Background
Tetrahydropapaverine (THP) and papaverine are naturally occurring plant alkaloids that are commercially important. THP is a precursor of the drugs atracurium and cisatracurium, used as muscle relaxants. Papaverine is used as an antispasmodic. These clinically useful molecules may be synthesized using traditional organic synthesis methods or using microorganisms.
Invention
The Ellington research team has developed an engineered methyltransferase enzyme capable of producing the pharmaceutically relevant compound tetrahydropapaverine (THP). The engineered enzyme uses the intermediate compound norlaudanosoline (NOR), a common intermediate for producing all benzylisoquinoline-based alkaloids. NOR can be manufactured from common metabolites using E.coli. Importantly, this engineered methytransferase performs four separate reactions that would otherwise require four individual enzymes, creating a simple path for biomanufacturing.
THP is a direct precursor to four different FDA-approved drugs; papaverine, atracurium, mivacurium, and cisatracurium. To date, the natural biosynthetic pathway to produce THP has not been characterized, and no other tools exist for producing THP biologically within microbes. In addition to the use of the novel methyltransferase enzyme for the sustainable biomanufacturing of THP within microbes, this technology can also be used as a template to produce other enzymes used in the manufacture of additional pharmaceutically relevant alkaloids, including opiates. Laboratory prototype experiments have been successfully completed, and the developed enzyme shows potential for use by pharmaceutical companies involved in the production of THP.
About the inventor
Dr. Ellington is a Professor in Molecular Biosciences, the Nancy Lee and Perry R. Bass Regents Chair in Molecular Biology, and the Wilson M. and Kathryn Fraser Research Professorship in Biochemistry at UT Austin with primary research interests in analytical chemistry, chemical biology, chemical theory/​computation, computational biology, drug development, and material characterization. He has published numerous articles/technical publications, and his research has broad applicability in developing novel synthetic organisms based on altering the translational apparatus and developing modular nucleic acid software.
