Mechanism and Role of Enzymatic P-Methyl Transfer

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With this award, the Chemistry of Life Processes Program in the Division of Chemistry is funding Dr. Susan Wang at Washington State University to characterize the unusual chemistry used by two enzymes that methylate phosphorus atoms: the "P-methyltransferases", PhpK and SD 1168. Compounds containing bonds between carbon and phosphorus (C-P) play important roles in agriculture, industry, and medicine. The C-P bond is resistant to being broken by water, making compounds that contain this stable structural feature commercially useful. In addition, it has been suggested that C-P formation may provide a mechanism for marine organisms to store, preserve, and cycle phosphorus. This project will investigate the physiological roles of the only known enzymes that form carbon-phosphorus-carbon (C-P-C) linkages, the "P-methyltransferases." Undergraduate and graduate students will receive broad multidisciplinary training in chemistry and biology. These trainees will also participate in an outreach program introducing rural and/or low-income preschool children to the life sciences as a potential career path.The focus here will be on two"P-methyltransferase enzymes, PhpK and SD 1168, that methylate phosphorus atoms. Both enzymes are capable of producing precursors for the important natural product phosphinothricin, a broad-spectrum herbicide with antibiotic properties. Both PhpK and SD 1168 are believed to utilize a combination of vitamin B12 and free radical chemistry to form C-P-C bonding sequences. SD 1168, from the marine bacterium Shewanella denitrificans, exhibits broader substrate specificity than PhpK. While its true biological function remains unknown, SD 1168 is a potential candidate for future engineering efforts to produce new C-P-C compounds. A multifaceted, collaborative approach combining spectroscopic, synthetic, molecular biology, microbiology, and crystallographic techniques will be used to determine the enzymatic mechanism for P-methylation and to pinpoint the physiological role of SD 1168 in its host organism. The results of the proposed research will provide insight into unusual, difficult chemistry and have implications for the biosynthesis of C-P natural products and related compounds.