Genetics and Biosynthesis of Novel Forms of Methanobactin

Regents Of The University Of Michigan - Ann Arbor, Ann Arbor MI

Investigators

Abstract

Trace metals, including copper, are essential for all forms of life. Copper, however, can be toxic at high levels. The human body must carefully and continuously remove excess copper. Wilson Disease is a congenital disorder where the body cannot control internal copper levels. This results in serious and irreversible damage to the liver and brain that is fatal if untreated. Current FDA-approved therapies are of no use if acute organ damage has already occurred, and in some patients, simply do not work. Better therapies are needed to treat Wilson Disease. Some bacteria produce a novel compound called methanobactin that binds copper extremely strongly. Based on animal studies, it has great potential to treat even advanced cases of Wilson Disease. This project will identify how bacteria synthesize methanobactin and craft strategies to enhance its production so it can be used in clinical trials. Further, “hands-on” science experiments will be developed and delivered to 3rd grade students at a local elementary school. The explicit objective of this effort is to engage and excite young children in science such that that they will pursue STEM careers in the future. Copper is critical for the activity of aerobic methane-oxidizing bacteria. To collect copper, some methanotrophs produce a copper binding compound, or chalkophore, called methanobactin. It is a ribosomally synthesized post-translationally modified polypeptide (RiPP). Methanobactin has exceptional promise in the treatment of copper-related human disorders, particularly Wilson Disease. Efforts to use methanobactin as a treatment option for these diseases are hindered by a lack of detailed knowledge regarding the genetics underlying methanobactin biosynthesis and an inability to scale up methanobactin production. Herein, a three-pronged strategy will be used to: (1) delineate the function of all the genes in the methanobactin gene cluster, (2) make modified forms of methanobactin that have the potential to expand the range of copper-related disorders methanobactin can be used to treat, and (3) characterize the mechanism whereby a key regulatory element controls methanobactin gene expression. Collectively, these efforts will not only enable us to define the entire biosynthetic pathway of methanobactin production, but also provide critical insights into how best to increase methanobactin production to accelerate its use in clinical trials. 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.