Hopanoids as functional analogues of cholesterol in bacterial membranes

Abstract

The functionality of cellular membranes relies on the molecular order imparted by lipids. In eukaryotes, sterols such as cholesterol modulate membrane order, yet they are not typically found in prokaryotes. The structurally similar bacterial hopanoids exhibit similar ordering properties as sterols in vitro, but their exact physiological role in living bacteria is relatively uncharted. We present evidence that hopanoids interact with glycolipids in bacterial outer membranes to form a highly ordered bilayer in a manner analogous to the interaction of sterols with sphingolipids in eukaryotic plasma membranes. Furthermore, multidrug transport is impaired in a hopanoid-deficient mutant of the gram-negative Methylobacterium extorquens, which introduces a link between membrane order and an energy-dependent, membrane-associated function in prokaryotes. Thus, we reveal a convergence in the architecture of bacterial and eukaryotic membranes and implicate the biosynthetic pathways of hopanoids and other order-modulating lipids as potential targets to fight pathogenic multidrug resistance.

Synthesis of arborane triterpenols by a bacterial oxidosqualene cyclase

“…In addition to sterols, plants synthesize a diverse array of cyclic triterpenoids that have a variety of functions, including defense against pests and pathogens (5-7). A few bacteria have been shown to produce sterols (8), however, the most common bacterial cyclic triterpenoids are the pentacyclic hopanoids, which are thought to function as "sterol surrogates" in bacterial membranes (9,10). Although the majority of interest in cyclic triterpenoids stems from their essential physiological roles and unique enzymatic biosynthesis (5,7,11), these lipids are also significant from a geological perspective.…”

Ordered Membrane Domain-Forming Properties of the Lipids of Borrelia burgdorferi

“…This shows that the acyl chain and galactose of ACGal are not absolutely required for domain formation in these mixtures. However, domains did not form, at least above 20 C, in 1:1 MGalD/Bb.PC vesicles lacking cholesterol lipids. The difference in F/Fo values at low temperature in mixtures containing cholesterol and ACGal could reflect a greater degree of donor and acceptor segregation due to a higher degree of ordered-domain formation in the vesicles with ACGal compared to those with cholesterol or a greater difference in the partitioning of donor and acceptor into ordered domains.…”

“…However, cholesterol, presumably acquired from the host or environment, is present in bacteria such as Mycoplasma, Ehrlichia, Anaplasma, Brachyspira, Helicobacter, and Borrelia (14)(15)(16)(17)(18). In addition, other bacteria have molecules with cholesterol-like properties (e.g., hopanoids), and may use them to form membrane microdomains (19)(20)(21)(22).…”

Cholesterol and nicotinic acetylcholine receptor: An intimate nanometer-scale spatial relationship spanning the billion year time-scale

“…Using a combination of deuterium NMR spectroscopy on multilamellar lipid-sterol systems in combination with Monte Carlo simulations of microscopic models of lipid-sterol interactions, Mouritsen and coworkers [88] concluded that the evolution in the molecular chemistry from lanosterol to cholesterol is manifested in the increase in the ability of the sterols to promote and stabilize lipid order, in the form of the Lo phase in model phospholipid-sterol membranes. However, experimental work using the simplest of bacterial sterol surrogates, the hopanoid diplopterol, demonstrated that this property was also present in bacteria early in evolution [117,118]. The second requirement, i.e.…”

“…Some of these functionally relevant mutations are very close to or within CARC/CARC-like domains. It has been proposed that the hopanoids may have originally participated in the ordering of the membrane bilayer in bacteria [117,118]. We surmise that the counterpart, interacting lipid-recognition moiety in the transmembrane protein segments (the CARC or CRAC recognition domains), may have co-evolved with the lipid biosynthetic apparatus along phylogeny thus facilitating the capacity of some membrane proteins to be recruited into Lo domains in prokaryotic channel-forming and other membrane-embedded proteins; however, upon appearance of oxygenic photosynthesis and the cholesterol synthesizing machinery in the course of phylogeny, this lipid probably acquired protagonism in Eukaryotes and added further functions, such as aiding the process of transducing regulatory signals from the plasma membrane to the protein moiety.…”