Abstract
Methanobactins (Mbns) are ribosomally produced, post-translationally modified natural products that bind copper with high affinity and specificity. Originally identified in methanotrophic bacteria, which have a high need for copper, operons encoding these compounds have also been found in many non-methanotrophic bacteria. The proteins responsible for Mbn biosynthesis include several novel enzymes. Mbn transport involves export through a multidrug efflux pump and re-internalization via a TonB-dependent transporter. Release of copper from Mbn and the molecular basis for copper regulation of Mbn production remain to be elucidated. Future work is likely to result in the identification of new enzymatic chemistry, opportunities for bioengineering and drug targeting of copper metabolism, and an expanded understanding of microbial metal homeostasis.
Highlights
Mbn structuresThe crystal structure of copper-loaded Mbn (CuMbn) from Methylosinus (Ms.) trichosporium OB3b was assigned as N-2isopropylester–(4-thionyl-5-hydroxy-imidazole)–Gly1–Ser2– Cys3–Tyr4–pyrrolidine–(4-hydroxy-5-thionyl-imidazole)– Ser5–Cys6–Met, with a disulfide bridge between the two cysteine residues [17]
Transition metals are key cofactors in metabolically important enzymes across all kingdoms of life [1]
Operons encoding Mbn precursor peptides along with proteins involved in Mbn biosynthesis, transport, and regulation have been identified in a range of bacteria, including non-methanotrophs, in which Mbn is increasingly believed to play a similar role in copper homeostasis [19, 20]
Summary
The crystal structure of copper-loaded Mbn (CuMbn) from Methylosinus (Ms.) trichosporium OB3b was assigned as N-2isopropylester–(4-thionyl-5-hydroxy-imidazole)–Gly1–Ser2– Cys3–Tyr4–pyrrolidine–(4-hydroxy-5-thionyl-imidazole)– Ser5–Cys6–Met, with a disulfide bridge between the two cysteine residues [17]. The second heterocycle (heterocycle B) is an oxazolone, as in Ms trichosporium OB3b Mbn. Two additional Mbns from the Methylocystis species have been characterized via X-ray crystallography and a third closely related Mbn via mass spectrometry (Fig. 1, D–F). One explanation is that Methylocystis Mbns may contain a hydroxypyrazinone or pyrazinedione tautomer (Fig. 1G), which would contain a heterocyclic secondary amine, as observed by NMR, and the six-membered rings observed via X-ray crystallography. Supporting this notion, the non-copper-chelating nitrogen in heterocycle A in the Methylocystis Mbn crystal structures appears to be protonated [24]. Major spectral shifts occur upon copper binding [22, 27], and oxazolone-derived fluorescence is mostly abolished (26 –28)
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