Vitally Important for Life – How Does Molybdenum Become Biologically Active? Mechanism of the molybdenum insertase elucidated

The metal molybdenum is commonly known to be an important amendment in engineering and is e.g. found in steel or motor oils. However next to this, it likewise possesses an important biological function: In the cell, molybdenum is part of the so-called molybdenum cofactor. Mutations in the enzyme molybdenum insertase, which catalyzes the ultimate step of molybdenum cofactor biosynthesis, are lethal for the affected patients. A team of scientists of Technische Universität Braunschweig led by Dr. Tobias Kruse has now discovered how the molybdenum insertase incorporates molybdenum into the molybdenum cofactor, thus providing the basis for a therapeutic approach to compensate missing molybdenum insertase activity. This work has now been published in the journal Nature Chemistry.

The molybdenum cofactor assembles from an organic and an inorganic component i.e. molybdenum. While the biosynthesis of the organic component is well characterized, as yet it was an open question how molybdenum is “incorporated” into the organic component.

To reveal the principles behind this reaction, the scientists in Dr. Tobias Kruse’s team at Technische Universität Braunschweig initially established a hypothesis based working model considering primarily a single patient mutation in the molybdenum insertase which results in its catalytic inactivity. As a consequence of this mutation, the metal molybdenum can no longer made available to the cell in the form of the molybdenum cofactor. Affected patients develop epilepsy-like seizures on average within 24 hours after birth. Subsequently, massive neuronal cell death occurs which ultimately leads to the death of affected individuals at an average age of three years. This disease is known as molybdenum cofactor deficiency and has so far been difficult to treat.

The “reconstruction” of the mutation in the patient’s defective molybdenum insertase was then the basis for the subsequent research work for Dr. Tobias Kruse and his colleagues. Together with collaboration partner Professor Douglas C. Rees at the California Institute of Technology (USA), the protein structure of the molybdenum insertase was elucidated, leading to the discovery of a new, previously unknown step in the molybdenum cofactor biosynthesis pathway. In cooperation with Prof. Martin L. Kirk (Department of Chemistry and Chemical Biology, The University of New Mexico, Albuquerque, USA) finally the mechanism of molybdenum insertion was deciphered.

Roughly 20 years ago, the mechanism of molybdenum insertion was already described, however for the synthesis of artificial molybdenum model compounds. These truly non biological compounds, mimic Moco´s chemical properties “in the test tube”. The researchers have now shown for the first time that the final step of molybdenum cofactor biosynthesis in the cell follows the same scheme as the synthesis of molybdenum model compounds in the chemistry laboratory suggesting that a single route exists by which molybdenum can be functionalized both in vivo and in vitro. It is now known that this mechanism underlies not only human but also plant and fungal molybdenum insertion. This indicates that this process originated very early in the evolution.

However, the most important aspect of this work has undoubtedly been named by one of the peer reviewers of the paper now published in Nature Chemistry: Knowing how molybdenum is functionalized – i.e. made biologically usable – in the cell, the foundations have now been laid for compensating for the lack of molybdenum insertase activity in affected patients. Suitable model compounds have already been and are being developed and synthesized in the group of Prof. Carola Schulzke (University of Greifswald) and are to be characterized in more detail at TU Braunschweig for applicability to therapy of molybdenum cofactor deficiency.