Diana Downs

The goal of the research in my laboratory is to understand the integration of metabolic pathways that results in the robust physiology associated with microbes.  In this effort we emphasize a biochemical genetic approach that utilizes in vivo analyses to inform the design of in vitro experiments. Currently the work in the lab is in two general areas.

1) Understanding the Rid system of endogenous metabolite stress.  My laboratory identified a new stress system that is conserved across all domains.  We showed that enamine metabolites, which are necessary intermediates in some PLP-dependent reactions, are able to damage cellular components. The RidA protein family  is responsible for deaminating the enamines to generate stable keto acid products.  These findings have opened an exciting new field of study in the lab. Immediate questions include; which enzymes generate enamine stressors? Which enzymes are targets of the damage? What is the specificity of RidA homologs? What are the biochemical consequences of lacking RidA in various organisms.  This project has not only defined a new stress and cellular response to it, but has implications for our understanding of the composition and characteristics of the cellular milieu.

2) Exploring metabolic integration and redundancy. By virtue of the selective pressure exerted through millions of years of evolution, a living cell is likely to be the most well tuned and complex system in existence. The research in the laboratory takes advantage of the emerging technologies to better understand molecular details of metabolic processes and identify the mechanisms used to integrate these processes into a productive physiology.  In our study of metabolic integration, we use a well-characterized biosynthetic pathway as a “nucleation point” from which to build and expand a model system.  Our strategy has been to utilize genetic techniques to identify metabolic connections to this central pathway and thus build a defined network that we can then dissect on the molecular level. A solid understanding of metabolic integration is critical for the advancement of many fields including; metabolic diseases, drug discovery, synthetic biology, successful manipulation of microbes for societal uses, etc.

Students from my laboratory have strong training in classical and molecular genetics particularly as applied to metabolic questions.  In addition they are exposed to, and utilize, standard biochemical and molecular biological approaches.  The students are encouraged to think logically about big biological questions and how to tease them apart. I strive to train students to think beyond linear pathways and transcriptional regulation to appreciate the integrated nature of metabolism and the inherent chemistry.