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Worming our way toward multiple evolutionary origins of convergent sterol pathways1

Open AccessPublished:December 23, 2019DOI:https://doi.org/10.1194/jlr.C119000600
      Sterols represent one of the most ubiquitous and diverse classes of biological molecules derived from the common precursor, mevalonic acid. While there are thematically similar modes by which various organisms synthesize sterols, there also are some unique twists in the pathways by which such organisms produce sterols as well as differences in the chemical nature of the dominant resident sterol present at steady-state in a given organism or cell type. In this issue of the Journal of Lipid Research, David Nes and colleagues [Zhou et al. (
      • Zhou W.
      • Fisher P.M.
      • Vanderloop B.H.
      • Shen Y.
      • Shi H.
      • Maldonado A.J.
      • Leaver D.J.
      • Nes W.D.
      A nematode sterol C4alpha-methyltransferase catalyzes a new methylation reaction responsible for sterol diversity.
      )] present a compelling and novel story, wherein they have elucidated a previously unknown alternative biosynthetic pathway utilized by nematodes (roundworms, of which Caenorhabditis elegans is an exemplar) to generate C4-methyl sterols. This provides an evolutionary “missing link” along the continuum from prokaryotes to eukaryotes or, eventually, a singular divergent evolution of roundworms with regard to diversification of sterols and the metabolic routes accessible to them to achieve such diversity.
      After condensation of two molecules of the branch-point intermediate, farnesylpyrophosphate, to form the 30-carbon intermediate, squalene, and its subsequent epoxidation to form the epoxide 2,3-oxidosqualene, sterol biosynthesis proceeds through the cyclization of 2,3-oxidosqualene to form the steroidal tetracyclic C30H50O products, lanosterol or cycloartenol. Decades of sterol research in prominent laboratories have unveiled the core enzymatic and genetic equipment of eukaryotes that shape sterol end-products by isomerization, desaturation, and reduction of double bonds, as well as demethylation reactions of the committed precursors (
      • Benveniste P.
      Biosynthesis and accumulation of sterols.
      ,

      Schaller, H., 2010. Sterol and Steroid Biosynthesis and Metabolism in Plants and Microorganisms. In Comprehensive Natural Products II: Chemistry and Biology, Volumes 1–10. L. N. Mander and L. Hung-Wen, editors. Elsevier Science, Amsterdam. 755–787.

      ,
      • Nes W.D.
      Biosynthesis of cholesterol and other sterols.
      ,
      • Tamura T.
      • Akihisa T.
      • Kokke W.
      Naturally Occurring Sterols and Related Compounds from Plants.
      ), with ∆7, ∆5,7, and ∆5 unsaturated tetracyclic rings accounting for the major types of sterol structures. For example, cholesterol, a C27 monounsaturated (∆5) 3β-hydroxy sterol, is the dominant sterol, by far, at steady-state in mammalian cells. An important set of enzymes that increase sterol diversity in eukaryotes are the sterol-C-methyltransferases (hereafter called SMTs), which carry out the addition of exocyclic carbon atoms on the sterol side chain to produce C28, and C29 ergostane and stigmastane backbones, respectively, besides the C27 cholestane backbone. A powerful diversification in multigenic families of lineage-specific SMTs confers to eukaryotes the capacity to produce epimeric 24α-alkyl-∆5 sterols or 24β-alkyl-∆5 sterols with distinct functionalities (
      • Nakamoto M.
      • Schmit A.C.
      • Heintz D.
      • Schaller H.
      • Ohta D.
      Diversification of sterol methyltransferase enzymes in plants and a role for beta-sitosterol in oriented cell plate formation and polarized growth.
      ). Such diversification of sterol-C24-methyltransferases is causative of the segmented sterol biosynthesis of eukaryotes, especially in viridiplantae, where two distinct enzymes contribute to the production of campesterol (a 24α−methyl-∆5 sterol) and sitosterol (a 24α-ethyl-∆5 sterol) (Fig. 1). Variation in the position and number of double bonds in sterol side chains is common in nonmammalian eukaryotes, although many fungi synthesize ergosterol (a 24β-methyl-∆5,7 sterol) because of the activity of a single SMT gene (
      • Bouvier-Nave P.
      • Husselstein T.
