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. Methane is a potent greenhouse gas, with a global warming potential more than 84 times that of carbon dioxide over a 20 year period. Global warming presents a significant threat to human health, and as the only biological methane sink, methanotrophs have attracted much attention as a means of mitigating methane emissions. Moreover, increasing natural gas reserves combined with an ongoing price spread between natural gas and gasoline have led to renewed interest in bioconversion of methane. 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 three-subunit, integral membrane protein whose active site structure and chemical mechanism remain one of the major unsolved problems in bioinorganic chemistry. Current efforts in the laboratory are directed at elucidating the atomic details of the pMMO 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

A multi-active enzyme installs copper-binding oxazolone/thioamide pairs on a nontypeable Haemophilus influenzae virulence factor. Manley OM, Shriver TJ, Xu T, Melendrez IA, Palacios Philip, Robson SA, Guo Y, Kelleher NL, Ziarek JJ, and Rosenzweig AC. Proc. Natl. Acad. Sci. USA 2024 June 1;121:e2100680118. 

Direct Methane oxidation by copper- and iron-dependent methane monooxygenases. Tucci FJ, and Rosenzweig AC. Chem. Rev. 2024 February 2;124(3):1288-1320.

Product Analog binding identifies the copper active site of particulate methane monooxygenase. Tucci FJ, Jodts RJ, Hoffman BM, and Rosenzweig AC. Nat. Cal. 2023 November 6;6:1194-1204.

Recovery of particulate methane monooxygenase structure and activity in a lipid bilayer. Koo CW, Tucci FJ, He Y, and Rosenzweig AC. Science. 2022 March 18;375(6586):1287-1291.

A mixed-valent Fe(II)Fe(III) species converts cysteine to an oxazolone/thioamide pair in methanobactin biosynthesis. Park YJ, Jodts RJ, Slater JW, Reyes RM, Winton VJ, Montaser RA, Thomas PM, Dowdle WB, Ruiz A, Kelleher NL, Bollinger JM, Krebs C, Hoffman BM, and Rosenzweig AC. PNAS. 2022 March 29;119(13):e2408092121.

 

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