Methanobactins: Maintaining copper homeostasis in methanotrophs and beyond

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 reinternalization 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.Transition metals are key cofactors in metabolically important enzymes across all kingdoms of life (1). Nevertheless, careful control of cellular metal levels is required: a cellular surplus can limit viability due to oxidative stress (2), but metal starvation can also be fatal. Investigations of metal influx during conditions of metal scarcity have often been limited to iron, which is poorly bioavailable under aerobic conditions (3). Ironchelating natural products (siderophores) are secreted by many species, and iron from siderophores is incorporated into the cellular iron pool after re-internalization (4). While efflux has historically dominated studies of non-iron homeostasis, there is increasing evidence that similar systems exist for uptake of other metal ions (5, 6).

The manifold roles of microbial ribosomal peptide–based natural products in physiology and ecology

“…Remarkably, some methanotrophic bacteria secrete methanobactin RiPPs as chalkophores (i.e. compounds with high binding affinity for copper) to acquire copper from the environment (207) (Fig. 2 and Table 1).…”

Chalkophores

“…( g ) Potential identities for the “N-terminal” heterocycle in Mbns from Methylocystis species. Figure adapted with permission from References 25 and 215.…”

“…Abbreviations: ABC, ATP-binding cassette transporter; CuMbn, copper-chelated Mbn; ICM, intracytoplasmic membrane; IM, inner membrane; OM, outer membrane; pMMO, particulate methane monooxygenase; sMMO, soluble methane monooxygenase. Figure adapted with permission from References 25 and 215.…”

Genome Editing Reveals Novel Thiotemplated Assembly of Polythioamide Antibiotics in Anaerobic Bacteria

“…Communications adenine nucleotide hydrolases (AANH;6-thioguanine [10] and thio-tRNAb iosynthesis [2b] ), YcaO proteins (thioviridamide biosynthesis [2a] and methyl-coenzyme Mr eductase maturation [11] ), and MbnB/MbnC proteins (methanobactin biosynthesis [7,12] ). However,t he R. cellulolyticum genome encoded too many AANH homologs and no YcaO or MbnB/MbnC homologs,preventing identification of acandidate CTAgene cluster.T herefore,weconsidered enzymes for the biosynthesis of p-hydroxybenzoic acid (PHBA), ap otential building block of CTA.…”