Case Western Reserve and University Hospitals (UH) Case Medical Center researchers and physicians have discovered that the molecule known as coenzyme A plays a key role in cell metabolism by regulating the actions of nitric oxide. Cell metabolism is the ongoing process of chemical transformations within the body's cells that sustains life, and alterations in metabolism are a common cause of human disease, including cancer and heart disease. Their findings about the mechanisms of action for coenzyme A, as well as discovering a new class of enzymes that regulate coenzyme A-based reactions, appear in the Dec. 15 edition of the Proceedings of the National Academy of Sciences (PNAS).
"The governing role of coenzyme A in nitric oxide function was completely unknown and unanticipated before this study," said senior author Jonathan Stamler, MD, professor of medicine, Case Western Reserve University School of Medicine, and director, Harrington Discovery Institute at UH Case Medical Center. "Nitric oxide operates in every cell and tissue of the body to influence cell function. We are trying to work through the basic control of nitric oxide biology to elucidate the machinery underlying its mechanisms of action."
Coenzyme A sets into motion a process known as protein nitrosylation, which unleashes nitric oxide to alter the shape and function of proteins within cells to modify cell behavior. The purpose of manipulating the behavior of cells is to tailor their actions to accommodate the ever-changing needs of the body's metabolism.
In addition, Case Western Reserve and UH investigators identified hundreds of proteins regulated by coenzyme A-driven protein nitrosylation. Many of the newly discovered targets of nitrosylation were noted to influence cellular energy production. Because coenzyme A itself serves as a source of energy for cells, the authors concluded that nitrosylation might influence the major building blocks of cells such as fats and sugars.
"We are trying to understand how nitrosylation works in ensuring that nitric oxide achieves its specificity in regulating cell function. We have found new enzymes that regulate nitrosylation by coenzyme A," Stamler said. "We know that aberrant protein nitrosylation is a common cause or contributor to disease. We anticipate that these new enzymes may play a role."
During their research, investigators studied yeast in making their discoveries about coenzyme A and also a new class of enzymes that control the ability of coenzyme A to nitrosylate proteins. These newly found enzymes have a profound effect on cell metabolism, particularly in sterol (cholesterol) synthesis, by regulating the signal mechanism of cell metabolism and protein nitrosylation. Alternations in cholesterol levels are a common cause of atherosclerosis and Alzheimer's.
"We are excited to say that these new classes of enzymes potentially provide entry into metabolic regulation in mammals and offer new pathways and new possibilities for understanding cell metabolism," Stamler said. "This new class of enzymes is present in every living cell, and it governs metabolic signaling molecules and regulates cellular metabolism in organisms from bacteria to humans."
In terms of next steps, Stamler and fellow researchers will work to identify the specific functions of each enzyme in the class of enzymes they discovered during the course of this investigation.
The fundamental basic discoveries of this new class of enzymes and of coenzyme A function could open a new avenue of scientific research. His findings anchor the development of new therapeutic approaches for patients with heart and other diseases.
"Cell metabolism is a hot topic today because alterations in cell metabolism serve as a signature for a whole variety of diseases," Stamler said. "Our findings about these cell metabolism mechanisms promise new understanding of health and disease."
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Joining Stamler in this research were lead author Puneet Anand and contributing authors Alfred Hausladen, Colin Stomberski and Douglas T. Hess, all members of the Institute for Transformative Molecular Medicine, Case Western Reserve School of Medicine, faculty of the medical school's Department of Medicine, CWRU School of Medicine as well as medical staff of UH Case Medical Center; Ya-Juan Wang, Center for Proteomics and Bioinformatics, CWRU School of Medicine; and Guo-Fang Zhang and Henri Brunengraber, both faculty of the Department of Nutrition, CWRU School of Medicine.
This research was funded by CWRU School of Medicine and UH Case Medical Center.
About Case Western Reserve University School of Medicine
Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation's top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School's innovative and pioneering Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the School of Medicine.
Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report's "Guide to Graduate Education."
The School of Medicine's primary affiliate is University Hospitals Case Medical Center and is additionally affiliated with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. http://casemed.case.edu
About University Hospitals
University Hospitals, the second largest employer in Northeast Ohio with 25,000 employees, serves the needs of patients through an integrated network of 15 hospitals, 29 outpatient health centers and primary care physician offices in 15 counties. At the core of our $3.5 billion health system is University Hospitals Case Medical Center, ranked among America's 50 best hospitals by U.S. News & World Report in all 12 methodology-ranked specialties. The primary affiliate of Case Western Reserve University School of Medicine, UH Case Medical Center is home to some of the most prestigious clinical and research centers of excellence in the nation, including cancer, pediatrics, women's health, orthopaedics, radiology, neuroscience, cardiology and cardiovascular surgery, digestive health, transplantation and genetics. Its main campus includes UH Rainbow Babies & Children's Hospital, ranked among the top children's hospitals in the nation; UH MacDonald Women's Hospital, Ohio's only hospital for women; and UH Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center at Case Western Reserve University. For more information, go to http://www.uhhospitals.org
Journal
Proceedings of the National Academy of Sciences