Hopanoids

Hopanoids are a diverse subclass of triterpenoids with the same hydrocarbon skeleton as the compound hopane. This group of pentacyclic molecules therefore refers to simple hopenes, hopanols and hopanes, but also to extensively functionalized derivatives such as bacteriohopanepolyols (BHP) and hopanoids covalently attached to lipid A.[1][2]

Some representative hopanoids: A. Diploptene, also called 22(29)-hopene B. Diplopterol (hopan-22-ol), the hydrated cyclomer of diploptene C. Bacteriohopanetetrol (BHT), a common extended hopanoid D. Hopane, the diagenetic product of A, B, and C
Cholesterol, a sterol compound.

The first known hopanoid, hydroxyhopanone, was isolated by two chemists at The National Gallery, London working on the chemistry of dammar gum, a natural resin used as a varnish for paintings.[3] The name hopane was derived from the genus Hopea (a source of the resin), which in turn was named after the botanist John Hope. Since this first finding in an angiosperm, however, hopanoids have been found in membranes of bacteria, lichens, bryophytes, ferns and fungi.[4] Because of their geostable structures, various hopanoids are preserved in petroleum reservoirs, rocks and sediment, allowing them to be used as biological markers.[5] Hopanoids have not been detected in archaea.[6][7]

Biological function

About 10% of sequenced bacterial genomes have a putative shc gene encoding a squalene-hopene cyclase and can presumably make hopanoids, which have been shown to play diverse roles in the plasma membrane and may allow some organisms to adapt in extreme environments.[8][8]

Since hopanoids modify plasma membrane properties in bacteria, they are frequently compared to sterols, such as cholesterol, which modulate membrane fluidity and serve other functions in eukaryotes.[9] Although hopanoids do not seem to rescue sterol deficiency, they do condense membranes and decrease permeability.[10] Also, gammaproteobacteria and eukaryotic organisms such as lichens and bryophytes have been shown to produce both sterols and hopanoids, suggesting these lipids may have other distinct functions.[4][11] Notably, the way hopanoids pack into the plasma membrane can change depending on what functional groups are attached. The hopanoid bacteriohopanetetrol assumes a transverse orientation in lipid bilayers, but diploptene localizes between the inner and outer leaflet, presumably thickening the membrane to decrease permeability.[12]

The hopanoid diplopterol orders membranes by interacting with lipid A, a common membrane lipid in bacteria, in ways similar to how cholesterol and sphingolipids interact in eukaryotic plasma membranes.[9] Diplopterol and cholesterol were demonstrated to promote condensation and inhibit gel-phase formation in both sphingomyelin monolayers and monolayers of glycan-modified lipid A. Furthermore, both diplopterol and cholesterol could rescue pH-dependent phase transitions in glycan-modified lipid A monolayers.[9] The role of hopanoids in membrane-mediated acid tolerance is further supported by observations of acid-inhibited growth and morphological abnormalities of the plasma membrane in hopanoid-deficient bacteria with mutant squalene-hopene cyclases.[13][14]

Hopanoids are produced in several nitrogen-fixing bacteria.[10] In the actinomycete Frankia, hopanoids in diazovesicle membranes likely restrict the entry of oxygen by making the lipid bilayer more tight and compact.[15] In Bradyrhizobium, hopanoids chemically bonded to lipid A increase membrane stability and rigidity, enhancing stress tolerance and intracellular survival in Aeschynomene legumes.[16] In the cyanobacterium Nostoc punctiforme, large quantities of 2-methylhopanoids localize to the outer membranes of survival structures called akinetes.[17] In another example of stress tolerance, hopanoids in the aerial hyphae (spore bearing structures) of the prokaryotic soil bacteria Streptomyces are thought to minimize water loss across the membrane to the air.[18]

Biosynthesis

Squalene synthesis

Since hopanoids are a C₃₀ terpenoid, biosynthesis begins with isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAP), which are combined to form longer chain isoprenoids.[2] Synthesis of these smaller precursors proceeds either via the mevalonate pathway or the methylerythritol-4-phosphate pathway depending on the bacterial species, although the latter tends to be more common.[19] DMAP condenses with one molecule of IPP to geranyl pyrophosphate, which in turn condenses with another IPP to generate farnesyl pyrophosphate.[2] Squalene synthase, coded for by the gene sqs, then catalyzes the condensation of two farnesyl pyrophosphate molecules to squalene while oxidizing NADPH.[20]

Active site of the squalene-hopene cyclase from Methylococcus capsulatus engaging the substrate, squalene, show in gold. Shown as a monomer rather than homodimer.

Cyclization
Alpha barrel structure of the squalene-hopene cyclase from Methylococcus capsulatus.

Next, a squalene-hopene cyclase catalyzes an elaborate cyclization reaction, engaging squalene in an energetically favorable all-chair conformation before creating 5 cycles, 6 covalent bonds, and 9 chiral centers on the molecule in a single step.[21][22] This enzyme, coded for by the gene shc, has a double ⍺-barrel fold characteristic of terpenoid biosynthesis[23] and is present in the cell as a monotopic homodimer, meaning pairs of the cyclase are embedded in but do not span the plasma membrane.[21][24] In vitro, this enzyme exhibits promiscuous substrate specificity, also cyclizing 2,3-oxidosqualene.[25]

Aromatic residues in the active site form several unfavorable carbocations on the substrate which are quenched by a rapid polycyclization.[22] In the last substep of the cyclization reaction, after electrons comprising the terminal alkene bond on the squalene have attacked the hopenyl carbocation to close the E ring, the C-22 carbocation may be quenched by mechanisms that lead to different hopanoid products. Nucleophilic attack of water will yield diplopterol, while deprotonation at an adjacent carbon will form one of several hopene isomers, often diploptene.[4]

