Blacktongue and Nicotinic Acid Metabolism: Philip Handler
Year: 2004
Type: article
Abstract: The Biochemical Defect in Nicotinic Acid Deficiency (Handler, P., and Dann, W. J. (1942) J. Biol. Chem. 145, 145-153) Synthesis of Nicotinamide Mononucleotide by Human Erythrocytes in Vitro (Leder, I. G., and Handler, P. (1951) J. Biol. Chem. 189, 889-899) Philip Handler (1917-1981) was born in New York City. As a child, he spent many summers on his grandparents' farm, which aroused in him a curiosity about the nature of living things. As a result, when Handler entered the College of the City of New York in 1933, he majored in biology and chemistry in preparation for a career in medicine. However, a biochemistry course taught by Benjamin Harrow, a particularly vibrant and exciting lecturer, converted Handler, and instead of entering medical school he attended graduate school at the University of Illinois. Despite the fact that the University of Illinois had a large number of prominent faculty members, Handler did his thesis research with the newly appointed Herbert E. Carter, who was the subject of a previous Journal of Biological Chemistry (JBC) Classic (1Classics JBC Carter H.E. J. Biol.Chem. 1935; 112 (http://www.jbc.org/cgi/content/full/277/41/e29): 769-773Google Scholar). Due to the lack of available scholarships, Handler also took a part-time job at the U.S. Department of Agriculture on the Illinois campus, working in a laboratory that studied soybeans and industrial byproducts. Although he had to divide his time between Carter's laboratory and the soybean laboratory, Handler managed to finish his doctorate in 3 years and graduate in 1939. At Illinois, Handler developed an interest in nutritional research and thus chose to do his postdoctoral work at the Duke University School of Medicine with William J. Dann, a nutritionist who studied human pellagra and the related disease in dogs, blacktongue. At the time, pellagra, which resulted from a dietary deficiency of nicotinic acid, was prevalent in the southern United States. Handler and Dann developed a method to determine the levels of nicotinic acid and pyridine nucleotides in the tissues of normal and vitamin-deficient animals. These studies, which established a link between the disease and metabolism of nicotinic acid, were published by Handler and Dann between 1940 and 1942 in a series of nine papers (2Dann W.J. Kohn H.I. Handler P. Theeffect of pyrazine acids and quinolinic acid on the V-factor content of humanblood and upon canine blacktongue.J. Nutr. 1940; 20: 477-490Google Scholar, 3Dann W.J. Handler P. Inactivity ofnicotinuric acid in canine blacktongue.Proc. Soc. Exp. Biol.Med. 1941; 48: 355-356Crossref Scopus (0) Google Scholar, 4Dann W.J. Handler P. The quantitativeestimation of nicotinic acid in animal tissues.J. Biol.Chem. 1941; 140: 201-213Abstract Full Text PDF Google Scholar, 5Dann W.J. Handler P. Synthesis ofnicotinic acid by the chick embryo.J. Biol. Chem. 1941; 140: 935-936Abstract Full Text PDF Google Scholar, 6Handler P. Dann W.J. The nicotinic acidand coenzyme content of animal tissues.J. Biol. Chem. 1941; 140: 739-745Abstract Full Text PDF Google Scholar, 7Dann W.J. Handler P. The nicotinic acidand coenzyme content of the tissues of normal and blacktongue dogs.J. Nutr. 1941; 22: 409-414Crossref Google Scholar, 8Dann W.J. Handler P. The nicotonic acidcontent of meat.J. Nutr. 1942; 24: 153-158Crossref Google Scholar, 9Handler P. Dann W.J. The inhibition ofrat growth by nicotinamide.J. Biol. Chem. 1942; 146: 357-368Abstract Full Text PDF Google Scholar). The first JBC Classic reprinted here is from this series. In this paper, Handler and Dann present their finding that saline alleviates the symptoms of blacktongue in dogs. Noticing that blacktongue is often accompanied by severe diarrhea and the refusal of the dogs to eat or drink, Hander and Dann hypothesized that, “dehydration and electrolyte imbalance might be factors of primary importance in death due to nicotinic acid deficiency.” To test this, they administered large volumes of 0.9% NaCl solution twice daily to dogs with blacktongue. The symptoms of blacktongue disappeared within about 2 weeks, and the dogs' lives were extended by as many as 180 days. When the animals finally did succumb to the disease, their nicotinic acid deficiencies