      • Desprez T.
      • Benveniste P.
      Identification of cDNAs encoding sterol methyl-transferases involved in the second methylation step of plant sterol biosynthesis.
      ,
      • Husselstein T.
      • Gachotte D.
      • Desprez T.
      • Bard M.
      • Benveniste P.
      Transformation of Saccharomyces cerevisiae with a cDNA encoding a sterol C-methyltransferase from Arabidopsis thaliana results in the synthesis of 24-ethyl sterols.
      ) (Fig. 1). Although the origin of the lineage-specific sterol pathways remains unclear, it has been established that the earliest eukaryotes (sponges and heterokonts) had evolved sterol side chain alkylation by distinct SMT gene duplication events as far back as the Proterozoic era (about one billion years ago) (
      • Gold D.A.
      • Grabenstatter J.
      • de Mendoza A.
      • Riesgo A.
      • Ruiz-Trillo I.
      • Summons R.E.
      Sterol and genomic analyses validate the sponge biomarker hypothesis.
      ).
      Figure thumbnail gr1
      Fig. 1Orthologous groups of sterol-C-methyltransferases in eukaryotes. Orthologous groups were retrieved from the OrthoDB database (Group 661953at2759 at Eukaryota level). The common tree was based on the NCBI taxonomy database using species names. Sterol autotroph organisms with SMT genes (shown in green), versus organisms without SMT genes (shown in purple). Sterol auxotroph organisms with 4-SMT (shown in orange), versus organisms without 4-SMT genes (shown in brown). Organisms that do not produce sterols are shown in black. 4-SMT, sterol-C4α-methyltransferase; SMT1, cycloartenol-C24-methyltransferase; SMT2, 24-methylenesterol-C24-methyltransferase; ERG6, zymosterol-24-methyltransferase.
      In their article in this issue, Nes and colleagues (
      • Zhou W.
      • Fisher P.M.
      • Vanderloop B.H.
      • Shen Y.
      • Shi H.
      • Maldonado A.J.
      • Leaver D.J.
      • Nes W.D.
      A nematode sterol C4alpha-methyltransferase catalyzes a new methylation reaction responsible for sterol diversity.
      ) present a comprehensive analysis of the unusual sterol pathway and novel sterol-C-methyltransferase (dubbed “4-SMT” to distinguish it from the SMTs operating at C-24 on the sterol side chain) utilized by the roundworm C. elegans. Nematodes such as C. elegans are atypical organisms in which to study sterol biosynthesis because they are sterol auxotrophs, exhibiting a strict dependence on dietary cholesterol. Nematodes lack the genetic equipment to make C30H50O precursors, although they autotrophically produce the C15 isoprenoid farnesylpyrophosphate, enabling them to carry out other biologically significant reactions unrelated to sterol synthesis, such as protein prenylation (
      • Morck C.
      • Olsen L.
      • Kurth C.
      • Persson A.
      • Storm N.J.
      • Svensson E.
      • Jansson J.O.
      • Hellqvist M.
      • Enejder A.
      • Faergeman N.J.
      Statins inhibit protein lipidation and induce the unfolded protein response in the non-sterol producing nematode Caenorhabditis elegans.
      ). Nematodes are also unusual with regard to other invertebrates. For example, whereas insects convert sterols into the molting hormone 20-hydroxy-ecdysone, nematodes convert cholesterol into a class of species-specific oxidized derivatives called dafachronic acids (DAs) (
      • Hannich J.T.
      • Entchev E.V.
      • Mende F.
      • Boytchev H.
      • Martin R.
      • Zagoriy V.
      • Theumer G.
      • Riezman I.
      • Riezman H.
      • Knolker H.J.
      Methylation of the sterol nucleus by STRM-1 regulates dauer larva formation in Caenorhabditis elegans.
      ), which in turn afford nematodes the ability to produce lophenol (4α-methyl-cholest-7-en-3β-ol) from cholesterol (i.e., essentially a retro-cholesterol biosynthetic pathway) (Fig. 2). [DAs are ligands for the nuclear hormone receptor DAF-12; binding of DAs to DAF-12 inhibits progression to the dauer stage, thereby promoting reproductive development in nematodes (
      • Hannich J.T.
      • Entchev E.V.
      • Mende F.
