The University Record, September 8, 1992

Marletta finds biochemical trigger for creation of nitric oxide

By Sally Pobojewski
News and Information Services

A U-M scientist has added a critical piece to the rapidly emerging picture of nitric oxide—a mysterious gas that appears to control blood vessel dilation, kill parasitic pathogens and regulate the transmission of nerve impulses in the brain.

Michael A. Marletta, who in 1985 discovered the key role nitric oxide plays in immune system response, has discovered a new and unusual characteristic of the enzyme that triggers or catalyzes production of nitric oxide in mammalian cells. Marletta is professor of medicinal chemistry and pharmacognosy and of biological chemistry.

A paper by Marletta and graduate student Kimberly A. White describing the enzyme’s structure appeared as an accelerated publication in the July 28 issue of Biochemistry.

Nitric oxide is currently the subject of intense international study by scientists who are trying to understand how ephemeral puffs of the gas can transmit nerve impulses, relax blood vessels, and kill foreign microorganisms and tumor cells. Until recently, scientists were unaware of nitric oxide’s ability to regulate cell activity, because it exists for just seconds in the body before being chemically transformed into other substances.

Nitric oxide is now being used to treat pulmonary hypertension in infants. New findings also show nitric oxide is involved in male erections and may prove useful in treating impotence.

While a little nitric oxide appears to be beneficial, too much can kill or damage cells, according to Marletta. Recent research has implicated nitric oxide as the possible cause of brain cell damage from strokes, Alzheimer’s disease and Huntington’s disease. Nitric oxide also has been associated with toxic shock syndrome and inflammation- related tissue damage, such as arthritis.

“Understanding the unusual and complex enzymatic reaction that produces nitric oxide will help us design new drugs to control its production within cells,” says Marletta.

According to Marletta, the enzyme that catalyzes production of nitric oxide is similar in structure to a family of protein molecules called P-450 hemoproteins, which are involved in cellular processes that produce hormones and metabolize drugs.

However, the protein that catalyzes nitric oxide, called nitric oxide synthase (NOS), has two features that make it different from other P-450 hemoproteins, he says.

“Unlike every other P-450 hemoprotein found in mammals, NOS floats freely in the cytoplasm or cellular fluid, instead of being locked within the cell membrane.”

“The second difference is that NOS is self-sufficient. Other P-450s require an additional protein called a reductase to carry out their reactions. NOS has this additional protein permanently joined to it, so it is really two proteins in one.” Marletta added that NOS is the first example of a “dual protein” of this type ever found in mammals.

Marletta believes the fact that NOS is a P-450 hemoprotein has significant implications for new drug design. “Because we know so much about other P-450s, we can bring that knowledge to bear on NOS to help us design new drugs to control the cellular processes regulated by nitric oxide,” he says.

“NOS is an enzyme of great biomedical importance, and its identification as part of the P-450 family is an extremely significant finding,” said Minor J. Coon, Victor C. Vaughan Distinguished University Professor of Biological Chemistry at the U-M Medical School. “Before Prof. Marletta‘s discovery, the nature of this enzyme was unknown. Now that we know its structure, rigorous progress can be made toward greater understanding of how it works in the human body.”

Marletta’s research was funded by the National Institutes of Health.