Metabolism and Biological Activities of 4-Methyl-Sterols

Darnet, Sylvain; Schaller, Hubert

doi:10.3390/molecules24030451

Cited by 34 publications

(30 citation statements)

References 166 publications

(212 reference statements)

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“…thesis in plants, mammals and fungi. The biochemical transformation requires the consecutive action of three enzymes widely conserved across phyla, namely sterol-4-methyl oxidase (SMO), 3-hydroxysteroid dehydrogenase/C4-decarboxylase (C4D), and a sterone ketoreductase (SKR) 52 . The complex is tethered to the membrane by ergosterol biosynthetic protein 28 (ERG28), a fourth protein that has no catalytic function but plays a key role in preventing accumulation of biosynthetic 4-methyl sterol intermediates 53,54 .…”

Section: C4-demetylation Of the Triterpene Precursor C4-demethylatiomentioning

confidence: 99%

Diatoms synthesize sterols by inclusion of animal and fungal genes in the plant pathway

Gallo

Landi

d’Ippolito

et al. 2020

Sci Rep

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Diatoms are ubiquitous microalgae that have developed remarkable metabolic plasticity and gene diversification. Here we report the first elucidation of the complete biosynthesis of sterols in the lineage. The study has been carried out on the bloom-forming species Skeletonema marinoi and Cyclotella cryptica that synthesise an ensemble of sterols with chemotypes of animals (cholesterol and desmosterol), plants (dihydrobrassicasterol and 24-methylene cholesterol), algae (fucosterol) and marine invertebrates (clionasterol). In both species, sterols derive from mevalonate through cyclization of squalene to cycloartenol by cycloartenol synthase. The pathway anticipates synthesis of cholesterol by enzymes of the phytosterol route in plants, as recently reported in Solanaceae. Major divergences stem from reduction of Δ24(28) and Δ24(25) double bonds which, in diatoms, are apparently dependent on sterol reductases of fungi, algae and animals. Phylogenetic comparison revealed a good level of similarity between the sterol biosynthetic genes of S. marinoi and C. cryptica with those in the genomes of the other diatoms sequenced so far. Sterols are vital components of all eukaryotic cells where they modulate structure and function of membranes and, as precursors of signaling molecules, they control growth and development. Plant sterols, commonly named phytosterols, are involved in morphogenesis, development, reproduction and stress response 1-3. Analogously, microalgal sterols showed critical physiological roles related to photosynthesis, growth, light response and fatty acid metabolism 4. Sterols are terpenes deriving from a complex process of polymerization of six isoprene units. In animals and fungi, the mevalonic acid (MVA) pathway is the only route for the biosynthesis of the isoprene units isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). In higher plants and algae, IPP and DMAPP derive either from the MVA pathway in the cytoplasm or the methylerythritol phosphate (MEP) pathway in the plastids 5. Without a clear cellular compartmentalization, both biochemical routes have been also reported in mosses and streptomyces. Sterol biosynthesis from IPP and DMAPP is generally taxa-specific and proceeds via lanosterol by lanosterol synthase (LSS) in nonphotosynthetic organisms (e.g. animals and fungi) or cycloartenol by cycloartenol synthase (CAS) in photosynthetic lineages (e.g. plants and algae) 6. Cholesterol is the major animal sterol but its biosynthesis in tomato has been recently shown to derive from a cycloartenol-dependent pathway composed of enzymes either shared with phytosterols or evolved from phytosterol biosynthetic genes 7. Furthermore, insects and lower eukaryotes, including marine invertebrates and a few microalgae, are suggested to convert phytosterols to cholesterol and vice versa 8-11. Diatoms represent an important component of the aquatic ecosystem 12,13 and form the largest biological group of marine phytoplankton 14,15. These microalgae are major global producers by contributing to...