      • Boytchev H.
      • Martin R.
      • Zagoriy V.
      • Theumer G.
      • Riezman I.
      • Riezman H.
      • Knolker H.J.
      Methylation of the sterol nucleus by STRM-1 regulates dauer larva formation in Caenorhabditis elegans.
      ).] The production of lophenol and 4α-methyl-cholest-8(
      • Darnet S.
      • Schaller H.
      Metabolism and biological activities of 4-methyl-sterols.
      )-en-3β-ol as pathway end-products is also mandatory for nematodes, which require 4α-methylsterols at precise stages of their lifespan (
      • Hannich J.T.
      • Entchev E.V.
      • Mende F.
      • Boytchev H.
      • Martin R.
      • Zagoriy V.
      • Theumer G.
      • Riezman I.
      • Riezman H.
      • Knolker H.J.
      Methylation of the sterol nucleus by STRM-1 regulates dauer larva formation in Caenorhabditis elegans.
      ). In fact, the accumulation of these 4α-methylsterols confers upon C. elegans the metabolic capacity to minimize the supply of DAs. This metabolic shift causes nematodes to enter a diapause stage typical of so-called “stress-resistant” dauer larvae. Hence, loss-of-function of 4-SMT (also known as STRM-1) promotes DA neosynthesis and blocks entry into the dauer stage (
      • Hannich J.T.
      • Entchev E.V.
      • Mende F.
      • Boytchev H.
      • Martin R.
      • Zagoriy V.
      • Theumer G.
      • Riezman I.
      • Riezman H.
      • Knolker H.J.
      Methylation of the sterol nucleus by STRM-1 regulates dauer larva formation in Caenorhabditis elegans.
      ). The sterol profiles and enzymology of C. elegans performed by the Nes group show that the 4-SMT-mediated alkylation at position C4 (ring A of the cholestane nucleus) applies to a cholesterol-derived 3-oxo-sterol substrate (see Fig. 2). Consequently, in agreement with a phylogenomic analysis of sterol-C-methyltransferases (see Fig. 1), the evolutionarily shaped specificity of the 4-SMT active site requires the amphiphilic sterol substrates to rotate for molecular recognition and catalysis. This is reminiscent of other examples in nature involving distinct sterol ligand or substrate recognition sites differing in the same functional groups of proteins;: for example, in the lysosomal cholesterol shuttle, cholesterol binds to the Niemann-Pick C proteins NPC1 and NPC2 in opposite orientation (
      • Vance J.E.
      Transfer of cholesterol by the NPC team.
      ), and in the case of certain hydroxylases, sterol nonheme iron-dependent oxidation is performed either at C4 of the tetracyclic ring (as is the case for sterol methyl oxidases) or at C25 of the side chain (as is the case for cholesterol-25-hydroxylase) (
      • Darnet S.
      • Rahier A.
      Plant sterol biosynthesis: identification of two distinct families of sterol 4α-methyl oxidases.
      ).
      Figure thumbnail gr2
      Fig. 2Simplified divergence of sterol biosynthesis and metabolism in mammals, plants, and other eukaryotes (left) versus nematodes (right). De novo synthesis of cholesterol (cholest-5-en-3β-ol) from acetyl-CoA through the mevalonate pathway proceeds via several isoprenoid and sterol intermediates [left; reviewed in (
      • Benveniste P.
      Biosynthesis and accumulation of sterols.
      ,

      Schaller, H., 2010. Sterol and Steroid Biosynthesis and Metabolism in Plants and Microorganisms. In Comprehensive Natural Products II: Chemistry and Biology, Volumes 1–10. L. N. Mander and L. Hung-Wen, editors. Elsevier Science, Amsterdam. 755–787.

      ,
      • Nes W.D.
      Biosynthesis of cholesterol and other sterols.
      )]. In this conventional pathway, lophenol (4α-methyl-cholest-7-en-3β-ol) is converted to cholesterol by enzymes a to e. Sterol-C24-methyltransferases (SMTs) when active in this pathway allow the production of 24-alkyl-sterols such as campesterol, bearing a 24-methyl side chain (highlighted in green). Pathway end-products are the precursors of bioactive oxygenated derivatives; e.g., 25-hydroxycholesterol produced from cholesterol, or castasterone, a brassinosteroid plant hormone derived from campesterol. a, sterol 4-methyl oxidase; b, 4-carboxysterol decarboxylase; c, sterone-∆3-reductase; d, sterol-∆5-desaturase; e, sterol-∆7-reductase. Alternatively (right), in nematodes such as C.elegans, lophenol is synthesized from dietary cholesterol in their environment [see (
      • Zhou W.
