Methanobactin: An Intriguing Copper-Chelating Peptide with a Unique Biosynthesis

Methanotrophs produce methanobactin (Mbn), a copper-chelating peptide, when copper levels in the environment are low.^1,2 These methanotrophs utilize the copper-dependent enzyme methane monooxygenase to oxidize methane, which is the methanotrophs only carbon source. Mbn has a high affinity for copper and chelates Cu(I) directly, or indirectly utilizes Cu(II) by conversion to Cu(I) through an unknown reductive process.^2,3 Mbn is an example of RiPPs, or ribosomally synthesized and post-translationally modified peptides, and these modifications are performed by two proteins, MbnB and MbnC, which, as the active complex MbnBC, modify MbnA, a precursor peptide.^1–3 Mbn includes two bidentate ligands that are composed of an oxazolone ring and a thioamide group, serving as “pincers” for the chelation of copper.^1,2,4 Current research has centered on the structural attributes of the MbnB and MbnC and how these characteristics enable the modification of MbnA, providing insight to the mechanism in which Mbn is formed.^4,5 MbnB has been found to contain either diiron or triiron clusters that function to catalyze the conversion of MbnA’s cysteines to the bidentate ligands, while MbnC’s function is still being investigated.^2,4,5 Research on the biosynthesis of Mbn can serve in the development of therapeutics for the treatment of copper accumulation-related disorders, such as Wilson’s disease, along with expanding our knowledge of non-heme multinuclear iron-dependent enzymes and the various reactions they can catalyze. 

References

(1)        DiSpirito, A. A., et. al. Methanobactin and the Link between Copper and Bacterial Methane Oxidation. Microbiol. Mol. Biol. Rev. MMBR. 2016. 80 (2), 387–409. 

(2)        Kenney, G. E., et. al. The Biosynthesis of Methanobactin. Science. 2018. 359 (6382), 1411–1416. 

(3)        Kenney, G. E.; Rosenzweig, A. C. Chalkophores. Annu. Rev. Biochem. 2018. 87, 645–676. 

(4)        Park, Y. J., et. al. A Mixed-Valent Fe(II)Fe(III) Species Converts Cysteine to an Oxazolone/Thioamide Pair in Methanobactin Biosynthesis. Proc. Natl. Acad. Sci. U. S. A. 2022. 119 (13), e2123566119. 

(5)        Dou, C., et. al. Crystal Structure and Catalytic Mechanism of the MbnBC Holoenzyme Required for Methanobactin Biosynthesis. Cell Res. 2022. 32 (3), 302–314.