A Role in Glucose Metabolism
After devising new methods to detect this unique lysine modification in human cell cultures, Dr. Moellering soon found it: on other glucose-metabolizing enzymes, as well as on proteins seemingly unrelated to glucose metabolism.
“With every step we took, the project became more interesting, because we were finding signs that this reaction occurs frequently in cells and in animal tissues, and in unexpected cellular locations, too,” he said.
Dr. Moellering detected the signature of the new lysine modification not only on proteins in the main volume of the cell (the cytosol), but also in the DNA-containing cell nucleus and even on the cell’s membrane compartments.
“It appears that wherever GAPDH goes within cells, it is capable of catalyzing the localized production of 1,3-BPG, which in turn reacts with nearby proteins to modify their structure and function,” explained Dr. Cravatt.
Dr. Moellering found that when 1,3-BPG’s lysine modification occurs on glucose-metabolizing enzymes, it tends to inhibit their activities, causing a slowdown of central glucose processing and a consequent buildup of certain glucose metabolites in the processing pathway. He and Dr. Cravatt suspect that these overabundant metabolites may end up being shunted into other cellular processes besides basic fuel-making—processes that contribute to the synthesis of new molecules and even cell proliferation.
Dr. Moellering also discovered that 1,3-BPG and the modification it makes on proteins become more prevalent as glucose levels rise. Within the context of glucose metabolism, 1,3-BPG’s modification thus seems to act as a “very old, maybe ancient feedback mechanism for regulating that central metabolic pathway,” he said.
The abnormal processing of glucose within cells features in a number of major diseases, including cancer and diabetes. “Cancer cells, for example, bring in as much as 20 times more glucose than non-cancerous cells of the same type,” according to Dr. Moellering. He now wants to find out whether 1,3-BPG is part of the problem in such cells. At abnormally high levels, it conceivably could help force glucose metabolism toward the runaway cell proliferation that is a hallmark of cancer.
Drs. Cravatt and Moellering also want to learn more about what 1,3-BPG’s lysine modification does in the nuclei and membrane compartments of cells, where they found evidence of it. “We suspect that it works to connect glucose metabolism to other pathways, perhaps as a kind of signaling mechanism,” said Dr. Moellering.
Dr. Moellering already has uncovered evidence that there are enzymes that work to reverse 1,3-BPG’s modification of lysines, which underscores the likelihood that this modification represents a fundamental, dynamic mechanism in cells.
“We’d like to discover which enzymes catalyze the removal of the modification,” said Dr. Cravatt, “Then, in principle, we could use inhibitors of these enzymes to control the levels of the modification and get a better understanding of its biological functions as well as the conditions under which it occurs.”