Profile of Michael A. Marletta

PROFILE Profile of Michael A. Marletta or more than three decades, largely in water, largely at a pH of 7.5, Michael Marletta has traveled and mostly at 37 degrees Celsius. Chem- a serpentine road, working to elu- ists would consider those conditions F ” cidate a molecule whose impor- about the worst to work with, he says. tance to human physiology is as well Marletta’s research during the next three recognized as his own contributions to his decades focused on the interface between field. Named “Molecule of the Year” in chemistry and biology. 1992 by Science, nitric oxide, a noxious Because of this work, he refuses to be atmospheric gas, plays a pivotal role in typecast. “At one time in my career, I biological functions as diverse as forming called myself a biochemist. Now, I call long-term memory and maintaining penile myself a chemical biologist, but I continue erections (1). Marletta, who was elected to do what I’ve always done—enzymol- to the National Academy of Sciences in ogy,” he says. 2006, has shed light on the biochemistry of When it came time to pick a Ph.D. nitric oxide and the cellular machinery program, Marletta was faced with a dearth through which the molecule performs of choices because there were not many its functions. chemistry departments during the early Marletta’s work on nitric oxide not only 1970s that were serious about biology. led to a fundamental understanding of However, a fortuitous tip from a professor enzyme reaction mechanisms, but it has at Fredonia, who had heard about a pro- informed the development of treatments. gram in pharmaceutical chemistry at For example, he showed that substrate UCSF, pointed the way to Marletta’s lookalikes, called arginine analogs, block graduate studies. the activity of the enzyme nitric oxide His doctoral project in the laboratory of synthase. The analogs help curb the over- UCSF biochemist George Kenyon, now production of nitric oxide, preventing va- at the University of Michigan at Ann sodilation and the precipitous drop in Michael A. Marletta. Arbor, was to investigate the mechanism blood pressure experienced by patients of action of creatine kinase, an enzyme suffering from septic shock (2). His dis- would come home at night, smelling like found abundantly in muscle and brain covery helped other researchers develop a spice mill. I can remember reading books tissues, where it maintains constant levels treatments for septic shock. of ATP, the cellular energy currency, by in the library about the constituents of Marletta’s scientific foray began in reversibly catalyzing the transfer of California, where he obtained his doctor- food, and I realized that foods smelled and a phosphoryl group from ATP to the or- ate in 1978 from the University of tasted the way they did because of the ganic acid creatine. “It was a perfect California, San Francisco (UCSF). That molecules in them,” Marletta says. project for me because it was my first journey, with stops in Massachusetts and He spent the next few years tinkering experience in mechanistic enzymology,” Michigan, has led him back to California, with chemicals in his basement laboratory. Marletta says. where he is now the Aldo DeBenedictis “In those days you could buy chemicals Marletta fashioned a substrate look- Distinguished Professor of Chemistry from drugstores. I had a paper route; I alike for rabbit skeletal muscle creatine and a professor of biochemistry and had money,” he chuckles. “And there was kinase, called epoxycreatine, to probe molecular biology at the University of a library with books to tell you what to the enzyme’s active site (3). Until then, California, Berkeley. mix.” By age 10, Marletta knew he wanted little structural information about the His love of science is deep-seated. Born to be a chemist. enzyme had been reported, and the en- ’ in Rochester, NY, to parents of Italian “ ” zyme s catalytic site had remained a black ancestry, Marletta says the space race of Biology Is for Wusses. box. By binding specifically to the en- the late 1950s spurred his scientific tem- Neither of Marletta’s parents attended zyme’s active site and blocking its action, perament. As a 6-year-old space buff, college, but both supported his interest in epoxycreatine helped explain the mecha- Marletta recalls watching Sputnik 1 fly science. “My mother was a strong, en- nism and kinetics of creatine kinase and overhead on a cold October night in 1957 couraging force. I can still hear her telling the bioenergetics of ATP use in muscles. in Rochester. “I was completely fascinated me that anything was possible,” he says. Additional studies using epoxycreatine by by the idea that a satellite launched by During the fall of 1969, he enrolled at the members of Kenyon’s laboratory showed humans was orbiting the earth,” he says. State University of New York College that a cysteine residue at