3-D forms link antibiotic resistance and brain disease

The story of what makes certain types of bacteria resistant to a specific antibiotic has a sub-plot that gives insight into the cause of a rare form of brain degeneration among children, according to investigators at St. Jude Children's Research Hospital. The story takes a twist as key differences among the structures of its main molecular characters disappear and reappear as they are assembled in the cell.

A report on this study appears in the August 16 issue of the journal Structure.

The story is based on a study of the 3-D structure of an enzyme called pantothenate kinase, which triggers the first step in the production coenzyme A (CoA), a molecule that is indispensable to all forms of life. Enzymes are proteins that speed up biochemical reactions. CoA plays a pivotal role in the cells' ability to extract energy from fatty acids and carbohydrates; bacteria need CoA to make their cell walls. The job of pantothenate kinase is to grab a molecule of pantothenic acid (vitamin B-5) and another molecule that contains a chemical group called "phosphate." The enzyme then removes the phosphate group from that molecule and sticks it onto pantothenic acid.

In humans, certain mutations in this enzyme block its ability to put the phosphate group onto pantothenic acid. That diminishes the production of CoA by this route and causes the neurodegenerative disease called pantothenate kinase associated neurodegeneration (PKAN), according to Suzanne Jackowski, Ph.D., a member of the St. Jude Department of Infectious Diseases and a co-author of the paper. "We also know that certain antibiotics called pantothenamides work by impersonating vitamin B-5 and slipping into the enzyme," Jackowski said. "This blocks the bacteria's ability to produce fatty acids." The researchers already knew that different types of bacteria build their own versions of the enzyme pantothenate kinase, which are called Types I, II and III. For example, bacteria c

Contact: Bonnie Kourvelas
St. Jude Children's Research Hospital

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