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

Research Interests

Methanotrophic bacteria oxidize methane to methanol in the first step of their metabolic pathway. 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 primary MMO in nature, particulate MMO (pMMO), is a th ree-subunit, integral membrane protein. Despite extensive research and the availability of multiple crystal structures, the active site structure and chemical mechanism of pMMO remain one of the major unsolved problems 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, and probing the function of pMMO 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, unraveling the mechanisms of its biosynthesis, and characterizing proteins and transporters involved in Mbn and copper import and export.

Selected Publications

Palmer, C. D.; Gamage, M. A. H.; Ho, M. B.; Withanage, N. T. L.; Hadley, R. C.; Hoffman, B. M.; Meloni, G.; Rosenzweig, A. C. A redox- and proton-coupled inner membrane transporter mediates copper import to the bacterial cytoplasm. Proc. Nat. Acad. Sci. USA 2026, 123, e2601726123

Tucci, F. J.; Rosenzweig, A. C. Structures of methane and ammonia monooxygenases in native membranes. Proc. Natl. Acad. Sci. USA 2024, 122, e2417993121.

Reyes, R. M.; Rosenzweig, A. C. Methanobactins: structures, biosynthesis, and microbial diversity. Annu. Rev. Microbiol.2024, 78, 383

Jodts, R. J.; Ho, M. B.; Reyes, R. M.; Park, Y. J.; Doan, P. E.; Rosenzweig, A. C.; Hoffman, B. M. Initial steps in methanobactin biosynthesis: substrate binding by the mixed-valent diiron enzyme MbnBC. Biochemistry 2024, 63, 1170

Tucci, F. J.; Jodts, R. J.; Hoffman, B. M.; Rosenzweig, A. C. Product analog binding identifies the active site of particulate methane monooxygenase. Nat. Catal. 2023, 6, 1194.

Koo, C. W.; Tucci, F. J.; He, Y.; Rosenzweig, A. C. Recovery of particulate methane monooxygenase structure and activity in a lipid bilayer. Science 2022, 375, 1287-1291.

Park, Y. J.; Jodts, R. J.; Slater, J. W.; Reyes, R. M.; Winton, V. J.; Montaser, R. A.; Thomas, P. M.; Dowdle, W. B.; Ruiz, A.; Kelleher, N. L.; Bollinger, J. M., Jr.; Krebs, C.; Hoffman, B. M. Rosenzweig, A. C. A mixed valent Fe(II)Fe(III) species converts cysteine to an oxazolone/thioamide pair in methanobactin biosynthesis. Proc. Natl. Acad. Sci. USA 2022, 119, e2123566119.

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