Conductor of your hormonal orchestra can suppress serious illness

Breaking new ground 5. jul 2021 3 min Associate Professor and Group Leader Nikos S. Hatzakis, Postdoctoral Fellow Simon Bo Jensen Written by Morten Busch

Illness is often caused by major or minor imbalances in the body. Restoring balance, however, is seldom simple, since you have to precisely adjust one of the thousands of signals – without switching everything off completely. Now researchers have found and learned to manipulate one of the conductors of the body’s orchestra, which controls not just one but many signals that control metabolism at once. By instead altering the conductor’s activity, the researchers can control several of the body’s instruments at once, helping in treating disorders such as prostate cancer and infertility.

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The conductor of an orchestra often makes minor adjustments to tempo and volume to control the musicians. Some need to play faster; others just need to calm down a bit. The body does the same things when it needs to adjust its metabolism. The body is not either on or off but constantly in adjustment so that the body’s orchestra does not play off key, resulting in illness. Researchers have closely studied one of the body’s conductors to learn how to get the body to function again when some of its key mechanisms fail.

“One key cellular conductor, P450 oxidoreductase (POR), selectively controls more than 50 of the human body’s instruments and more than 300 in plants. Using fluorescence measurements, we found that POR is a pharmaceutical target and found three molecules that can bind to POR and thus affect how the conductor controls the body’s orchestra – and thereby can prevent illness from developing. Our ambition in our further research is to discover molecules that can effectively combat disorders such as prostate cancer and infertility,” explains Simon Bo Jensen, Postdoctoral Fellow, Department of Chemistry, University of Copenhagen.

Breaks down drugs in the liver

POR has been known for almost 50 years. Its most important function was previously thought to be as an electron donor in many reactions in cells in humans and in plants. However, recent research has revealed that POR does not merely behave randomly around the electrons.

“Previous results began to show that POR may be selective as an electron donor and in activating other processes. The fact that it is not just a random electron donor but one with specificity made me consider that POR could be a very important pharmaceutical target if we could also selectively influence the individual processes. So a goal of our study was to determine whether we could identify molecules that could influence POR to activate different processes,” explains Nikos S. Hatzakis, Associate Professor and Group Leader, Nano-Science Center, University of Copenhagen who led the study.

POR donates electrons and selectively activates several cytochrome P450 enzymes (CYPs), which in turn control and conduct or regulate many hormones and break down medicine in the liver. In plants, the enzymes are equally important, for example in biosynthesizing natural products and defence compounds in plants. Nevertheless, the mechanisms underlying POR control are not well understood.

“When we started, we still did not know that POR can be targeted by small molecules or the identity of any of the molecules that can regulate the specificity of POR. We therefore developed a method, based on machine learning, to screen for small molecules that can bind to POR, thereby regulating the creation of certain hormones or helping to break down certain drugs in the liver. We thus found three molecules that bind to and activate POR,” says Nikos S. Hatzakis.

Adjusting up and down instead of switching off

Combining computational modelling and functional assays enabled the researchers to discover the three molecules among thousands of candidates such as existing drugs. The researchers used a technique called fluorescence resonance energy transfer (FRET) to determine how the selected small molecules bound to POR can control how POR activates other enzymes. FRET also enabled them to determine whether POR changes shape when the small molecules bind.

“Our theory is that the small molecules cause POR to change shape slightly and that the shape of POR influences mechanisms in the cell. So, POR is exactly like the conductor of an orchestra who directs the musicians. Imagine a violin that controls testosterone levels, a saxophone that affects cholesterol levels, and a cello that is implicated in cancer. We can direct them now,” explains Nikos S. Hatzakis.

Examples of disorders the researchers potentially believe can be treated are elevated cholesterol and imbalance in sex hormones, which can lead to infertility but also to diseases such as prostate cancer.

“People with prostate cancer typically have trouble regulating a specific P450 protein called CYP17. With our new method, we can design a molecule that can bind to POR and regulate CYP17 without affecting the other P450 proteins. We may therefore be able to treat diseases such as prostate cancer much more effectively and avoid serious side-effects,” says Simon Bo Jensen.

Two of the molecules the researchers found are already being used in medicines today, and the third is a natural product, dhurrin, derived from the sorghum plant. The hope is that these three molecules can pave the way for designing more molecules that are even more effective in preventing or treating diseases. It may also pave the way for personalised plants producing high-value pharmaceuticals targeting metabolic diseases, a direction on which the collaborating groups of this publications will continue to work.

“By using artificial intelligence to sort data on hundreds of molecules, we can investigate which molecules bind to the POR conductor, enabling us to control its operations as required,” concludes Simon Bo Jensen.

Biased cytochrome P450-mediated metabolism via small-molecule ligands binding P450 oxidoreductase” has been published in Nature Communications. Nikos S. Hatzakis is affiliated with the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen. The Novo Nordisk Foundation awarded co-author Birger Lindberg Møller a Distinguished Grant and an Interdisciplinary Synergy grant for the research. The Foundation awarded scholarships to co-authors Tomas Laursen and Rita Del Giudice.

Nikos Hatzakis' main research interest is to obtain a fundamental understanding of the parameters underlying regulation of protein function and how ab...

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