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Superoxide Dismutase. An Enzymic Function for Erythrocuprein (Hemocuprein) (McCord, J. M., and Fridovich, I. (1969) J. Biol. Chem. 244, 6049–6055)
Superoxide Dismutase. Organelle Specificity (Weisiger, R. A., and Fridovich, I. (1973) J. Biol. Chem. 248, 3582–3592)
Regulation of the Synthesis of Superoxide Dismutase in Escherichia coli. Induction by Methyl Viologen (Hassan, H. M., and Fridovich, I. (1977) J. Biol. Chem. 252, 7667–7672)
Irwin Fridovich was born in New York City in 1929. As a child he was enthralled by what he called the “miracle of insect metamorphosis” (
), which led him to an interest in biology. However, he found that the mere descriptions provided by biology were not enough and that he wanted an explanation at the molecular level. Thus, when he entered the City College of New York he majored in both chemistry and biology. During his senior year he enrolled in a biochemistry course taught by Abraham Mazur. Fridovich found Mazur to be an enthusiastic and effective teacher, both in the classroom and in the laboratory, and he soon became interested in biochemistry himself. Fridovich recalls, “Abe Mazur made it clear that biochemistry was the highest use of chemistry and could lead to real, testable explanations for the processes of life (
Toward the end of his senior year Mazur offered Fridovich a job doing research at Cornell Medical School. Fridovich accepted, and after graduating in 1951 he spent a year at Cornell isolating vasopressor material from hog kidneys. When the year was almost over Mazur suggested Fridovich consider graduate school. When asked where he should apply, Mazur replied that Fridovich had already been accepted into the Department of Biochemistry at Duke University School of Medicine. Mazur and Philip Handler, who was Chairman of Biochemistry at Duke and was also the author of a previous Journal of Biological Chemistry (JBC) Classic (
), were old friends, and Mazur had been empowered to make a limited number of admissions to Handler's department. Although Fridovich had no idea where Duke University was located, he agreed to go.
At Duke, Fridovich began working on sulfite oxidation, an interest that would last throughout his career. He found that dialyzing liver extract caused it to lose most of its sulfite oxidase activity but that the activity could be restored with the addition of a concentrated dialysate or by a boiled extract of liver. This indicated the presence of a heat-stable cofactor of sulfite oxidation, which Fridovich set out to isolate. He obtained 5 lbs of fresh beef liver and isolated this cofactor, hypoxanthine. This experiment was part of Fridovich's Ph.D. thesis, which he defended in 1955.
After graduating, Fridovich stayed on at Duke as an Instructor in Biochemistry. He worked his way up the academic ladder at Duke and became an Assistant Professor (1961), Associate Professor (1966), and Professor (1971). In 1976 he was named James B. Duke Professor of Biochemistry, a title he still holds today as an emeritus professor.
Throughout his time at Duke, Fridovich has continued to focus on the biology of oxidation. His initial identification of hypoxanthine led Fridovich to further investigate the ability of xanthine oxidase to catalyze sulfite oxidation. He discovered that the enzyme could do so, but only while oxidizing its substrates hypoxanthine or xanthine. Since tens of thousands of sulfites were oxidized per electron pair removed from hypoxanthine, Fridovich deduced that the reaction was occurring by a free radical chain. Other studies looking at the oxygen dependence of cytochrome c reduction suggested that was conducting electrons from xanthine oxidase to cytochrome c.
Eventually, Fridovich's graduate student, Joe M. McCord, showed that xanthine oxidase was releasing into free solution where it could initiate sulfite oxidation, reduce cytochrome c, or be intercepted by protein inhibitors of cytochrome c. It became clear to Fridovich that inhibitors of cytochrome c must be acting catalytically to eliminate by catalyzing the following dismutation reaction (Reaction 1).