      • Fisher P.M.
      • Vanderloop B.H.
      • Shen Y.
      • Shi H.
      • Maldonado A.J.
      • Leaver D.J.
      • Nes W.D.
      A nematode sterol C4alpha-methyltransferase catalyzes a new methylation reaction responsible for sterol diversity.
      ,
      • Benveniste P.
      Biosynthesis and accumulation of sterols.
      ,

      Schaller, H., 2010. Sterol and Steroid Biosynthesis and Metabolism in Plants and Microorganisms. In Comprehensive Natural Products II: Chemistry and Biology, Volumes 1–10. L. N. Mander and L. Hung-Wen, editors. Elsevier Science, Amsterdam. 755–787.

      ,
      • Nes W.D.
      Biosynthesis of cholesterol and other sterols.
      ,
      • Tamura T.
      • Akihisa T.
      • Kokke W.
      Naturally Occurring Sterols and Related Compounds from Plants.
      ,
      • Nakamoto M.
      • Schmit A.C.
      • Heintz D.
      • Schaller H.
      • Ohta D.
      Diversification of sterol methyltransferase enzymes in plants and a role for beta-sitosterol in oriented cell plate formation and polarized growth.
      ,
      • Bouvier-Nave P.
      • Husselstein T.
      • Desprez T.
      • Benveniste P.
      Identification of cDNAs encoding sterol methyl-transferases involved in the second methylation step of plant sterol biosynthesis.
      ,
      • Husselstein T.
      • Gachotte D.
      • Desprez T.
      • Bard M.
      • Benveniste P.
      Transformation of Saccharomyces cerevisiae with a cDNA encoding a sterol C-methyltransferase from Arabidopsis thaliana results in the synthesis of 24-ethyl sterols.
      ,
      • Gold D.A.
      • Grabenstatter J.
      • de Mendoza A.
      • Riesgo A.
      • Ruiz-Trillo I.
      • Summons R.E.
      Sterol and genomic analyses validate the sponge biomarker hypothesis.
      ,
      • Morck C.
      • Olsen L.
      • Kurth C.
      • Persson A.
      • Storm N.J.
      • Svensson E.
      • Jansson J.O.
      • Hellqvist M.
      • Enejder A.
      • Faergeman N.J.
      Statins inhibit protein lipidation and induce the unfolded protein response in the non-sterol producing nematode Caenorhabditis elegans.
      ,
      • Hannich J.T.
      • Entchev E.V.
      • Mende F.
      • Boytchev H.
      • Martin R.
      • Zagoriy V.
      • Theumer G.
      • Riezman I.
      • Riezman H.
      • Knolker H.J.
      Methylation of the sterol nucleus by STRM-1 regulates dauer larva formation in Caenorhabditis elegans.
      )]. Successive putative or demonstrated enzymes are: e', cholesterol-∆7-dehydrogenase (DAF36); d', sterol dehydrogenase (DHS16); c', sterol-∆4-reductase; b', sterol-4-methyltransferase or 4-SMT; a', sterone-∆3-reductase. The 3-oxo-sterol substrate of the 4-SMT is also a precursor of a dafachronic acid (∆7-DAF). 25-OH, 25-hydroxycholesterol. C4 of the sterol nucleus is indicated by the red 4.
      Whereas C4-methylsterols generally serve as sterol biosynthetic intermediates (C4-SBIs) in most other organisms and cell types (
      • Darnet S.
      • Schaller H.
      Metabolism and biological activities of 4-methyl-sterols.
      ), 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. Nematodes have compact genomes as a consequence of a high rate of large spontaneous deletions, which is responsible, for example, for the loss of steroidogenic genes (
      • Witherspoon D.J.
      • Robertson H.M.
      Neutral evolution of ten types of mariner transposons in the genomes of Caenorhabditis elegansCaenorhabditis briggsae.