position 282 of That Christmas, Marletta asked his father at Fredonia to study chemistry. Between the enzyme’s amino acid sequence was for a telescope and spent many a winter’s his sophomore and junior years, Marletta likely crucial to catalysis (4). Other re- night stargazing. Over the next few years, took a general biology course at the searchers have since solved the enzyme’s his interest turned from astronomical to University of Rochester while working crystal structure (5). biological; he peered at living organisms a summer job on campus. “Frankly, I Marletta’s doctoral work on enzymes procured from the neighborhood pond remember thinking biology is for wusses. was not the only factor that cemented his through a microscope. I figured if I got biology out of the way, long-term research interest. For his post- His Italian heritage largely cultivated his I could have more time to take advanced doctoral training between 1978 and 1980, interest in chemistry. “The Italians’ love chemistry courses,” he recalls. However, for food was certainly prevalent in my the course helped him realize that na- house. My father worked at the R.T. ture’s ability to do chemistry surpassed that of chemists. “It’s almost unbelievable This is a Profile of a recently elected member of the Na- French Company [a manufacturer of con- tional Academy of Sciences to accompany the member’s diments, such as French’s mustard]. He how nature does intracellular chemistry Inaugural Article on page 19753 in issue 47 of volume 106. www.pnas.org/cgi/doi/10.1073/pnas.1007505107 PNAS Early Edition | 1of3 Downloaded by guest on October 1, 2021 Marletta worked with enzymologist ability to kill invaders,” Marletta recalls. P450 and requires oxygen, NADPH, and Christopher Walsh at the Massachusetts “I decided to take my chances and con- tetrahydrobiopterin as cofactors for ca- Institute of Technology (MIT) on de- tinue to pursue that line of research rather talysis (14). “The enzyme catalyzes one veloping fluorinated analogs to study the than something more predictable that of the most complicated redox trans- mechanism of enzyme catalysis. The might have gotten me tenure at MIT.” formations known, and that’s what drew training turned into an assistant profes- At the University of Michigan at Ann me to it. I’ve always been interested in sorship for Marletta at MIT that lasted Arbor, where he was a faculty member for enzyme catalysis,” he says. 6 years. “During my first year in Walsh’s 14 years, Marletta pursued that high- This fact is finely illustrated by the slew lab, I managed to get a couple of papers stakes research, which paid off in a big of studies on nitric oxide synthase that published, so I decided to test the job way. In 1980, pharmacologist Robert Marletta published while at the University market,” he says. Fortunately, MIT’s nu- Furchgott found that endothelial cells of Michigan, including reports on the trition department was being restructured lining blood vessels produced a chemical enzyme’s structure, catalytic mechanism, into the now-defunct applied biological compound, called endothelium-derived regulation, and inhibition (2, 15–18). sciences department into which Marletta relaxing factor (EDRF), which made was hired as an enzymologist for the the smooth muscles of vessel walls relax, A New Direction toxicology program. thereby causing vasodilation (10). Ex- “I’ve always picked projects by looking for tending Furchgott’s findings, biochemist fundamental science with implications for The Nitric Oxide Narrative Salvador Moncada at University human health and disease,” Marletta At MIT, he met toxicologist Steven Tan- says. Thus, he turned his attention in 1995 nenbaum, whose work led to Marletta’s to the biochemistry of malaria, a disease research on nitric oxide. Tannenbaum Nature walks a tricky that kills nearly 2 million people each studied how carcinogenic nitrosamines year. “My wife and I had our only child are made by the human body from ni- tightrope between two months before I won the fellowship. I trates found in drinking water and vege- asked myself what new project I should tables. Bacteria in saliva were known to toxicity and function. work on. Seventy percent of those dying convert nitrates into nitrites, which were from malaria are under the age of 10, so I then transformed into nitrosamines by decided to study the biochemistry of the intestinal bacteria. Tannenbaum’s dis- College London and researchers else- parasite,” he says. covery that there were surprisingly high where showed that EDRF was nitric oxide, The malarial parasite Plasmodium amounts of nitrates in the urine of ex- a discovery with implications for the devel- falciparum degrades the hemoglobin in perimental subjects fed a low-nitrate diet opment of blood pressure drugs (11, 12). host erythrocytes for its nutrition.

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