A mycobacterial ABC transporter mediates the uptake of hydrophilic compounds

Rempel, S.; Gati, Cornelius; Nijland, Mark; Thangaratnarajah, Chancievan; Karyolaimos, Alexandros; Gier, J.W. de; Guskov, Albert; Slotboom, Dirk-Jan

doi:10.1038/s41586-020-2072-8

Cited by 87 publications

(99 citation statements)

References 41 publications

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“…Despite the name, it has generally not been experimentally demonstrated that exporters have a unique transport directionality, or how this directionality is maintained. An informative example is provided by the recent studies of mycobacterial ABC transporters with exporter folds that mediate the uptake of various water-soluble compounds ( 6 , 7 ). The structural characterization of ABC exporters in distinct conformational states has been achieved primarily by controlling the nucleotide state, often in combination with the ATPase deficient “E-to-Q” mutant in the Walker-B motif ( 8 ).…”

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confidence: 99%

A structural framework for unidirectional transport by a bacterial ABC exporter

Fan

Kaiser

Rees

2020

Proc. Natl. Acad. Sci. U.S.A.

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The ATP-binding cassette (ABC) transporter of mitochondria (Atm1) mediates iron homeostasis in eukaryotes, while the prokaryotic homolog from Novosphingobium aromaticivorans (NaAtm1) can export glutathione derivatives and confer protection against heavy-metal toxicity. To establish the structural framework underlying the NaAtm1 transport mechanism, we determined eight structures by X-ray crystallography and single-particle cryo-electron microscopy in distinct conformational states, stabilized by individual disulfide crosslinks and nucleotides. As NaAtm1 progresses through the transport cycle, conformational changes in transmembrane helix 6 (TM6) alter the glutathione-binding site and the associated substrate-binding cavity. Significantly, kinking of TM6 in the post-ATP hydrolysis state stabilized by MgADPVO4 eliminates this cavity, precluding uptake of glutathione derivatives. The presence of this cavity during the transition from the inward-facing to outward-facing conformational states, and its absence in the reverse direction, thereby provide an elegant and conceptually simple mechanism for enforcing the export directionality of transport by NaAtm1. One of the disulfide crosslinked NaAtm1 variants characterized in this work retains significant glutathione transport activity, suggesting that ATP hydrolysis and substrate transport by Atm1 may involve a limited set of conformational states with minimal separation of the nucleotide-binding domains in the inward-facing conformation.

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confidence: 99%

A structural framework for unidirectional transport by a bacterial ABC exporter

Fan

Kaiser

Rees

2020

Proc. Natl. Acad. Sci. U.S.A.

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“…We also observed overexpression of histidine metabolism in DKD; its product histamine might be involved in mediating the inflammatory response [ 51 ]. ABC transporters mediate the transport of hydrophilic compounds and promote the growth of various bacteria, such as Mycobacterium tuberculosis [ 52 ]. The PTS is involved in the phosphorylation of sugars [ 53 ], and the interconversion of pentose and glucoronate provides substrates for the synthesis of nucleic acids and maintains the reducing state of glutathione.…”

Section: Discussionmentioning

confidence: 99%

The gut microbiome in differential diagnosis of diabetic kidney disease and membranous nephropathy

Shang

Guo

et al. 2020

Renal Failure

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Background Diabetic kidney disease (DKD) and membranous nephropathy (MN) are the two major causes of end-stage renal disease (ESRD). Increasing evidence has shown that intestinal dysbiosis is associated with many diseases. The aim of this study was to explore the composition of the gut microbiome in DKD and MN patients. Methods 16S rRNA gene sequencing was performed on 271 fecal samples (DKD = 129 and MN = 142), and taxonomic annotation of microbial composition and function was completed. Results We observed distinct microbial communities between the two groups, with MN samples exhibiting more severe dysbiosis than DKD samples. Relative increases in genera producing short-chain fatty acids (SCFAs) in DKD and a higher proportion of potential pathogens in MN were the main contributors to the microbiome alterations in the two groups. Five-fold cross-validation was performed on a random forest model, and four operational taxonomic unit (OTU)-based microbial markers were selected to distinguish DKD from MN. The results showed 92.42% accuracy in the training set and 94.52% accuracy in the testing set, indicating high potential for these microbiome-based markers in separating MN from DKD. Overexpression of several amino acid metabolic pathways, carbohydrate metabolism and lipid metabolism was found in DKD, while interconversion of pentose/glucoronate and membrane transport in relation to ABC transporters and the phosphotransferase system were increased in MN. Conclusion The composition of the gut microbiome appears to differ considerably between patients with DKD and those with MN. Thus, microbiome-based markers could be used as an alternative tool to distinguish DKD and MN.

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“…It therefore appears that cobamide remodeling mechanisms have independently evolved multiple times. Together with the multiple pathways that exist for cobamide biosynthesis, transport, and precursor salvaging (31,33,35,(93)(94)(95)(96)(97)(98)(99), the addition of CbiR to the growing list of enzymes involved in cobamide metabolism highlights the importance of cobamide physiology in the evolution of bacteria.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel cobamide remodeling enzyme in the beneficial human gut bacteriumAkkermansia muciniphila

Mok

Sokolovskaya

Nicolas

et al. 2020

Preprint

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The beneficial human gut bacterium Akkermansia muciniphila provides metabolites to other members of the gut microbiota by breaking down host mucin, but most of its other metabolic functions have not been investigated. A. muciniphila is known to use cobamides, the vitamin B12 family of cofactors with structural diversity in the lower ligand, though the specific cobamides it can use have not been examined. We found that growth of A. muciniphila strain MucT was nearly identical with each of seven cobamides tested, in contrast to nearly all bacteria that have been studied. Unexpectedly, this promiscuity is due to cobamide remodeling – the removal and replacement of the lower ligand – despite the absence of the canonical remodeling enzyme CbiZ in A. muciniphila. We identified a novel enzyme, CbiR, that is capable of initiating the remodeling process by hydrolyzing the phosphoribosyl bond in the nucleotide loop of cobamides. CbiR does not share homology with other cobamide remodeling enzymes or B12-binding domains, and instead is a member of the AP endonuclease 2 enzyme superfamily. We speculate that CbiR enables bacteria to repurpose cobamides they otherwise cannot use in order to grow under a cobamide-requiring condition; this function was confirmed by heterologous expression of cbiR in E. coli. Homologs of CbiR are found in over 200 microbial taxa across 22 phyla, suggesting that many bacteria may use CbiR to gain access to the diverse cobamides present in their environment.ImportanceCobamides, the vitamin B12 family of cobalt-containing cofactors, are required for metabolism in all domains of life, including most bacteria. Cobamides have structural variability in the lower ligand, and selectivity for particular cobamides has been observed in most organisms studied to date. Here, we discover that the beneficial human gut bacterium Akkermansia muciniphila can use a diverse range of cobamides due to its ability to change the cobamide structure via “cobamide remodeling”. We identify and characterize the novel enzyme CbiR that is necessary for initiating the cobamide remodeling process. The discovery of this enzyme has implications not only for understanding the ecological role of A. muciniphila in the gut, but for other bacteria that carry this enzyme as well.

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A mycobacterial ABC transporter mediates the uptake of hydrophilic compounds

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Cited by 87 publications

References 41 publications

A structural framework for unidirectional transport by a bacterial ABC exporter

A structural framework for unidirectional transport by a bacterial ABC exporter

The gut microbiome in differential diagnosis of diabetic kidney disease and membranous nephropathy

Identification of a novel cobamide remodeling enzyme in the beneficial human gut bacteriumAkkermansia muciniphila

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