenum enzymes, xanthine oxidase from cows milk (31) and aldehyde oxidase from rabbit liver (16) are closely related to one another as they are to the xanthine dehydrogenases from chicken liver (17) and from bacteria (18). 

Of experimental methods for studying the metal in enzymes, light absorption in the visible region from molybdenum chromophores is likely to be weak and frequently masked by stronger absorption from other enzyme constituents. Indeed only recently has a small molybdenum contribution to the absorption spectrum of even the most studied of these enzymes, xanthine oxidase, been demonstrated 33, see Section V F). 

Molybdenum (Mo) is present in all plant, human, and animal tissues, and is considered an essential micronutrient for most life forms (Schroeder et al. 1970 Underwood 1971 Chappell and Peterson 1976 Chappell et al. 1979 Goyer 1986). The first indication of an essential role for molybdenum in animal nutrition came in 1953 when it was discovered that a flavoprotein enzyme, xanthine oxidase, was dependent on molybdenum for its activity (Underwood 1971). It was later determined that molybdenum is essential in the diet of lambs, chicks, and turkey poults (Underwood 1971). Molybdenum compounds are now routinely added to soils, plants, and waters to achieve various enrichment or balance effects (Friberg et al. 1975 Friberg and Lener 1986). 

The inhibition of enzyme systems dues nut necessarily cause unwarned effects. Consider the enzyme xanthine oxidase. It contains two atoms of molybdenum, four Fe2S2, and two FAD (flavin adenine dinucleotidei moieties, and it has a molecular weight of 275.000-300.000. There is no evidence that the two units (Mo/SFe Sj/FAD) are near each other or interact in any way. It is believed that the immediate environment of each molybdenum atom consists of one oxygen and three sulfur atoms (additional ligands may be present) 12... 

Restriction of the molybdenum intake by young rats in a synthetic purified casein diet results in a decreased level of tissue, particularly small intestinal, xanthine oxidase. The enzyme levels arc rest tired to normal by the inclusion of sodium molybdate and other molybdate compounds. Sodium tungstate is a competitive inhibitor of molybdate, and dietary intakes of tungstate greatly reduce the molybdenum and xanthine oxidase concentrations in tissues. 

General Considerations. Much experimental information is available concerning the role of molybdenum in xanthine oxidase (19, 20). In early work (prior to 1970), there was much confusion in the literature because of the presence of various inactive forms of the enzyme. It is now known that both demolybdo and desulfo forms of xanthine oxidase were present in most early preparations and remain present in many current preparations as well (20, 64). 

Coughlan, M. P., Rajagopalan, K. V., and Handler, P., 1969, The role of molybdenum in xanthine oxidase and related enzymes. Reactivity with cyanide, arsenite, and methanol, J. Biol. Chem. 244 2658112663. 

Turner, N. A., Bray, R. C., and Diakun, G. P., 1989, Information from e.x.aT.s. spectroscopy on the structures of different forms of molybdenum in xanthine oxidase and the catalytic mechanism of the enzyme, Biochem. X 260 563n571. 

Xanthine dehydrogenase The enz)une is used in the catabolism of the purine ring. It catalyzes the NAE>-dependent oxidation of xanthine to uric acid. The enzyme also contains FAD and molybdenum. A fraction of the enzyme normally occurs in the body as xanthine oxidase, which represents an altered form of the enzyme. Xanthine oxidase uses O2 as an oxidant, rather than NAD. Xanthine oxidase converts xanthine to uric acid, and O2 to HOOH and the hydroxyl radical. 

In general, molybdenum and its compounds are considered to be of low toxicity to humans however, molybdenum dust and fumes can cause irritation of the eyes, nose, throat, and respiratory tract. The trioxide and ammonium molybdate are more toxic than the ore molybdenite, the metal or the dioxide. It is not irritating to the skin, and is not a sensitizer. Mild cases of molybdenosis may be clinically identifiable only by biochemical changes (e.g., increases in uric acid levels due to the role of molybdenum in the enzyme xanthine oxidase). Excessive intake of molybdenum causes a physiological copper deficiency, and conversely, in cases of inadequate dietary intake of copper, molybdenum toxicity may occur at lower exposure levels. 

Other oxidoreductases that can play a major or less important role in drug metabolism are hemoglobin, monoamine oxidases (EC 1.4.3.4 MAO-A and MAO-B), which are essentially mitochondrial enzymes, the cytosolic molybdenum hydroxylases (xanthine oxidase, EC 1.1.3.22 xanthine dehydrogenase, EC 1.1.1.204 and aldehyde oxidase, EC 1.2.3.1), d the broad group of copper-containing amine oxidases (EC 1.4.3.6) (36-39). 

The biosynthesis of uric acid from the immediate purine precursor xanthine that results from adenine, via the intermediate hypoxanthine, or from guanine is illustrated in Figure 36.32. The enzyme xanthine oxidase (a molybdenum hydroxylase enzyme) is involved in two steps, the conversion of hypoxanthine to xanthine, and the final step, the conversion of xanthine to uric acid. Allopurinol originally was designed... 

The importance of coordination in the biochemistry of essential metallic elements may be illustrated by numerous examples of metal complexes of which the following are representative the iron complex hemoglobin and numerous enzymes containing the heme and related structures such as catalases, peroxidases and cytochromes and the iron-containing proteins ferritin, transferrin, and hemosiderin the zinc complexes zinc-insulin, carbonic anhydrase and the carboxypeptidases the cobalt complex vitamin B12 the copper complex, ceruloplasmin the molybdenum-containing enzymes, xanthine oxidase, and nitrate reductase DNA-metal ion complexes. 

Although the essential role of molybdenum in plants is well known, the essentiality of this element in man is less well established. Evidence that molybdenum is an essential trace element is based on the facts that it is part of the molecular structure of two enzymes, xanthine oxidase (involved in the oxidation of xanthine to uric acid) and aldehyde oxidase (involved in the oxidation of aldehydes... 

There are some molybdenum-containing enzymes, e.g. nitrogenase, with clearly defined and obviously vital biological roles and other such enzymes with much more nebulous roles. From a mechanistic point of view all molybdenum enzymes seem closely related to one another (Stiefel, 1973). Even so, it is perhaps a little unfortunate that the enzyme xanthine oxidase, which has proved to be the most amenable to study by EPR of molybdenum and is thus the enzyme whose catalytic mechanism is the best understood, is also the enzyme whose biological role is the least clear. 

Molybdenum has an essential function in the following enzymes xanthine oxidase, aldehyde oxidase, nitrate reductase, and nitrogenase. In all of these it seems, on the basis of the electron spin resonance spectrum, to be bound to sulphur and to undergo the valency change iron is usually present as well. Molybdenum is essential for nitrogen fixation, by the various species of Rhizobium and Azotobacter in plant root nodules. 

Complexes of molybdenum and tungsten with bidentate sulfur ligands have been investigated extensively. In recent years, the work in this field has been escalated by the impetus of designing models of such bioinorganic enzymes as nitrogenase and xanthine oxidase (125). The early work reviewed by Coucouvanis (1) dealt exclusively with the isolation of oxomolybdenum(V) and -(VI) species. 

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 enzymes that utilize molybdenum can be grouped into two broad categories (1) the nitrogenases, where Mo is part of a multinu-clear metal center, or (2) the mononuclear molybdenum enzymes, such as xanthine oxidase (XO), dimethyl sulfoxide (DMSO) reductase, formate dehydrogenase (FDH), and sulfite oxidase (SO). The last... 

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