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1. Novel sterol binding domains in bacteria

   https://doi.org/10.7554/eLife.90696.3  

   Zhai, Liting; Bonds, Amber C; Smith, Clyde A; Oo, Hannah; Chou, Jonathan Chiu-Chun; Welander, Paula V; Dassama, Laura MK (February 2024, eLife)

   Sterol lipids are widely present in eukaryotes and play essential roles in signaling and modulating membrane fluidity. Although rare, some bacteria also produce sterols, but their function in bacteria is not known. Moreover, many more species, including pathogens and commensal microbes, acquire or modify sterols from eukaryotic hosts through poorly understood molecular mechanisms. The aerobic methanotrophMethylococcus capsulatuswas the first bacterium shown to synthesize sterols, producing a mixture of C-4 methylated sterols that are distinct from those observed in eukaryotes. C-4 methylated sterols are synthesized in the cytosol and localized to the outer membrane, suggesting that a bacterial sterol transport machinery exists. Until now, the identity of such machinery remained a mystery. In this study, we identified three novel proteins that may be the first examples of transporters for bacterial sterol lipids. The proteins, which all belong to well-studied families of bacterial metabolite transporters, are predicted to reside in the inner membrane, periplasm, and outer membrane ofM. capsulatus,and may work as a conduit to move modified sterols to the outer membrane. Quantitative analysis of ligand binding revealed their remarkable specificity for 4-methylsterols, and crystallographic structures coupled with docking and molecular dynamics simulations revealed the structural bases for substrate binding by two of the putative transporters. Their striking structural divergence from eukaryotic sterol transporters signals that they form a distinct sterol transport system within the bacterial domain. Finally, bioinformatics revealed the widespread presence of similar transporters in bacterial genomes, including in some pathogens that use host sterol lipids to construct their cell envelopes. The unique folds of these bacterial sterol binding proteins should now guide the discovery of other proteins that handle this essential metabolite. 

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2. De novo cholesterol biosynthesis in bacteria

   https://doi.org/10.1038/s41467-023-38638-8  

   Lee, Alysha K.; Wei, Jeremy H.; Welander, Paula V. (May 2023, Nature Communications)

   Abstract Eukaryotes produce highly modified sterols, including cholesterol, essential to eukaryotic physiology. Although few bacterial species are known to produce sterols, de novo production of cholesterol or other complex sterols in bacteria has not been reported. Here, we show that the marine myxobacteriumEnhygromyxa salinaproduces cholesterol and provide evidence for further downstream modifications. Through bioinformatic analysis we identify a putative cholesterol biosynthesis pathway inE. salinalargely homologous to the eukaryotic pathway. However, experimental evidence indicates that complete demethylation at C-4 occurs through unique bacterial proteins, distinguishing bacterial and eukaryotic cholesterol biosynthesis. Additionally, proteins from the cyanobacteriumCalothrixsp. NIES-4105 are also capable of fully demethylating sterols at the C-4 position, suggesting complex sterol biosynthesis may be found in other bacterial phyla. Our results reveal an unappreciated complexity in bacterial sterol production that rivals eukaryotes and highlight the complicated evolutionary relationship between sterol biosynthesis in the bacterial and eukaryotic domains. 

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3. Common origin of sterol biosynthesis points to a feeding strategy shift in Neoproterozoic animals

   https://doi.org/10.1038/s41467-023-43545-z  

   Brunoir, T.; Mulligan, C.; Sistiaga, A.; Vuu, K. M.; Shih, P. M.; O’Reilly, S. S.; Summons, R. E.; Gold, D. A. (December 2023, Nature Communications)

