ABSTRACT

With the support of the Chemical Synthesis (SYN) program in the Division of Chemistry, Takashi L. Suyama of Waynesburg University will work to develop a hybrid chemo/biocatalytic entry into the synthesis of an interesting and biologically active class of polybrominated aryl ethers. Most of the research will be conducted with undergraduate students and there is an enzyme engineering aspect of the project to be conducted in collaboration with Bradley Moore of the University of California-San Diego. This hybrid route shows promise for efficient synthesis of medicinally important compounds. The enzyme engineering will be conducted via a directed evolution approach using random mutation caused by chemical reagents, followed by selection of mutated enzymes based on their desired chemical properties. A number of undergraduate students will be financially supported by this award to devote more time to this research project both during the academic year and summers and will gain invaluable experience that will propel them into successful careers in science, technology, engineering, and mathematics (STEM). Graduates from this laboratory are demographically diverse and have been placed in prestigious graduate schools. High school students will also be hosted by the lab during the summer to participate in the research as part of outreach. The proposed funds are the first significant federal research grant received by the University in decades and will drastically impact the research and education climate on campus and its surrounding communities, which are located in a federally designated county of Appalachia. NSF-supported students will have opportunities to publish findings in peer-reviewed journals and present them at national scientific conferences and compete well against graduates from economically privileged areas. These students will lead and participate in scientific outreach to local communities and K-12 students by leveraging the University?s American Chemical Society program as well as the marine biology lab.

Polybrominated aromatics, such as polybrominated diphenyl ethers (PBDEs) and their derivatives dibenzo-p-dioxins have attracted attention due to their toxicity. The origin of such compounds in the marine environment has been somewhat ambiguous because some PBDEs and their derivatives have been shown to be natural products while the majority of PBDEs are produced industrially as flame retardants. Recently isolated from marine Pseudoalteromonas found on nudibranchs, TBFP (2,3,5,7-tetrabromobenzofuro[3,2-b]pyrrole) has shown anti-MRSA (methicillin resistant Staphylococcus aureus) activities and possesses 3-phenoxypyrrole ether linkage reminiscent of PBDEs. To elucidate TBFP?s biogenesis and to provide facile access to this anti-MRSA compound, a biocatalytic synthesis of TBFP will be pursued. To this end, the putative biosynthetic precursor for TBFP, pentabromopsuedilin (PBP), will be subjected to an intramolecular Ullmann-type reaction catalyzed by the cytochrome P450 enzyme involved in the biosynthesis of PBP to cause the phenolic cyclization onto the pyrrole ring. The research team will work to improve the yield of this reaction by directed evolution of the enzyme through chemical mutagenesis and selection based on LCMS-analysis. Traditional Ullmann-type reaction conditions are not compatible with labile pyrroles and are ineffective in converting PBP to TBFP. The versatility of this engineered enzyme in natural product synthesis will be examined for constructing the scaffolds of other medicinally important metabolites, such as marinopyrrole B, that possess a heteroatom-C bond at C3 of pyrrole similar to that in TBFP. If successful, this project would lead to facile access to medicinally important chemical scaffolds for wider adaptation of engineered biocatalysts in total synthesis of natural products.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Please report errors in award information by writing to: awardsearch@nsf.gov.