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Molybdenum-bearing enzymes are by far the most common bacterial catalysts for breaking the chemical bond in atmospheric molecular nitrogen in the process of biological nitrogen fixation. At least 50 molybdenum enzymes are now known in bacteria and animals, although only bacterial and cyanobacterial enzymes are involved in nitrogen fixation. These nitrogenases contain molybdenum in a form different from other molybdenum enzymes, which all contain fully oxidized molybdenum in a molybdenum cofactor. These various molybdenum cofactor enzymes are vital to the organisms, and molybdenum is an essential element for life in all higher eukaryote organisms, though not in all bacteria.

Biological role


The most important role of molybdenum in living organisms is as a metal heteroatom at the active site in certain enzymes.[65][66] In bacterial nitrogen fixation, the nitrogenase enzyme involved in the terminal step of reducing molecular nitrogen usually contains molybdenum in the active site (though replacement of Mo with iron or vanadium is also known). The structure of the catalytic center of the enzyme is similar to that in iron-sulfur proteins: it incorporates a Fe4S3 and multiple MoFe3S3 clusters.[67]

The reaction that nitrogenase enzymes perform is:

{\displaystyle \mathrm {N_{2}+8\ H^{+}+8\ e^{-}+16\ ATP+16\ H_{2}O\longrightarrow 2\ NH_{3}+H_{2}+16\ ADP+16\ P_{i}} }

With protons and electrons from the electron transport chain, nitrogen is reduced to ammonia and free hydrogen gas. This is an energy-using process, requiring the splitting (hydrolysis) of ATP into ADP plus free phosphate (Pi).

In 2008, evidence was reported that a scarcity of molybdenum in the Earth's early oceans was a limiting factor for nearly two billion years in the further evolution of eukaryotic life (which includes all plants and animals). The chain of causation is as follows:[68]

  1. The relative lack of oxygen in the early ocean resulted in a scarcity in dissolved molybdenum. Most molybdenum compounds have low solubility in water, but the molybdate ion MoO42− is soluble and forms when molybdenum-containing minerals are in contact with oxygen and water.
  2. The lack of dissolved molybdenum limited the growth of prokaryotic nitrogen-fixing bacteria, which require molybdenum-bearing enzymes for the process
  3. The lack of prokaryotic nitrogen-fixing bacteria limited the growth of ocean eukaryotes, which require oxidized nitrogen suitable for the production of organic nitrogen compounds or the organics themselves (like proteins) from prokaryotic bacteria.[69][70][71]

However, once oxygen had been created in seawater by the limited eukaryotes, it reacted with water and the molybdenum in minerals on the sea bottom to produce soluble molybdate, making it available to nitrogen-fixing bacteria. Those bacteria provided fixed usable nitrogen compounds for higher forms of life.

Although oxygen once promoted nitrogen fixation by making molybdenum available in water, it also directly poisons nitrogenase enzymes. Thus, in Earth's ancient history, after oxygen arrived in large quantities in Earth's air and water, organisms that continued to fix nitrogen in aerobic conditions isolated and protected their nitrogen-fixing enzymes from too much oxygen in heterocysts or equivalent structures. This structural isolation of nitrogen fixation reactions in aerobic organisms continues to the present.

Skeletal structure of a molybdopterin with a single molybdenum atom bound to both of the thiolate groups

The molybdenum cofactor (pictured) is composed of a molybdenum-free organic complex called molybdopterin, which has bound an oxidized molybdenum(VI) atom through adjacent sulfur (or occasionally selenium) atoms. Except for the ancient nitrogenases, all known Mo-using enzymes use this cofactor.

Molybdenum cofactor enzymes

Though molybdenum forms compounds with various organic molecules, including carbohydrates and amino acids, it is transported throughout the human body as MoO42−.[72] At least 50 molybdenum-containing enzymes were known by 2002, mostly in bacteria, and the number is increasing with every year;[73][74] those enzymes include aldehyde oxidasesulfite oxidase and xanthine oxidase.[7] In some animals, and in humans, the oxidation of xanthine to uric acid, a process of purine catabolism, is catalyzed by xanthine oxidase, a molybdenum-containing enzyme. The activity of xanthine oxidase is directly proportional to the amount of molybdenum in the body. However, an extremely high concentration of molybdenum reverses the trend and can act as an inhibitor in both purine catabolism and other processes. Molybdenum concentration also affects protein synthesismetabolism, and growth.[72]