   Abstract Steranes preserved in sedimentary rocks serve as molecular fossils, which are thought to record the expansion of eukaryote life through the Neoproterozoic Era ( ~ 1000-541 Ma). Scientists hypothesize that ancient C₂₇steranes originated from cholesterol, the major sterol produced by living red algae and animals. Similarly, C₂₈and C₂₉steranes are thought to be derived from the sterols of prehistoric fungi, green algae, and other microbial eukaryotes. However, recent work on annelid worms–an advanced group of eumetazoan animals–shows that they are also capable of producing C₂₈and C₂₉sterols. In this paper, we explore the evolutionary history of the24-C sterol methyltransferase(smt) gene in animals, which is required to make C₂₈₊sterols. We find evidence that thesmtgene was vertically inherited through animals, suggesting early eumetazoans were capable of C₂₈₊sterol synthesis. Our molecular clock of the animalsmtgene demonstrates that its diversification coincides with the rise of C₂₈and C₂₉steranes in the Neoproterozoic. This study supports the hypothesis that early eumetazoans were capable of making C₂₈₊sterols and that many animal lineages independently abandoned its biosynthesis around the end-Neoproterozoic, coinciding with the rise of abundant eukaryotic prey. 

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4. Sterol–lipids enable large-scale, liquid–liquid phase separation in bilayer membranes of only two components

   https://doi.org/10.1073/pnas.2401241121  

   Wilson, Kent J; Nguyen, Huy Q; Gervay-Hague, Jacquelyn; Keller, Sarah L (September 2024, Proceedings of the National Academy of Sciences)

   Despite longstanding excitement and progress toward understanding liquid–liquid phase separation in natural and artificial membranes, fundamental questions have persisted about which molecules are required for this phenomenon. Except in extraordinary circumstances, the smallest number of components that has produced large-scale, liquid–liquid phase separation in bilayers has stubbornly remained at three: a sterol, a phospholipid with ordered chains, and a phospholipid with disordered chains. This requirement of three components is puzzling because only two components are required for liquid–liquid phase separation in lipid monolayers, which resemble half of a bilayer. Inspired by reports that sterols interact closely with lipids with ordered chains, we tested whether phase separation would occur in bilayers in which a sterol and lipid were replaced by a single, joined sterol–lipid. By evaluating a panel of sterol–lipids, some of which are present in bacteria, we found a minimal bilayer of only two components (PChemsPC and diPhyPC) that robustly demixes into micron-scale, liquid phases. It suggests an additional role for sterol–lipids in nature, and it reveals a membrane in which tie-lines (and, therefore, the lipid composition of each phase) are straightforward to determine and will be consistent across multiple laboratories. 

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5. Analysis of Sterol Diagenesis Stages in a Peat Core from Kamchatka, Russia

   Ogus, T.; Nichols, J. E.; Peteet, D. M.; Andreev, A. (December 2018, American Geophysical Union, Fall Meeting 2018, abstract #PP23A-05)

   Peatlands are a critical part of the global carbon cycle. While many studies of peat carbon focus on accumulation, less is known about peat decay. We use the diagenesis of sterols to track the decomposition of peat in a Holocene-length core of a sedge fen on the Kamchatka Peninsula, Russia. Diagenesis can transform sterols as soon as the peat is initially deposited, but they can also remain unchanged for millennia. We have quantified the transformation of sterols into their diagenetic products to measure the maturity of peat and estimate carbon loss. Further, there are two pathways in sterol diagenesis, oxidative and reductive, and the products of these two pathways can indicate the conditions under which the peat degraded. This project focuses on the transformations of cholesterol, campasterol, and β- sitosterol, to cholestanol, campastanol, and stigmasta-3,5-diene-7-one, respectively. During the late Glacial period (before 10 ka) the oxidative pathway dominated sedimentary sterol transformation, indicating strongly reducing conditions. These sediments were deposited before the site transitioned to a peatland, and are dominated by sapropel, supporting the steroid evidence for reducing conditions. During the Early Holocene, (about 8 -6 ka) sterols, and, presumably, peat, were well preserved, and coincided with high carbon accumulation rates. In the middle Holocene (5 – 2 ka) the reductive diagenetic pathway dominated, indicating oxidizing conditions, and coincided with low rates of C accumulation. At 2.5 ka, conditions favoring the preservation of sterols returned, along with higher C accumulation. 

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