Novel enzymology in bacterial secondary metabolic pathways

• Applicant: Professor Dr. Robin Teufel
• Subject Area: Metabolism, Biochemistry and Genetics of Microorganisms
• Term: from 2014 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 264679367

Secondary metabolism is a true treasure trove for unusual enzymology as exemplified by flavin-dependent enzymes that catalyze a wide array of astonishing redox reactions and thereby contribute to the rich structural diversity of natural products. Yet, despite decades of intensive studies, we only partially comprehend the chemical versatility and reactivity of the flavin cofactor. My research program aims to elucidate the flavin-dependent biosynthesis of the highly unusual antibiotic griseorhodin A from marine Streptomyces bacteria. Like other members of the rubromycin family of polyketides, griseorhodin A exhibits significant bioactivity against the clinically important enzymes HIV reverse transcriptase and human telomerase. Rubromycins were consequently suggested as potential lead structures for the engineering of drugs for medical application. Notably, a drastic distortion of the otherwise planar rubromycin structure is caused by a unique spiroketal moiety that is crucial for the bioactivity. Flavin-dependent enzymes most likely assemble these spiroketal pharmacophores through highly complex rearrangements of the carbon backbone. To investigate this biosynthetic feat, I will employ heterologously produced enzymes to fully reconstitute the griseorhodin A biosynthetic pathway in vitro, which should allow for the identification of all enzymatic reactions, pathway intermediates, and uncharacterized griseorhodin analogues. Subsequent to their functional assignment, the key enzymes will be mechanistically and structurally characterized. An in-depth knowledge of this unprecedented redox-chemistry may then enable the bioengineering of the biosynthetic pathway in order to develop griseorhodin analogues with improved pharmacological features. I anticipate that my studies will have a profound impact on extending our mechanistic understanding of how chemical reactivity is controlled in nature, knowledge that is paramount to the emerging field of synthetic biology. As countless life processes depend on flavin cofactor catalysis, discovery of novel flavin biochemistry may ultimately shed light into various aspects of cell biology and physiology.

• DFG Programme: Independent Junior Research Groups