Amy C. Rosenzweig Structure, function, & mechanism of metalloproteins and metalloenzymes

Research Interests

Current research in our laboratory focuses on methanotrophic bacteria, organisms that oxidize methane to methanol in the first step of their metabolic pathway. Methanotrophs have attracted much attention as a means of mitigating methane emissions and for their potential applications in bioconversion of methane to fuels and chemicals. Whereas current catalysts that can selectively activate the 105 kcal mol-1 C-H bond in methane require high temperatures and pressures, methanotrophs perform this chemistry under ambient conditions using methane monooxygenase (MMO) enzymes. The predominant MMO in nature, particulate MMO (pMMO), is a three-subunit, integral membrane protein. Despite extensive research and the availability of multiple crystal structures, the active site structure and chemical mechanism of pMMO remain a major unsolved problem in bioinorganic chemistry. Current efforts in the laboratory are directed at elucidating the atomic details of the copper active site, understanding the mechanisms of dioxygen activation and methane oxidation, including how substrates, products, electrons, and protons access the active site, delineating pathways for copper acquisition and loading into pMMO, and probing pMMO function within the larger context of methanotroph physiology.

In a related project, we are studying a natural product first identified in methanotrophs called methanobactin (Mbn). Mbn, a ribosomally-produced post-translationally modified natural product (RiPP) that binds copper with high affinity, is a potential copper chelating drug for human disorders of copper metabolism as well as a starting point for developing new metal-chelating drugs and antibiotics. All Mbns characterized thus far bind Cu(I) with two nitrogen-containing heterocycles and two adjacent thioamide groups. The biosynthetic and transport machinery for Mbn is encoded by operons, which are also found in a range of non-methanotrophic bacteria, including gram-positive pathogens, suggesting a broader role in and perhaps beyond copper acquisition. Current efforts in the laboratory are focused on discovering new Mbns and related natural products, characterizing the proteins involved in Mbn export and import, and unraveling the mechanisms of its biosynthesis. 

Selected Publications

Native top-down mass spectrometry provides insights into the copper centers of membrane-bound methane monooxygenase. Ro SY, Schachner LF, Koo CW, Purohit R, Remis JP, Kenney GE, Liauw BW, Thomas PM, Patrie SM, Kelleher NL, and Rosenzweig AC. Nature Communications. 2019 June 17;10:2675.

Particulate methane monooxygenase contains only mononuclear copper centers. Ross MO, MacMillan F, Wang J, Nisthal A, Lawton TJ, Olafson BD, Mayo SL, Rosenzweig AC, and Hoffman BM. Science. 2019 May 10;364(6440):566-570.

Characterization of a long overlooked copper protein from methane- and ammonia-oxidizing bacteria. Fisher OS, Kenney GE, Ross MO, Ro SY, Lemma BE, Batelu S, Thomas PM, Sosnowski VC, DeHart CJ, Kelleher NL, Stemmler TL, Hoffman BM, and Rosenzweig AC. Nature Communications. 2018 October 15;9:4276.

The biosynthesis of methanobactin. Kenney GE, Dassama LMK, Pandelia M-E, Gizzi AS, Martinie RJ, Gao P, DeHart CJ, Schachner LF, Skinner OS, Ro SY, Zhu X, Sadek M, Thomas PM, Almo SC, Bollinger JM, Krebs C, Kelleher NL, and Rosenzweig AC. Science. 2018 March 23;359(6382):1411-1416.

Cu+-specific CopB transporter: Revising P1B-type ATPase classification. Purohit R, Ross MO, Batelu S, Kusowski A, Stemmler TL, Hoffman BM, and Rosenzweig AC. PNAS. 2018 February 27;115(9):2108-2113.

 View all publications by Amy C. Rosenzweig listed in the National Library of Medicine (PubMed). Current and former IBiS students in blue.