The biogenic methanobactin is an effective chelator for copper in a rat model for Wilson disease

Summer, K; Lichtmannegger, Josef; Bandow, Nathan L.; Choi, Donghyun; DiSpirito, Alan A.; Michalke, Bernhard

doi:10.1016/j.jtemb.2010.12.002

Cited by 41 publications

(32 citation statements)

References 29 publications

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“…Current treatments have significant side effects, are incapable of mobilizing copper in both oxidation states, and/or chelate other physiologically relevant transition metals (163, 164). In a rat model of Wilson disease, Mbn can reverse acute liver failure (165, 166). Copper overload may also play a role in a range of neurological disorders (167), and if that role is verified, Mbns might be widely applicable as copper-chelating drugs.…”

Section: Methanobactinsmentioning

confidence: 99%

Chalkophores

Kenney

Rosenzweig

2018

Annu. Rev. Biochem.

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Copper-binding metallophores, or chalkophores, play a role in microbial copper homeostasis that is analogous to that of siderophores in iron homeostasis. The best-studied chalkophores are members of the methanobactin (Mbn) family—ribosomally produced, posttranslationally modified natural products first identified as copper chelators responsible for copper uptake in methane-oxidizing bacteria. To date, Mbns have been characterized exclusively in those species, but there is genomic evidence for their production in a much wider range of bacteria. This review addresses the current state of knowledge regarding the function, biosynthesis, transport, and regulation of Mbns. While the roles of several proteins in these processes are supported by substantial genetic and biochemical evidence, key aspects of Mbn manufacture, handling, and regulation remain unclear. In addition, other natural products that have been proposed to mediate copper uptake as well as metallophores that have biologically relevant roles involving copper binding, but not copper uptake, are discussed.

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Section: Methanobactinsmentioning

confidence: 99%

Chalkophores

Kenney

Rosenzweig

2018

Annu. Rev. Biochem.

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“…In the animal model for Wilson's disease, the Long Evans Cinnamon (LEC) rat, intravenous application of mb-OB3b extracted copper from the liver into the bile as Cu-mb-OB3b, without measurable side effects (213,222). It was also found that mb-OB3b reversed both the buildup of copper in liver mitochondria and protein cross-linking, allowing the liver to function normally (213), and also stripped copper from metallothionein (222). Insoluble forms of copper were not observed.…”

Section: Possible Therapeutic Treatment Of Human Ailmentsmentioning

confidence: 99%

Methanobactin and the Link between Copper and Bacterial Methane Oxidation

DiSpirito

Semrau

Murrell

et al. 2016

Microbiol Mol Biol Rev

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127

157

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SUMMARYMethanobactins (mbs) are low-molecular-mass (<1,200 Da) copper-binding peptides, or chalkophores, produced by many methane-oxidizing bacteria (methanotrophs). These molecules exhibit similarities to certain iron-binding siderophores but are expressed and secreted in response to copper limitation. Structurally, mbs are characterized by a pair of heterocyclic rings with associated thioamide groups that form the copper coordination site. One of the rings is always an oxazolone and the second ring an oxazolone, an imidazolone, or a pyrazinedione moiety. The mb molecule originates from a peptide precursor that undergoes a series of posttranslational modifications, including (i) ring formation, (ii) cleavage of a leader peptide sequence, and (iii) in some cases, addition of a sulfate group. Functionally, mbs represent the extracellular component of a copper acquisition system. Consistent with this role in copper acquisition, mbs have a high affinity for copper ions. Following binding, mbs rapidly reduce Cu2+to Cu1+. In addition to binding copper, mbs will bind most transition metals and near-transition metals and protect the host methanotroph as well as other bacteria from toxic metals. Several other physiological functions have been assigned to mbs, based primarily on their redox and metal-binding properties. In this review, we examine the current state of knowledge of this novel type of metal-binding peptide. We also explore its potential applications, how mbs may alter the bioavailability of multiple metals, and the many roles mbs may play in the physiology of methanotrophs.

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“…There is increasing interest in understanding the methanobactin biosynthesis pathway; e.g., it has been recently shown that methanobactin from M. trichosporium OB3b has the potential to treat individuals afflicted with Wilson disease (11)(12)(13). Wilson disease is an autosomal recessive disorder in which the body is unable to correctly assimilate copper, with copper accumulating in the liver and brain, and can result in severe and irreversible damage (14,15).…”

mentioning

confidence: 99%

An Aminotransferase Is Responsible for the Deamination of the N-Terminal Leucine and Required for Formation of Oxazolone Ring A in Methanobactin of Methylosinus trichosporium OB3b

Baral

DiSpirito

et al. 2017

Appl Environ Microbiol

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Gene expression in methanotrophs has been shown to be affected by the availability of a variety of metals, most notably copper-regulating expression of alternative forms of methane monooxygenase. A copper-binding compound, or chalkophore, called methanobactin plays a key role in copper uptake in methanotrophs. Methanobactin is a ribosomally synthesized and posttranslationally modified peptide (RiPP) with two heterocyclic rings with an associated thioamide for each ring, formed from X-Cys dipeptide sequences that bind copper. The gene coding for the precursor polypeptide of methanobactin, mbnA, is part of a gene cluster, but the role of other genes in methanobactin biosynthesis is unclear. To begin to elucidate the function of these genes, we constructed an unmarked deletion of mbnABCMN in Methylosinus trichosporium OB3b and then homologously expressed mbnABCM using a broad-host-range cloning vector to determine the function of mbnN, annotated as coding for an aminotransferase. Methanobactin produced by this strain was found to be substantially different from wild-type methanobactin in that the C-terminal methionine was missing and only one of the two oxazolone rings was formed. Rather, in place of the N-terminal 3-methylbutanoyl-oxazolone-thioamide group, a leucine and a thioamide-containing glycine (Gly-⌿) were found, indicating that MbnN is used for deamination of the N-terminal leucine of methanobactin and that this posttranslational modification is critical for closure of the N-terminal oxazolone ring in M. trichosporium OB3b. These studies provide new insights into methanobactin biosynthesis and also provide a platform for understanding the function of other genes in the methanobactin gene cluster.

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The biogenic methanobactin is an effective chelator for copper in a rat model for Wilson disease

Cited by 41 publications

References 29 publications

Chalkophores

Chalkophores

Methanobactin and the Link between Copper and Bacterial Methane Oxidation

An Aminotransferase Is Responsible for the Deamination of the N-Terminal Leucine and Required for Formation of Oxazolone Ring A in Methanobactin of Methylosinus trichosporium OB3b

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