Functionalization

After cyclization, hopanoids are frequently modified by hopanoid biosynthesis enzymes encoded by genes in the same operon as shc, hpn.[26] For instance, the radical SAM protein HpnH adds an adenosine group to diploptene, forming the extended C35 hopanoid adenosylhopane, which can then be further modified by other hpn gene products to form bacteriohopanetetrol (BHT).[27][28] Additional modification occurs as the glycosyltransferase HpnI converts BHT to N-acetylglucosaminyl-BHT.[29] In sequence, the hopanoid biosynthesis associated protein HpnK mediates deacetylation to glucosaminyl-BHT, from which radical SAM protein HpnJ generates a cyclitol ether.[29]

Importantly, C30 and C35 hopanoids alike may be methylated at C-2 and C-3 positions by the radical SAM methyltransferases HpnP and HpnR, respectively.[30][31] These two methylations are particularly geostable compared to side-chain modifications and have entertained geobiologists for decades.[10]

In a biosynthetic pathway exclusive to some bacteria, diploptene is a precursor for the pentacyclic triterpenoid tetrahymanol, which instead is produced directly from squalene by a cyclase in eukaryotes.[32]

In paleobiology

Hopanoids have been estimated to be the most abundant natural products on Earth, remaining in the organic fraction of all sediments, independent of age, origin or nature.[33] Biomolecules like DNA and proteins are degraded during diagenesis, but polycyclic lipids persist in the environment over geologic timescales due to their fused, stable structures.[34] Although hopanoids and sterols are reduced to hopanes and steranes during deposition, these diagenetic products can still be useful biomarkers, or molecular fossils, for studying the coevolution of early life and Earth.[34][35]

2-methylhopanes supposedly from photosynthetic cyanobacteria and steranes were reported by Roger Summons and colleagues as molecular fossils preserved in 2.7 Gya shales from the Pilbara region in Western Australia.[36] The presence of abundant 2-alpha-methylhopanes preserved in these shales was interpreted as evidence of oxygenic photosynthesis at least 2.7 Gya, unexpectedly suggesting a 400 million year gap between the evolution of oxygenic metabolism and when atmosphere became oxidizing. This interpretation of the biomarker record was challenged when Geobacter sulfurreducens was demonstrated to synthesize diverse hopanols, although not 2-methyl-hopanols, when grown under strictly anaerobic conditions.[8] The integrity of 2-methylhopanes as biomarkers for oxygenic photosynthesis was then further attenuated by evidence that the phototroph Rhodopseudomonas palustris produced 2-methyl-BHPs only under anoxic conditions.[37] Concrete evidence came from studies showing that not all cyanobacteria make hopanoids and that genes coding for the methyltransferase HpnP are present in nonphotosynthetic alphaproteobacteria and acidobacteria.[30][38]

Biomarker findings in the Pilbara-Craton shales were later rejected altogether during more recent evaluations of the fossil triterpenoid record.[39] Currently, the oldest detected triterpenoid fossils are Mesoproterozoic okenanes, steranes, and methylhopanes from a 1.64 Gya basin in Australia.[40] However, molecular clock analyses estimate that the earliest sterols were likely produced around 2.3 Gya, around the same time as the Great Oxidation Event, with hopanoid synthesis arising even earlier.[41]

For several reasons, hopanoids and squalene-hopene cyclases have been hypothesized to be more ancient than sterols and oxidosqualene cyclases. First, diplopterol is formed from water quenching the C-22 carbocation, meaning it can be made without molecular oxygen and could have served as a sterol surrogate before Earth's atmosphere became oxic. [1] Furthermore, squalene binds to squalene-hopene cyclases in a low-energy, all-chair conformation while oxidosqualene is cyclized in a more strained, chair-boat-chair-boat conformation.[4][42] Squalene-hopene cyclases also display more substrate promiscuity in that they cyclize oxidosqualene in vitro, causing some scientists to hypothesize that they are evolutionary predecessors to oxidosqualene cyclases.[42] Other scientists have proposed that squalene-hopene and oxidosqualene cyclases diverged from a common ancestor, a putative bacterial cyclase that would have made a tricyclic malabaricanoid or tetracyclic dammarinoid product.[1][43]

Industrial Relevance

The elegant mechanism behind the protonase activity of squalene-hopene cyclase was appreciated and adapted by chemical engineers at the University of Stuttgart, Germany. Active site engineering resulted in loss of the enzyme's ability to form hopanoids, but enabled Brønsted acid catalysis for the stereoselective cyclization of the monoterpenoids geraniol, epoxygeraniol, and citronellal.[44]

Agricultural Relevance

The application of hopanoids and hopanoid-producing nitrogen fixers has been proposed and patented as a biofertilizer technique that increases environmental resistance of plant-associated microbial symbionts.[45]

Medical Relevance

During later studies of interactions between diplopterol and lipid A in Methylobacterium extorquens, multidrug transport was found to be a hopanoid-dependent process. Squalene-hopene cyclase mutants derived from a wild type capable of multidrug efflux, a drug-resistance mechanism mediated by integral transport proteins, lost the ability to perform both multidrug transport and hopanoid synthesis.[46] Researchers indicate this could be due to direct regulation of transport proteins by hopanoids or indirectly by altering membrane ordering in a way that disrupts the transport system.[46]

gollark: Functional programming is another cool thing but also has a much steeper learning curve.
gollark: Yes, probably.
gollark: Go isn't exactly comparable to C, and I personally find it horrible.
gollark: Indeed.
gollark: Loads of libraries, though.

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