De novo cholesterol biosynthesis in bacteria

Lee, Alysha K.; Wei, Jeremy H.; Welander, Paula V.

doi:10.1038/s41467-023-38638-8

Cited by 18 publications

(11 citation statements)

References 72 publications

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“…Enhygromyxa salina is an aerobic heterotrophic marine myxobacterium. A recent study reported that E. salina is capable of de novo cholesterol synthesis, [10] indicating the possible existence of unique lipid transporters in this bacterium. Use of Bst proteins in a search for putative sterol transporters in the E. salina genome revealed the presence of two homologs of BstC: one localized next to genes encoding homologs of DctP (a periplasmic solute binding protein), and DctQM (membrane proteins that typically mediate the import of small metabolites); we named this homolog of BstC in E. salina Es_TatT because this protein belongs to the TatT family.…”

Section: Bioinformatics On the T-component Of Tpat Systemsmentioning

confidence: 97%

“…Given that BstC in M. capsulatus binds sterols [9] and E. salina produces sterols, [10] we first investigated the ability of these proteins to bind to purified sterols. Using microscale thermophoresis (MST), we determine interactions with potential substrates that included cholesterol, lanosterol, and 4,4-dimethylsterol from M. capsulatus.…”

Section: Interaction Of the E Salina Proteins With Individual Lipophi...mentioning

confidence: 99%

“…Focusing on Enhygromyxa salina, a marine myxobacterium recently shown to make various forms of sterols, we identified two homologs of BstC. [10] One homolog resembles a traditional TPAT and has adjacent PQM homologs (we have called this protein Es_TatT), while the other has a BstB homolog (termed Es_BstC). Assessment of interactions with substrates shows that neither protein binds to sterols with appreciable affinity, but Es_TatT demonstrates a preference for fatty acids.…”

Section: Introductionmentioning

confidence: 99%

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Structures and Mechanisms of a Novel Bacterial Transport System for Fatty Acids

Zhai

Chou

et al. 2023

ChemBioChem

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Bacterial acquisition of metabolites is largely facilitated by transporters with unique substrate scopes. The tripartite ATPindependent periplasmic (TRAP) transporters comprise a large family of bacterial proteins that facilitate the uptake of a variety of small molecules. It has been reported that some TRAP systems encode a fourth protein, the T component. The Tcomponent, or TatT, is predicted to be a periplasmic-facing lipoprotein that enables the uptake of metabolites from the outer membrane. However, no substrates were revealed for any TatT and their functional role(s) remained enigmatic. We recently identified a homolog in Methylococcus capsulatus that binds to sterols, and herein, we report two additional homologs that demonstrate a preference for long-chain fatty acids. Our bioinformatics, quantitative analyses of protein-ligand interactions, and high-resolution crystal structures suggest that TatTs might facilitate the trafficking of hydrophobic or lipophilic substrates and represent a new class of bacterial lipid and fatty acid transporters.

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Section: Bioinformatics On the T-component Of Tpat Systemsmentioning

confidence: 97%

Section: Interaction Of the E Salina Proteins With Individual Lipophi...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structures and Mechanisms of a Novel Bacterial Transport System for Fatty Acids

Zhai

Chou

et al. 2023

ChemBioChem

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“…18C). 148,149 Furthermore, Liebeke and coworkers found that gutless marine annelids predominantly synthesized sitosterol, a plant sterol, by a noncanonical SMT, indicating the broader occurrence of plant-like sterol biosynthesis in animals. 150,151…”

Section: Methylation and Demethylationmentioning

confidence: 99%

Recent developments in the enzymatic modifications of steroid scaffolds

Wang,

Abe

2024

Org. Biomol. Chem.

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“…These biochemical transformations include demethylations, isomerizations, saturations, and desaturations that are essential for sterols to function properly in eukaryotes (Nes et al, 1993; Xu et al, 2005). Although bacterial production of fully modified sterols such as cholesterol is rare (Lee et al, 2023), some bacteria, including several aerobic methanotrophs and myxobacteria, do modify their sterols. For example, M. capsulatus produces sterols that are demethylated once at the C-4 and C-14 positions and contain a unique desaturation between C-8 and C-14 (Bouvier et al, 1976) (Fig.1A).…”

Section: Introductionmentioning

confidence: 99%

Novel sterol binding domains in bacteria

Zhai¹,

Bonds

Oo³

et al. 2022

Preprint

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Sterol lipids are widely present in eukaryotes and play essential roles in signaling and modulating membrane fluidity. Although rare, some bacteria species produce sterols, but their function in the bacterial domain remains unknown. The aerobic methanotroph Methylococcus capsulatus was the first bacterium shown to synthesize sterols, producing a mixture of C-4 methylated sterols that are distinct from those observed in eukaryotes. Subsequent studies demonstrated that C-4 methylated sterols synthesized in the cytosol are localized to the outer membrane, suggesting that a bacterial sterol transport machinery exists. While proteins involved in eukaryotic sterol transport have been identified and characterized, their counterparts in bacteria remain enigmatic. In this study, we used bioinformatics, ligand binding analysis, and structural approaches to identify three novel bacterial sterol transporters from Methylococcus capsulatus. These proteins reside in the inner membrane, periplasm, and outer member of the bacterium, thereby working as a conduit to move modified sterols to the outer membrane. We report their remarkable specificity for recognizing 4-methylsterols, reveal the structural bases for substrate binding, and describe their structural divergence from eukaryotic sterol transporters. These findings provide unequivocal evidence for a distinct sterol transport system within the bacterial domain, which provide insights into our understanding of bacterial sterols and their divergence from similar lipids in higher-order organisms.SignificanceSterol lipids, such as cholesterol, were once thought to be unique to eukaryotes. However, a few bacterial species also produce sterols, albeit with structural modifications not observed in eukaryotes. While little is known about the function of bacterial sterols, it is known that sterols in certain bacteria are localized to the outer membrane. However, how bacteria transport these lipids from the cytoplasm to the outer membrane remains unknown. Here, we identify three novel bacterial sterol transporter proteins in the bacterium Methylococcus capsulatus that bind sterols methylated at the C-4 position. Through structural characterization of these proteins, we reveal insights into the mechanisms of sterol transport in bacteria with implications for understanding how bacterial cells interact with sterol lipids more broadly.

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De novo cholesterol biosynthesis in bacteria

Cited by 18 publications

References 72 publications

Structures and Mechanisms of a Novel Bacterial Transport System for Fatty Acids

Structures and Mechanisms of a Novel Bacterial Transport System for Fatty Acids

Recent developments in the enzymatic modifications of steroid scaffolds

Novel sterol binding domains in bacteria

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