May. 19, 2020
AUSTIN, Texas —Santiago Toledo, associate professor of Chemistry at St. Edward’s University, has received a three-year, $330,602 National Institutes of Health (NIH) grant to study a metalloenzyme and the role it might play in the progression of cancer and other diseases.
This is the first individual grant from the National Institutes of Health to a St. Edward’s professor.
“Dr. Toledo's grant is the latest demonstration of what our researchers are capable of doing,” said Gary Morris, Dean of the School of Natural Sciences. “This new grant is enhancing a research program that has supported more than 300 undergraduates with more than $1 million of support over the last four summers. It is part of what makes St. Edward’s such a great place for students to pursue STEM degrees.”
One reason the NIH selected Toledo’s grant proposal is because scientists are starting to find some correlations between the presence of the enzyme, called acireductone dioxygenase (ARD), and certain cancer types. The enzyme’s function and mechanism of action is still an active subject of investigation, and Toledo’s grant proposal has this as one of its main scientific aims.
One of the study’s goals is to expand the availability of biomimetic molecular model compounds to explain how ARD operates. These models explore how the reactivity, or path, of the enzyme works and what kind of products develop because of it.
“We think that we have something to say about how this enzyme might be impacting cancer types or disease in general,” Toledo said. “By understanding the mechanism of function of the enzyme, we’re hoping to better understand how the enzyme is actually influencing disease states. And if scientists understand that better, then treatments could be derived from there.”
When Toledo started this project at St. Edward’s in 2015, he learned that ARD was understudied by the scientific community. The novelty and unique metal dependent functions of the enzyme intrigued him.
At the time, very little was known about the role of this enzyme in mammals. That changed in 2014, when another lab discovered that the enzyme can be expressed in mammalian cells. This finding led to more questions at the biochemistry level about how the enzyme is involved in disease, Toledo said.
Explaining what the research involves, Toledo says he and his researchers do not work with the enzyme itself. Instead, they work with model molecular compounds similar to the active-site of the enzyme — or what is called biomimetic chemistry because it mimics the biological systems. The problem is that there are still very few models that are accurate and able to describe how the ARD enzyme functions.
In 2018, Toledo and his undergraduate students — Denisa Ivan, Alexander Gremillion, Anthony Sanchez, and Servando Sanchez — published an article that introduced the first structural model for the enzyme.
They expect a second article related to this work to be published soon, also co-authored by students at St. Edward’s.
The NIH grant funding will allow Toledo and his undergraduate team to come up with compounds to model the enzyme that is found in mammalian cells. First, they will wrap up work on a family of nickel-based acireductone dioxygenase model compounds and then move on to three human-relevant metals — manganese, cobalt and iron. One of the unique traits of ARD is that metals can be exchanged in the enzyme causing different reactivity.
“Every compound that I presented in this grant proposal, every idea generated came from the work that my students have done, and every result that will get done in the future will also come from work done with undergraduates in our lab,” he said.
In addition to student researchers, Toledo assembled a set of collaborators and mentors from The University of Texas at Austin, University of North Texas, Baylor University, and Trinity University to provide scientific expertise, access to specialized equipment, and guidance through the duration of the project.
While Toledo is excited to be able to shed light on the enzyme’s functioning, he says he is already proud of the work that he and his students have achieved.
“It really shows that high-quality research that’s valued by the scientific community can be done at a primarily undergraduate institution like St. Edward’s with students that are, in some cases, just starting their training in Chemistry,” Toledo said.
What is Oxygenase and what does it do? Oxygenases are a sub-set of metalloenzymes that are capable of inserting oxygen into substrate molecules. Enzymes transform such molecules. The transformation this enzyme catalyzes is the insertion of an oxygen molecule into another molecule, breaking it apart. Dioxygenases means the insertion of two oxygen atoms into molecules.