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Section: C4-demetylation Of the Triterpene Precursor C4-demethylatiomentioning

confidence: 99%

Diatoms synthesize sterols by inclusion of animal and fungal genes in the plant pathway

Gallo

Landi

d’Ippolito

et al. 2020

Sci Rep

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“…However, this route is deemed impractical because no sterol  5 desaturase is believed to be active in C. elegans. An alternative metabolism of zymosterol may proceed as follows: saturation of the 24 (25) bond to form cholest-8-enol, followed by backward isomerization of the 8(9) bond to the 9(11) position, followed by ring-C7 desaturation to yield the  7,9(11) diene intermediate, then another backward migration, this time of the  7 bond to the 8(14) position, which is followed by C4 methylation to yield the C4-methylated cholesta-8(14),9(11)-dienol product (proposed pathway shown in supplemental Fig. 18).…”

Section: Elucidation Of a Cryptic Sterol Metabolism Backward Isomerizmentioning

confidence: 99%

“…1). In contrast to C4-methyl sterol utilization in sterol prototrophs, in which the C4-methyl group(s) is necessarily removed in conversion to cholesterol for growth support (25,26), in C. elegans the inclusion of a C4-methyl group on the metabolite product is essential for larval growth or to effect dauer formation (27)(28)(29)(30). This work nevertheless leaves open questions regarding the number, properties, and evolutionary origin of sterol metabolases in nematodes, most notably the 4-SMT that controls the balance of neutral C 28 to acidic C 27 sterols in C. elegans (23); its substrate specificity and reaction mechanism remain enigmatic.…”

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confidence: 99%

A nematode sterol C4α-methyltransferase catalyzes a new methylation reaction responsible for sterol diversity

Zhou

Fisher

Vanderloop

et al. 2020

Journal of Lipid Research

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Primitive sterol evolution plays an important role in fossil record interpretation and offers potential therapeutic avenues for human disease resulting from nematode infections. Recognizing that C4-methyl stenol products [8(14)-lophenol] can be synthesized in bacteria while C4-methyl stanol products (dinosterol) can be synthesized in dinoflagellates and preserved as sterane biomarkers in ancient sedimentary rock is key to eukaryotic sterol evolution. In this regard, nematodes have been proposed to convert dietary cholesterol to 8(14)-lophenol by a secondary metabolism pathway that could involve sterol C4 methylation analogous to the C2 methylation of hopanoids (radicle-type mechanism) or C24 methylation of sterols (carbocation-type mechanism). Here, we characterized dichotomous cholesterol metabolic pathways in Caenorhabditis elegans that generate 3-oxo sterol intermediates in separate paths to lophanol (4-methyl stanol) and 8(14)-lophenol (4-methyl stenol). We uncovered alternate C3-sterol oxidation and Δ7 desaturation steps that regulate sterol flux from which branching metabolite networks arise, while lophanol/8(14)-lophenol formation is shown to be dependent on a sterol C4α-methyltransferse (4-SMT) that requires 3-oxo sterol substrates and catalyzes a newly discovered 3-keto-enol tautomerism mechanism linked to S-adenosyl-l-methionine-dependent methylation. Alignment-specific substrate-binding domains similarly conserved in 4-SMT and 24-SMT enzymes, despite minimal amino acid sequence identity, suggests divergence from a common, primordial ancestor in the evolution of methyl sterols. The combination of these results provides evolutionary leads to sterol diversity and points to cryptic C4-methyl steroidogenic pathways of targeted convergence that mediate lineage-specific adaptations.

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“…Whereas C4-methylsterols generally serve as sterol biosynthetic intermediates (C4-SBIs) in most other organisms and cell types (14), they are pathway end-products in nematodes. This raises questions regarding the evolutionary origin of 4-SMT and, more generally, of other enzymes implicated in the "retro-cholesterol pathway" mentioned above as well as questions regarding the exact function(s) of C4-methylsterols.…”

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Worming our way toward multiple evolutionary origins of convergent sterol pathways

Darnet

Fliesler

Schaller

2020

Journal of Lipid Research

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Metabolism and Biological Activities of 4-Methyl-Sterols

Cited by 34 publications

References 166 publications

Diatoms synthesize sterols by inclusion of animal and fungal genes in the plant pathway

Diatoms synthesize sterols by inclusion of animal and fungal genes in the plant pathway

A nematode sterol C4α-methyltransferase catalyzes a new methylation reaction responsible for sterol diversity

Worming our way toward multiple evolutionary origins of convergent sterol pathways

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