Molybdenum: Genetic Connections, Sulfur Metabolism, and Cofactor Deficiency

Key takeaways:
~ Molybdenum is an essential trace mineral that we get in small amounts through our diet.
~ As a cofactor, molybdenum is essential for the metabolism of sulfur-containing amino acids, breaking down purine, and the metabolism of certain medications.
~ A few common genetic variants mildly affect molybdenum-dependent enzymes, while rare mutations related to molybdenum can have a large effect size.

What is molybdenum used for in the body?

Molybdenum is a trace mineral that occurs naturally in foods and has a biological function in all forms of life. It’s especially important for metabolizing sulfur and in the formation of uric acid.[ref]

Molybdenum levels:

The RDA for molybdenum for adults is 45 mcg/day, and the upper limit is set at 2,000 mcg/day. Molybdenum deficiency is rare in the US and most developed nations since it is found in groundwater and food in most areas.[ref]

Epidemiological studies show that higher urinary molybdenum levels are associated with lower levels of gout and hyperuricemia.[ref] However, not all studies agree, and a very high level of molybdenum, such as from industrial exposure or high doses of supplementation, is also associated with gout. In addition, some epidemiological studies show that higher molybdenum levels are positively associated with metabolic syndrome.[ref] It is possible that both the lack of molybdenum and excess molybdenum could cause an increased risk of gout — the sweet spot may be a moderate amount for most people.

Molybdenum as a cofactor:

Molybdenum is used by the body as a cofactor for several key enzymes:[ref]

• Xanthine oxidase (XDH)– an enzyme that breaks down purines, which are metabolized to form uric acid
• Sulfite oxidase (SUOX) – an enzyme that breaks down sulfur-containing amino acids in the body.
• Aldehyde oxidase (AOX1)  – a molybdenum-based enzyme that catalyzes the reactions converting aldehydes into carboxylic acids
• Mitochondrial amidoxime reducing component (MARC1) – an enzyme that is involved in the reduction of N-hydroxylated compounds found in certain medications.
• Molybdenum cofactor synthesis (MOCS1-3) – a family of genes necessary for creating the molybdenum cofactor used in other molybdenum-dependent enzymes

Let’s take a look at each of these enzymes in a little more depth.

Xanthine Oxidase (XDH gene):

Xanthine oxidase is a molybdenum-dependent enzyme that catalyzes the final step of the process for breaking down purines into uric acid. Under some circumstances, it can also produce superoxide ions (reactive oxygen species).

Excess uric acid increases the risk of gout, and multiple studies have investigated whether higher or lower molybdenum levels can increase or decrease uric acid.

A large study published in 2024 found that higher urinary molybdenum levels, indicating more molybdenum in the diet, are associated with decreased uric acid levels and a lower risk of gout. In addition, higher urinary molybdenum levels were associated with lower levels of oxidative stress and lower CRP. Molybdenum was shown to upregulate MnSOD, an endogenous antioxidant.[ref]

Related article: Uric acid and gout risk factors

Sulfite (sulphite) oxidase (SUOX gene):

Sulfite oxidase converts sulfite from foods to sulfate. It is also the final step in breaking down sulfur-containing amino acids such as cysteine and methionine. The molybdenum molecule at the center of the enzyme is central to catalyzing the redox reaction.[ref]

Keep in mind when reading about sulfur compounds:
Sulfite – toxic; sulfate – useful in the body

Rare mutations in the SUOX gene cause isolated sulfite oxidase deficiency (ISOD). This is a genetic condition that is diagnosed within a few days of birth and causes profound effects, including encephalopathy, seizures, and feeding difficulties. Mutations in the SUOX gene that prevent the breakdown of sulfites cause toxic metabolites to accumulate in the infant’s body. Prognosis is not good.[ref][ref]

Aldehyde oxidase:

Aldehyde oxidase is important in the oxidation of aldehydes and kinase inhibitors, the hydrolysis of amines, and the reduction of N- and S-oxides. Pharmaceutical companies are very interested in the role of aldehyde oxidase because it can change the way certain medications are metabolized or how drugs interact.[ref][ref]

The AOX1 gene encodes aldehyde oxidase. Examples of aldhyde reactions include the conversion of retinal (vitamin A aldehyde) to retinoic acid as well as breaking down and detoxifying the aldehydes produced in dopamine and serotonin metabolism.

Molybdenum cofactor sulfurase (MOCOS):

Encoded by the MOCOS gene, molybdenum cofactor sulfurase transfers sulfur to xanthine dehydrogenase and aldehyde oxidase to activate the enzymes.[ref] A reduced expression of MOCOS allows for a hypersensitivity to oxidative stress during brain development. A couple of studies show that lower MOCOS expression could be involved in autism spectrum disorder.[ref][ref][ref]

Molybdenum cofactor deficiency (MOCS): Rare genetic mutations

The molybdenum cofactor complex is essential for the proper function of several enzymes, including sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase, that utilize molybdenum as a cofactor.

Molybdenum Cofactor Deficiency is a rare genetic disorder caused by mutations in one of the genes involved in the molybdenum cofactor complex.[ref] These genes include:

• MOCS1 (Molybdenum Cofactor Synthesis 1) – encodes the first step of molybdenum cofactor synthesis
• MOCS2 (Molybdenum Cofactor Synthesis 2) – involved in the second step of molybdenum cofactor synthesis
• GPHN – final step of molybdenum cofactor synthesis.
• MOCS3 (Molybdenum Cofactor Synthesis 3)

Deficiency of these molybdenum cofactor synthesis enzymes leads to the accumulation of toxic metabolites, causing severe neurological damage and other systemic effects.

Note that these are really rare conditions that are detected in infancy. Symptoms can include seizures, developmental delay, lens dislocation, and microcephaly. The prognosis is usually not good.

Lifehacks:

Let’s take a look at safety first and then at dietary and supplement sources of molybdenum.

Molybdenum toxicity, effect on fertility:

The tolerable upper limit of molybdenum intake is set at 2,000 mcg/day (2mg/day). In animals, excess molybdenum can cause copper deficiency, but this hasn’t been seen in humans. Older studies in humans show that a very high intake (10 – 15 mg/day) increases uric acid.

Most studies show no negative effects from molybdenum. However, animal studies show that high molybdenum can negatively affect testosterone and sperm quality. Epidemiological studies also show that higher molybdenum levels are associated with lower testosterone levels in men.[ref][ref][ref]

Dietary sources of molybdenum:

Foods high in molybdenum include legumes (red beans, mung beans, peanuts), grains, pumpkin seeds, and nuts. The amount of molybdenum in food depends on the level of molybdenum in the soil or in the fertilizer.

Mineral water and well water can also contain molybdenum, depending on the mineral content in the soil. It varies quite a bit from location to location.[ref]

Molybdenum is absorbed in the intestines through a passive process (no transporter), and adults generally absorb half or more of dietary molybdenum. The kidneys then excrete out any excess.

In animals, higher molybdenum intake can cause copper deficiency, but that isn’t directly seen in humans except in cases of Wilson’s disease.[ref]

Supplemental Molybdenum:

Supplements containing molybdenum are readily available and come in doses ranging from 50 mcg to 1000 mcg. Please talk with your doctor or a nutritionist about whether supplementing is needed. Most people get all that they need from their diet.

Studies on molybdenum show that up to 60% of dietary molybdenum is excreted in the urine, and over 90% is excreted at higher intake levels (e.g., >467 μg/day).[ref]

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