Mechanism for hMTH1's broad substrate specificity revealed

March 29, 2017

Human MutT homolog 1 (hMTH1) protein acts as the primary enzyme for breaking down (hydrolyzing) damaged (oxidized) deoxynucleoside triphosphates (dNTPs) the substrates of DNA synthesis. Recently, hMTH1 has drawn attention as a popular target for new anticancer therapies because it is non-essential for normal cells, but cancer cells require it to avoid incorporating oxidized nucleotides into DNA, which would result in cancer cell death. Now, hMTH1 inhibitors are developed as anticancer drug candidates. Even though some reports argue against the usefulness of hMTH1 inhibition, highly potent and selective inhibitors of hMTH1, which would allow for the introduction of oxidized nucleotides into cancer cell DNA, are expected for future cancer treatment.

Enzymes are usually very particular about the material they catalyze (substrate). Some, however, can catalyze more than one substrate, and hMTH1 is known to hydrolyze several oxidized dNTPs. The reasons behind the broad substrate specificity had not yet been explored when researchers from Japan began considering the issue.

Scientists from Kumamoto University, the National Institutes for Quantum and Radiological Science and Technology, and Kyushu University performed structural and kinetic analyses on hMTH1 to determine the mechanisms behind its ability to hydrolyze various oxidized mutagenic dNTPs, such as 8-oxo-dGTP and 2-oxo-dATP, with similar efficiency. Their experiments found evidence that the protonation state between the aspartate residues Asp-119 and Asp-120 was the determining factor in hMTH1's broad substrate specificity. In other words, the addition or removal of one or more protons at Asp-119 or Asp-120 is what causes hMTH1 to recognize 8-oxo-dGTP or 2-oxo-dATP. This allows hMTH1 to hydrolyze the oxidized mutagenic dNTPs before they are used for DNA synthesis; DNA that contains oxidized nucleotides would cause cancer cell death.

"We found that differing protonation states between Asp-119 and Asp-120 is the signal for hMTH1 to hydrolyze the damaged nucleotides. If this action by hMTH1 can be suppressed, cancer cells would accumulate damaged nucleotides and eventually undergo apoptosis," said Kumamoto University's Professor Yuriko Yamagata, leader of the research group. "The clarification of this mechanism should help in the development of hMTH1 targeting anticancer drugs."
This research can be found in the Journal of Biological Chemistry online, and has been nominated as an F1000Prime recommended article.


S. Waz, T. Nakamura, K. Hirata, Y. K. Ogawa, M. Chirifu, T. Arimori, T. Tamada, S. Ikemizu, Y. Nakabeppu, and Y. Yamagata, "Structural and kinetic studies of the human nudix hydrolase mth1 reveal the mechanism for its broad substrate specificity," Journal of Biological Chemistry, VOL. 292, NO. 7, pp. 2785-2794, February 17, 2017 DOI: 10.1074/jbc.M116.749713

Kumamoto University

Related Cancer Cells Articles from Brightsurf:

Cancer researchers train white blood cells to attacks tumor cells
Scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and Dresden University Medicine, together with an international team of researchers, were able to demonstrate that certain white blood cells, so-called neutrophil granulocytes, can potentially - after completing a special training program -- be utilized for the treatment of tumors.

New way to target some rapidly dividing cancer cells, leaving healthy cells unharmed
Scientists at Johns Hopkins Medicine and the University of Oxford say they have found a new way to kill some multiplying human breast cancer cells by selectively attacking the core of their cell division machinery.

Breast cancer cells use message-carrying vesicles to send oncogenic stimuli to normal cells
According to a Wistar study, breast cancer cells starved for oxygen send out messages that induce oncogenic changes in surrounding normal epithelial cells.

Breast cancer cells turn killer immune cells into allies
Researchers at Johns Hopkins University School of Medicine have discovered that breast cancer cells can alter the function of immune cells known as Natural killer (NK) cells so that instead of killing the cancer cells, they facilitate their spread to other parts of the body.

Breast cancer cells can reprogram immune cells to assist in metastasis
Johns Hopkins Kimmel Cancer Center investigators report they have uncovered a new mechanism by which invasive breast cancer cells evade the immune system to metastasize, or spread, to other areas of the body.

Engineered immune cells recognize, attack human and mouse solid-tumor cancer cells
CAR-T therapy has been used successfully in patients with blood cancers such as lymphoma and leukemia.

Drug that keeps surface receptors on cancer cells makes them more visible to immune cells
A drug that is already clinically available for the treatment of nausea and psychosis, called prochlorperazine (PCZ), inhibits the internalization of receptors on the surface of tumor cells, thereby increasing the ability of anticancer antibodies to bind to the receptors and mount more effective immune responses.

Engineered bone marrow cells slow growth of prostate and pancreatic cancer cells
In experiments with mice, researchers at the Johns Hopkins Kimmel Cancer Center say they have slowed the growth of transplanted human prostate and pancreatic cancer cells by introducing bone marrow cells with a specific gene deletion to induce a novel immune response.

First phase i clinical trial of CRISPR-edited cells for cancer shows cells safe and durable
Following the first US test of CRISPR gene editing in patients with advanced cancer, researchers report these patients experienced no negative side effects and that the engineered T cells persisted in their bodies -- for months.

Zika virus' key into brain cells ID'd, leveraged to block infection and kill cancer cells
Two different UC San Diego research teams identified the same molecule -- αvβ5 integrin -- as Zika virus' key to brain cell entry.

Read More: Cancer Cells News and Cancer Cells Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to