A new regulatory mechanism has been found for a key enzyme for cell division

 Researchers from the University of Salamanca published today in the journal Nature Communications an article that describes a new regulation mechanism of the IMP dehydrogenase enzyme, which is key to cell division. Scientists associate this finding with eye diseases such as retinitis pigmentosa, but also with cancer, since many antitumor drugs used today attack this enzyme.

Specifically, the enzyme IMP dehydrogenase regulates the production of nucleotides, which are the components of DNA and, if there are not enough nucleotides to replicate DNA, the cell cannot divide. For this reason, "nowadays it is one of the chemotherapeutic targets used in the treatment of cancer", explains to DiCYT José Luis Revuelta Doval, director of the Metabolic Engineering Group of the University of Salamanca and main author of the work together with Rubén Martínez -Bow, both professors of the Department of Microbiology and Genetics.

Some of the drugs with antitumor, immunosuppressive or antiviral activity that are currently used are based on preventing the production of nucleotides and, therefore, the division of cells, reducing the activity of this enzyme by mechanisms known for years. However, "we have discovered that the enzyme has another more sophisticated mechanism to regulate its activity and we have characterized it at the molecular level, elucidating the three-dimensional structure of the enzyme at atomic resolution," says Revuelta.

Scientists have discovered a direct implication of this new mechanism in certain retinopathies, such as retinitis pigmentosa (also called retinitis pigmentosa) or Leber's congenital amaurosis. These diseases are characterized by the progressive alteration of the photoreceptors of the retina, which ultimately leads to blindness. Some of the patients with retinitis pigmentosa or Leber congenital amaurosis have mutations in the IMP dehydrogenase enzyme, in such a way that it cannot regulate its activity through the mechanism now described. In this way, abnormal amounts of nucleotides are generated that, ultimately, mainly affect the cells of the retina and are the cause of said retinopathies.

Retinopathy treatments

Retinitis pigmentosa is the most common hereditary degeneration of the retina, it occurs in one in every 4,000 individuals, is suffered by more than a million and a half people worldwide and is one of the most important causes of blindness. For this reason, this discovery has a special relevance and the researchers from the University of Salamanca are already in contact with an Irish research group expert in retinopathies with which they hope to use this new information to search for possible treatments, using tests with animal models as well as human cell cultures.

Produce more vitamins B2 and B9 in microorganisms

Apart from its biomedical potential, this research also has biotechnological applications. As in human cells, dysregulation of the IMP dehydrogenase enzyme in certain microorganisms increases the production of nucleotides that are direct precursors of vitamins B2 and B9. Therefore, its genetic manipulation allows to generate mutants with an intentionally altered metabolism to produce more vitamins. “In this case, the goal is to remove the regulatory mechanism through genetic engineering to allow the enzyme to develop its full potential. In this way, we get the microorganisms to reprogram their metabolism to increase the production of vitamins, which is very interesting for the food industry ”, indicates Revuelta.

Two other groups from Salamanca have also participated in this study, the Structural Biology Unit of the Cancer Research Center (CIC, mixed center of the CSIC and the University of Salamanca) and the Department of Abiotic Stress of the Institute of Natural Resources and Agrobiology of Salamanca (IRNASA, CSIC); in addition to the National Center for Biotechnology (CNB, CSIC) and the Institute of Biocomputation and Physics of Complex Systems of the University of Zaragoza.