Lipid Storage Disorders and the Biosynthesis of Inositol Phosphatide: the Work of Roscoe Brady
Year: 2005
Type: article
Abstract: The Enzymatic Synthesis of Inositol Phosphatide (Agranoff, B. W., Bradley, R. M., and Brady, R. O. (1958) J. Biol. Chem. 233, 1077–1083) Roscoe Owen Brady was born in 1923 in Philadelphia. He attended Pennsylvania State University from 1941 to 1943 and then received his medical degree from Harvard Medical School in 1947. After interning at the Hospital of the University of Pennsylvania for 1 year, Brady did a postdoctoral fellowship in the Department of Physiological Chemistry at the University of Pennsylvania School of Medicine (1948 to 1950) and then was a fellow in clinical medicine in the Department of Medicine (1950 to 1952). In 1954, following 2½ years on active duty in the U.S. Naval Medical Corps, he joined the National Institutes of Health (NIH) to become section chief of the National Institute of Neurological Diseases and Blindness. He remained in this position until 1967 when he became assistant laboratory chief of neurochemistry at the National Institute of Neurological Diseases and Blindness. Currently, Brady is Chief of the Developmental and Metabolic Neurology Branch of the National Institute of Neurological Disorders and Stroke, a position he has held since 1972. Early in his career at the NIH, Brady started studying lipids, specifically inositol and the synthesis of inositol phosphatide. This is the subject of the Journal of Biological Chemistry (JBC) Classic reprinted here. Although inositol had been isolated more than 100 years before the Classic was published, little was known about its metabolism. In his Classic, Brady uses tritium-labeled inositol and a preparation from guinea pig kidney mitochondria to study inositol metabolism. He found that the enzyme system catalyzed the incorporation of inositol into inositol phosphatide in the presence of Mg2+ and cytidine diphosphate-choline (CDP) or cytidine 5′-phosphate. From these results, Brady proposed a mechanism for the synthesis of inositol phosphatide in which CDP is transphosphorylated to form CDP-d-α,β-diglyceride, which then reacts with the hydroxyl group of inositol to form inositol phosphatide. These early studies stimulated Brady's interest in lipid storage disorders, in particular, Gaucher disease. In 1967, he showed that people with Gaucher disease had low levels of glucocerebrosidase and thus were unable to break down the lipid glucocerebroside and clear it out of their bodies. He also developed a diagnostic test for Gaucher disease, which worked by measuring glucocerebrosidase activity in white blood cells. A year later, Brady suggested a therapy for Gaucher disease based on replacing the enzyme. Using human placentas, his team isolated a tiny sample of purified glucocerebrosidase and gave it to two patients. The patients' health improved, and Brady soon developed large scale purification and targeting methods for glucocerebrosidase to use in further clinical trials. Eventually, in 1991, Brady's macrophage-targeted glucocerebrosidase enzyme replacement therapy was approved as a specific treatment for Gaucher disease by the Food and Drug Administration. In addition to studying Gaucher disease, Brady has discovered the metabolic basis of Niemann-Pick disease, Fabry disease, and the specific biochemical defect in Tay-Sachs disease. He has applied this knowledge to developing diagnostic tests, carrier identification procedures, and the prenatal detection of such conditions. Currently his research is focused on examining enzyme replacement therapy and gene therapy for patients with these other hereditary metabolic disorders. In recognition of his scientific achievements, Brady received the Gairdner International Award (1973), the Cotzias Award from the American Academy of Neurology (1980), the Passano Foundation Award (1982), the Lasker Foundation Clinical Medical Research Award (1982), and the Kovalenko Medal from the National Academy of Sciences (1991). He is a member of the National Academy of Sciences and a member of the Institute of Medicine of the National Academy of Sciences. He has served on the editorial boards and advisory boards of many journals and organizations.
Source: Journal of Biological Chemistry
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W1525269716