In animals and plants, a tricyclic compound called molybdopterin (which, despite the name, contains no molybdenum) is reacted with molybdate to form a complete molybdenum-containing cofactor called molybdenum cofactor. Other than the phylogenetically-ancient nitrogenases (discussed above) that fix nitrogen in some bacteria and cyanobacteria, all molybdenum-using enzymes (so far identified) use the molybdenum cofactor, where molybdenum is in the oxidation state of VI, similar to molybdate.[75] Molybdenum enzymes in plants and animals catalyze the oxidation and sometimes reduction of certain small molecules in the process of regulating nitrogensulfur, and carbon.[76]

Human dietary intake and deficiency

Molybdenum is a trace dietary element necessary for the survival of humans and the few mammals that have been studied.[77] Four mammalian Mo-dependent enzymes are known, all of them harboring a pterin-based molybdenum cofactor (Moco) in their active site: sulfite oxidasexanthine oxidoreductasealdehyde oxidase, and mitochondrial amidoxime reductase.[78] People severely deficient in molybdenum have poorly functioning sulfite oxidase and are prone to toxic reactions to sulfites in foods.[79][80] The human body contains about 0.07 mg of molybdenum per kilogram of body weight,[81] with higher concentrations in the liver and kidneys and in lower in the vertebrae.[36] Molybdenum is also present within human tooth enamel and may help prevent its decay.[82]

The average daily intake of molybdenum varies between 0.12 and 0.24 mg, depending on the molybdenum content of the food.[83] Pork, lamb, and beef liver each have approximately 1.5 parts per million of molybdenum. Other significant dietary sources include green beans, eggs, sunflower seeds, wheat flour, lentils, cucumbers and cereal grain.[7] Acute toxicity has not been seen in humans, and the toxicity depends strongly on the chemical state. Studies on rats show a median lethal dose (LD50) as low as 180 mg/kg for some Mo compounds.[84] Although human toxicity data is unavailable, animal studies have shown that chronic ingestion of more than 10 mg/day of molybdenum can cause diarrhea, growth retardation, infertility, low birth weight, and gout; it can also affect the lungs, kidneys, and liver.[83][85] Sodium tungstate is a competitive inhibitor of molybdenum. Dietary tungsten reduces the concentration of molybdenum in tissues.[36]

Low soil concentration of molybdenum in a geographical band from northern China to Iran results in a general dietary molybdenum deficiency, and is associated with increased rates of esophageal cancer.[86][87] Compared to the United States, which has a greater supply of molybdenum in the soil, people living in those areas have about 16 times greater risk for esophageal squamous cell carcinoma.[88]

Molybdenum deficiency has also been reported as a consequence of non-molybdenum supplemented total parenteral nutrition (complete intravenous feeding) for long periods of time. It results in high blood levels of sulfite and urate, in much the same way as molybdenum cofactor deficiency. However (presumably since pure molybdenum deficiency from this cause occurs primarily in adults), the neurological consequences are not as marked as in cases of congenital cofactor deficiency.[89]

Related diseases

A congenital molybdenum cofactor deficiency disease, seen in infants, is an inability to synthesize molybdenum cofactor, a heterocyclic molecule that binds molybdenum at the active site in all known human enzymes that use molybdenum. The resulting deficiency results in high levels of sulfite and urate, and neurological damage.[90][91]

Copper-molybdenum antagonism

High levels of molybdenum can interfere with the body's uptake of copper, producing copper deficiency. Molybdenum prevents plasma proteins from binding to copper, and it also increases the amount of copper that is excreted in urineRuminants that consume high levels of molybdenum suffer from diarrhea, stunted growth, anemia, and achromotrichia (loss of fur pigment). These symptoms can be alleviated by copper supplements, either dietary and injection.[92] The effective copper deficiency, can be aggravated by excess sulfur.[36][93]

Copper reduction or deficiency can also be deliberately induced for therapeutic purposes by the compound ammonium tetrathiomolybdate, in which the bright red anion tetrathiomolybdate is the copper-chelating agent. Tetrathiomolybdate was first used therapeutically in the treatment of copper toxicosis in animals. It was then introduced as a treatment in Wilson's disease, a hereditary copper metabolism disorder in humans; it acts both by competing with copper absorption in the bowel and by increasing excretion. It has also been found to have an inhibitory effect on angiogenesis, potentially by inhibiting the membrane translocation process that is dependent on copper ions.[94] This is a promising avenue for investigation of treatments for cancerage-related macular degeneration, and other diseases that involve a pathologic proliferation of blood vessels.[95][96]