REACTION 1
Using bovine erythrocytes obtained from a gallon of blood from a slaughterhouse, Fridovich and McCord purified the enzyme that catalyzed the dismutation of superoxide radicals, superoxide dismutase (SOD). The purification and subsequent characterization of SOD is the subject of the first JBC Classic reprinted here. Fridovich and McCord found that their purified enzyme contained copper, which was required for its activity, and that it existed in many tissues including bovine heart, brain, and liver, horse heart, and porpoise skeletal muscle. They also showed that SOD is identical to the copper-containing erythrocuprein and hemocuprein.
Soon, SODs were isolated from a variety of eukaryotes and prokaryotes. All of the eukaryotic SODs contained copper and zinc whereas the prokaryotic SODs contained manganese. While looking at the SOD of chicken liver, Fridovich noticed that it contained two types of SOD, one localized to the mitochondria and the other to the cytosol. Surprisingly, the mitochondrial SOD contained manganese. The differences between the two dismutases and their purification are discussed in the second JBC Classic by Fridovich and Richard A. Weisiger. The similarity between mitochondrial and bacterial SODs suggested that mitochondria evolved from aerobic prokaryotes, which entered into an endocellular symbiotic relationship with a prokaryote. Along with Fred Yost, Fridovich also isolated an iron-containing SOD (
), determined the amino acid sequence of the first 29 residues from the amino terminus of the mitochondrial manganese dismutase, the bacterial manganese dismutase, and the bacterial iron dismutase (
). The high degree of sequence identity among the bacterial and mitochondrial dismutases served as further support for the endosymbiotic origin of mitochondria.
Several years later, with Hosni M. Hassan, Fridovich investigated the effect of paraquat (methyl viologen) on Escherichia coli, which is the subject of the final JBC Classic reprinted here. They showed that the herbicide caused a marked increase in the rate of biosynthesis of Mn-SOD. The cells that had augmented levels of Mn-SOD also showed an increase in resistance to the toxicities of oxygen and the quinone streptonigrin. Because paraquat also increased cyanide-resistant respiration, it seemed likely that it engaged in a cycle of alternate reduction and autoxidation within E. coli to increase the production of while providing a cyanideinsensitive route for electron flow to O2. A wide variety of quinines and dyes were subsequently shown to behave similarly, and enhanced sensitivity to paraquat has become a routinely observed phenotypic marker for SOD-null mutants.
Almost 40 years after his initial isolation of SOD, Fridovich is still actively involved in SOD research at Duke. In his current investigations he has been seeking efficient, stable, and non-toxic mimics of SOD activity. He has also been tabulating the biological targets for and the controls on the biosynthesis of SODs.
Fridovich has received many awards and honors in recognition of his contributions to the biology of oxidation. He received the Founders' Award from the Chemical Industry Institute of Toxicology (1980), the Senior Passano Award from the Passano Foundation (1987), the Herty Award from the Georgia section of the American Chemical Society (1980), the Cressy A. Morrison Award from the New York Academy of Science (1984), and the Anlyan Lifetime Achievement Award from the Duke University Medical Center (1998). Fridovich has served on the editorial boards of the Journal of Biological Chemistry, Biochemica Biophysica Acta, Archives of Biochemistry and Biophysics, the Biochemical Journal, Bioinorganic Chemistry, Biochemistry, Biochemical Pharmacology, Analytical Biochemistry, and Advances in Free Radicals in Biology and Medicine. He is a member of the New York Academy of Sciences, the National Academy of Sciences, and the American Academy of Arts and Sciences. Fridovich has been president of the American Society of Biological Chemists (1982) and the Society for Free Radical Research International (1992). He was a founding member and first president of the Oxygen Society (1990), now called the Society for Free Radical Biology and Medicine, which publishes a monthly journal of the same name and holds an annual meeting with several hundred in attendance. The Oxygen Society was formed as an outcome of Fridovich's research on the superoxide dismutases and superoxide. PubMed lists over 49,000 papers published on superoxide dismutase since its discovery in 1965. Few other biochemists have had such an impact on the field of biochemistry.
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