were seldom as extreme as in classic cases of blacktongue. Subsequently, Handler observed that blacktongue was not a disease resulting from a lack of dietary nicotinic acid but rather a product of eating corn. It was later shown that corn was deficient in tryptophan, which was a metabolic precursor of nicotinic acid, explaining Handler's observations. These studies prompted Handler to investigate the biosynthesis and degradation of nicotinic acid. In the second JBC Classic reprinted here, Handler and Irwin G. Leder describe the synthesis of nicotinamide mononucleotide by erythrocytes in a solution of inorganic phosphate, glucose, and nicotinamide. Other laboratories had attempted to synthesize pyridine nucleotides from nicotinic acid but had only been able to produce small amounts of diphosphopyridine nucleotide. Using nicotinamide, rather than nicotinic acid, Handler and Leder were able to obtain 10 times the normal pyridine nucleotide concentration. They also found that synthesis could be optimized by washing the cells prior to incubation to remove “an inhibitor which was not associated with the plasma.” Using an enzyme that forms diphosphopyridine nucleotide from ATP and nicotinamide mononucleotide to assay their product, Handler and Leder were able to demonstrate that 75-95% of the product was nicotinamide mononucleotide, and the remainder was diphosphopyridine nucleotide. Handler, along with Jack Preiss, later determined the steps leading to NAD synthesis from nicotinic acid and ATP and showed that the degradation of NAD yields nicotinamide and adenosine diphosphoribose. These pathways, now called the Handler-Preiss cycle, helped elucidate one on the major principles of biochemistry: that major metabolic pathways are essentially irreversible and that the interconversion of two metabolites usually proceeds by different metabolic pathways. Handler remained at Duke University for the duration of his research career. He was promoted to associate professor of biochemistry in 1945, chairman of the Department of Biochemistry in 1950, and James B. Duke professor in 1961. During his time at Duke, Handler transformed the biochemistry department from a small department with limited activities to one of the outstanding research departments in the country. His research activities at Duke encompassed a wide variety of subjects including coenzyme metabolism, renal hypertension, the mechanisms of hormone action, amino acid metabolism, biological oxidations, the mechanism of action of enzymes, and biochemical evolution. While at Duke, Handler also coauthored the “Principles of Biochemistry” with Abraham White, DeWitt Stetten, and Emil L. Smith. Handler was also heavily involved in public service at a variety of academic institutions, societies, and government institutions. He served as president of the American Society of Biological Chemists (now the American Society for Biochemistry and Molecular Biology) and chairman of the board of the Federation of American Societies for Experimental Biology (FASEB). He was also appointed to the National Science Board and the President's Science Advisory Committee. In 1969 Handler was elected president of the National Academy of Sciences and served two 6-year terms. During his 12 years in office he became a major spokesman for science in the U.S. and internationally. He always emphasized that the Academy was not a branch of government but an independent body with a mandate to advise the government on science policy. Handler's leadership as president was especially important during the Vietnam War, the arms race with the Soviet Union, and the violation of the human rights of scientists worldwide. In recognition of his great contributions to science, Handler was awarded the National Medal of Science by Ronald Reagan in 1981. 1All biographical information on Philip Handler was taken from Ref. 10Smith E.L. Hill R.L. Biographical memoir of Philip Handler. 55. NationalAcademy of Sciences, Washington, D. C.1985: 305-353Google Scholar.1All biographical information on Philip Handler was taken from Ref. 10Smith E.L. Hill R.L. Biographical memoir of Philip Handler. 55. NationalAcademy of Sciences, Washington, D. C.1985: 305-353Google Scholar.
Source: Journal of Biological Chemistry
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W1528154415