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click on the pictures at right for other research projects in the Burgmayer Research group

Moco icon...Ru icon

molybdenum cofactor modeling-- --ruthenium interactions with DNA

metal pterin icon .....Tri icon

metals & pteridines--- --molybdenum tris-dithiolenes--

Molybdenum enzymes

Molybdenum enzymes are described as ubiquitous because they have been isolated from organisms throughout the entire kingdom of life, from simple bacteria to humans. Conservation of the molybdenum enzymes through a billion years of evolution underscores their importance to the health of evolving organisms. It is now believed that the molybdenum enzymes are the chemical descendants of tungsten enzymes. This hypothesis is based on the discovery of tungsten enzymes in archaebacteria, the most ancient organisms, where these tungsten enzymes have structures and functions very similar to those of the molybdenum enzymes found in higher organisms, including humans. The selection of tungsten over molybdenum by the archaebacteria is, in hindsight, consistent with the biogeochemistry of the anaerobic prehistoric environment.
Molybdenum is an essential trace element for all higher organisms where molybdenum enzymes have a number of important roles in the health of these organisms. Molybdenum in nitrate reductase is required by all plants for proper nitrogen assimilation. Molybdenum in xanthine oxidase, sulfite oxidase and aldehyde oxidase is the functional center for these enzymes involved in the human diseases of gout, combined oxidase deficiency and radical damage following cardiac failure. Combined oxidase deficiency is a rare genetic disease responsible for such severe neurological disorder that infant children with this defect rarely survive. As a consequence of research directed at understanding the basis for this fatal disease, the tools of molecular biology and genetics have uncovered a link between one of the many proteins required to synthesize the molybdenum cofactor of these enzymes and a protein used in neuronal synapses. This illustrates how the biological impact of the molybdenum enzymes may reach beyond the limited context of their unique catalytic function.

for more information see: (1) Burgmayer, SJN Dithiolenes in Biology in Progress in Inorganic Chemistry . (2) Hille R. Chem. Reviews 1999
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the Molybdenum Cofactor  
  Molybdenum and the related tungsten enzymes are the only biological molecules to utilize the dithiolene as a metal liagnd. The dithiolene ligand bound to molybdenum in all molybdenum enzymes has been given the name molybdopterin. Shown below, the differently colored portions denote each of the key features in the structure: the dithiolene, the pterin and the pyran ring.  
The transition metal molybdenum, atomic number 42, is a crucial component of both natural and synthetic catalysts. In biological catalysis molybdenum has a wider and more important role where it occupies the catalytic site in over forty enzymes to enable oxidation and reduction reactions of a broad range of inorganic and organic substrates. Molybdenum is unique as the only second row transition metal element required in biological reactions. Molybdenum enzymes are described as ubiquitous because they have been isolated from organisms throughout the entire kingdom of life, from simple bacteria to humans. The conservation of the molybdenum enzymes during evolution underscores their importance to the health of evolving organisms. Molybdenum is an essential trace element for all higher organisms because molybdenum enzymes have a number of important roles for maintaining the health of these organisms. All plants require molybdenum in nitrate reductase for proper nitrogen assimilation. In humans, the molybdenum enzymes xanthine oxidase, sulfite oxidase and aldehyde oxidase are involved in the human diseases of gout, combined oxidase deficiency and radical damage following cardiac failure. In industrial catalysis, molybdenum is used by the petroleum refining industry in multiple hydrotreating processes. In both industrial and biological catalysts molybdenum is found in an environment including at least two, and typically more, sulfur atoms. Both molybdenum and sulfur exhibit an unusually wide range of formal oxidation states (+6 to -2) in their compounds and the reduction potentials needed to access these oxidation states have considerable overlap between Mo and S. The redox versatility of the molybdenum-sulfur partnership is clearly at the heart of their catalytic function.
The molybdenum cofactor as found in the enzyme sulfite oxidase.
 The Dithiolene. The dithiolene ligand, -S2C2RR’, is a bidentate chelating ligand attached to the metal by two sulfur atoms linked by a double bond. Dithiolenes have long been recognized to have highly delocalized, covalent interactions with transition metals. This electronic delocalization occurs because the frontier orbital energies of the metal and -S2C2RR’ ligand are similar. Two resonance structures can be drawn for for the -S2C2RR’ ligand when bound to a metal: 1) the dianionic ene-1,2-dithiolate form and 2) the neutral 1,2-dithioketone form. These two forms are related by a two-electron transfer between the reduced form of the ligand (ene-1,2-dithiolate) and the oxidized form (neutral 1,2-dithioketone) with a concommittent redox change at the metal. This redox flexibility is almost certainly a critical feature of the molybdopterin structure in the enzymes.
Pterins are molecules comprising a sub-class of pteridines. Pterins were the first members of the pteridine family to be structurally characterized. Their isolation from butterfly wings led to their unusual name (pterin) that has its root in the Greek word for ‘wing’, pteron. This common name was later modified to pteridine to represent the parent family. As an aid to remembering the pterin structure, note that pterin is structurally related to guanine.
Pteridines may be viewed as heterocyclic cousins of naphthalene. Their polar -C=N- bonds make the pteridine structure inherently reactive. Members of the pteridine family are key players in important biochemical reactions ranging from metabolism to catabolism. Except for those pteridines whose role is solely pigmentation, as in butterflies, all other systems make use of pteridine redox or their propensity for nucleophilic addition reactions. The familiar vitamin B2, folic acid, is a pterin substituted at the 6-position by a p-aminobenzoic acid esterified to mono- or polyglutamic acid groups. Folates refer more generally to the family of related structures including reduced forms (as tetrahydro and dihydro) and methylated structures. These are important molecules involved in methyl group transfer, often in conjunction with cobalamin, for protein biosynthesis.
Addition of a third, pyran, ring completes the construction of the pyranopterin ring system that is characteristic of all molybdenum and tungsten enzymes.		  
     
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