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Tuberculosis enzyme structure discovered

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Tuberculosis enzymes being studied by scientists can pave the way for discovering anti-tuberculosis drugs.

Scientists, mostly from the US Department of Energy's Argonne National Laboratory, were able to reveal the structures of a number of important tuberculosis enzymes, which could possibly pave a way to finding new drugs for the disease.

Tuberculosis is a relatively common disease, affecting about one third of the world's population, and is caused by the bacteria Mycobacterium tuberculosis. It is a very stubborn disease and treating it can actually take up to nine months. Because this bacteria has the ability to hide inside the body's cells, the immune system is not able to detect it, and it only waits for a good opportunity to multiply. Aside from that, it also is fast in acquiring resistance to antibiotics.

In order to find drugs that work against this microorganism, scientists need to browse through the myriad of proteins that bacteria possess and find one that is very important to this specific bacteria that it will not survive without it, and make a drug that particularly targets this protein.

One target that is being considered is IMPDH (inosine-5-monophosphate dehydrogenase), which is involved in a process inside bacterial cells that produces the guanine nucleotide, which is essential for both the production of DNA and RNA. It is a very important compound such that practically all living organisms have their own versions of it.

The IMDPH Enzyme

Andrez Joachimiak, an Argonne Distinguished Fellow, head of the Structural Biology Center, co-principal investigator at the Center for Structural Genomics of Infectious Diseases, and a corresponding author of the study says that What we discovered earlier this year is that the human and bacterial versions bind differently. This is very important for finding a molecule to build a drug around “ you don't want to inhibit a human enzyme, just the pathogen one.

Until now, scientists have been really interested in knowing the characteristics of the IMPDH enzyme, but unfortunately, most have been unsuccessful in acquiring adequate amounts of it for research analysis.

Joachimiak's team was able to observe that one part of the protein was quite wobbly and unstable, so they opted to modify it without that part using equipment from their Advanced Protein Characterization Facility and then determined the detailed structure of the protein using synchrotron protein crystallography at their Advanced Photon Source laboratory.

The version that they were able to produce has properties that are very similar to the original protein, but it is much easier to purify and crystallize for analysis.

Collaborators from Brandeis University and University of Minnesota Professor Lizbeth Hedstrom and Professor Courtney Aldrich, respectively, who are collaborators of the study, have been able to identify some inhibitor molecules that target IMPDH. These molecules may be a good basis for making a drug, but in the past, they were not able to image these molecules while interacting with the enzyme itself. But because of Joachimiak's modified version, they are now able to take images of these molecules while they are bound to IMPDH.

Another collaborator from the National Institute of Allergens and Infectious Diseases, Helena Boshoff, conducted complementary studies that were able to show that these inhibitors in fact did inhibit the growth of mycobacteria.
The newly discovered structures were deposited into the Protein Data Bank for further study.

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Written by: Yevgeny Aster Dulla, MSc