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| |  Primitive Protease Discovery May Unlock Mysteries Of Enzyme Evolution SAN FRANCISCO -- May 6, 1997 -- Researchers at the San Francisco VA Medical Center and UC San Francisco have identified a primitive protease (an enzyme that cleaves proteins), that may hold the key to a better understanding of how enzymes evolved. Enzymes, which are protein catalysts, are critical to every physiological function within the body. Without them, even the most basic biological functions would occur so slowly that our bodies would simply shut down. The new finding is important because unlocking the mysteries of enzyme evolution could shed light on how enzymes work in digestion, development, and immune defense. The researchers report their findings in the May 2, 1997, issue of the journal Cell. Lead author is James H. McKerrow, M.D., Ph.D., director of the tropical disease research unit at SFVAMC and professor of pathology and pharmaceutical chemistry at UCSF. The enzyme is believed to be the earliest known branch of the cathepsin B family, a group of related enzymes found in both plants and animals. McKerrow and colleagues dub the cathepsin enzyme family "nature's Swiss army knife" because of its ability, with very minor modifications, to serve a wide variety of functions within many different kinds of cells. More evolved members of this enzyme family are involved in the immune response and bone remodeling, and pathologic problems like cancer cell invasion. The research team made its discovery by focusing on Giardia, a highly successful parasite and a leading cause of diarrhea around the world. Considered half way between bacteria and mammalian cells, Giardia has provided researchers with important clues about how cells were first formed. Examining the DNA of the newly discovered enzyme, the team realized that it too was very primitive and in fact, is one of the earliest proteases of eukaryotic cells, which make up all forms of life with the exception of bacteria and viruses. The key to Giardia's survival is its ability to encapsulate itself in an extremely tough shell called a cyst and then to "hatch" from this protective coating at the optimal time, according to McKerrow. The shell allows it to survive extreme environmental conditions such as drought, high heat, or the chemical onslaught of gastric acid within the host's digestive system. Hatching occurs when the threat has subsided, for instance, after a drought has ended or after the parasite has passed through the stomach. Focusing on the hatching mechanism, investigators discovered the protease enzyme that Giardia produces to dissolve the cyst wall. "While normal enzymes are highly beneficial," said McKerrow, "mutated enzymes have been tied to numerous diseases." Several childhood mental disorders are associated with damaged enzymes that cause lipid metabolism to occur too slowly or fail completely, allowing a dangerous lipid build-up in the brain. The next step for the research team is to build a 3-D model of the enzyme to better help them understand how it works. Other members of the research team are Wendy Ward, M.D.; Juan Engel, Ph.D.; and Christopher Franklin, all of the UCSF Department of Pathology; Lilia Alvarado, BSc, Unidad de Investigacion Medica en Enfermedades Infecciosas y Parasitarias, Mexico City, Mexico; and Neil Rawlings, Department of Immunology, Babraham Institute, Cambridgeshire, United Kingdom. The research was supported with a grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Additional funding was provided by the Burroughs Wellcome Foundation and the Howard Hughes Foundation.
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