      ). Nematodes also have a very high rate of evolutionary progression, which is two- to three-fold higher than for any other animal group (
      • Aguinaldo A.M.
      • Turbeville J.M.
      • Linford L.S.
      • Rivera M.C.
      • Garey J.R.
      • Raff R.A.
      • Lake J.A.
      Evidence for a clade of nematodes, arthropods and other moulting animals.
      ). This supports the view that 4-SMT has diverged from remnant SMT genes defining ancient sterol metabolism in LECA (Last Eukaryotic Common Ancestor) (
      • Zhou W.
      • Fisher P.M.
      • Vanderloop B.H.
      • Shen Y.
      • Shi H.
      • Maldonado A.J.
      • Leaver D.J.
      • Nes W.D.
      A nematode sterol C4alpha-methyltransferase catalyzes a new methylation reaction responsible for sterol diversity.
      ). Consequently, sterol methylation at C4 and C24 obligatorily relies upon cooption of exapted ancient enzymes. Alternatively, the lophenol pathway in nematodes may have arisen evolutionarily by horizontal gene transfer (HGT). Such processes have been documented in the case of an HGT between bacteria and nematodes to facilitate parasite-host interactions (
      • Bird D.M.
      • Jones J.T.
      • Opperman C.H.
      • Kikuchi T.
      • Danchin E.G.
      Signatures of adaptation to plant parasitism in nematode genomes.
      ). In this regard, the triterpenoid hopane-C2-methyltransferases presumably utilized by ancient cyanobacteria are consistent with the latter speculation (
      • Welander P.V.
      • Coleman M.L.
      • Sessions A.L.
      • Summons R.E.
      • Newman D.K.
      Identification of a methylase required for 2-methylhopanoid production and implications for the interpretation of sedimentary hopanes.
      ).
      As alluded to above, organisms or cell types with 4α-methylsterols as functional pathway end-products are not frequent, but this is the case for dinoflagellates and the prokaryote Methyloccocus capsulatus. Like C. elegans, these bacteria synthesize 4α-methyl-cholest-8(14)-en-3β-ol, albeit from lanosterol and not from cholesterol; C4-dealkylation of lanosterol (bacteria) and C4-alkylation of ∆7-cholestenone (nematodes) converge to the production of 4α-methyl-cholest-8(14)-en-3β-ol (
      • Gold D.A.
      • Grabenstatter J.
      • de Mendoza A.
      • Riesgo A.
      • Ruiz-Trillo I.
      • Summons R.E.
      Sterol and genomic analyses validate the sponge biomarker hypothesis.
      ,
      • Morck C.
      • Olsen L.
      • Kurth C.
      • Persson A.
      • Storm N.J.
      • Svensson E.
      • Jansson J.O.
      • Hellqvist M.
      • Enejder A.
      • Faergeman N.J.
      Statins inhibit protein lipidation and induce the unfolded protein response in the non-sterol producing nematode Caenorhabditis elegans.
      ,
      • Hannich J.T.
      • Entchev E.V.
      • Mende F.
      • Boytchev H.
      • Martin R.
      • Zagoriy V.
      • Theumer G.
      • Riezman I.
      • Riezman H.
      • Knolker H.J.
      Methylation of the sterol nucleus by STRM-1 regulates dauer larva formation in Caenorhabditis elegans.
      ). In this process, bacteria perform a C4 demethylation reaction of lanosterol (a 4α,4β-dimethylsterol) with an enzyme classified as a Rieske-type oxygenase belonging to a sterol-C4-demethylation complex notably different from the eukaryotic sterol-C4-demethylation complex of unlinked evolutionary origin (
      • Lee A.K.
      • Banta A.B.
      • Wei J.H.
      • Kiemle D.J.
      • Feng J.
      • Giner J.L.
      • Welander P.V.
      C-4 sterol demethylation enzymes distinguish bacterial and eukaryotic sterol synthesis.
      ). The presence of 4-methylsterols in dinoflagellates and bacteria has been related to adaptation to water stress, high salt, or low oxygen conditions (
      • Darnet S.
      • Schaller H.
      Metabolism and biological activities of 4-methyl-sterols.
      ,
      • Witherspoon D.J.
      • Robertson H.M.
      Neutral evolution of ten types of mariner transposons in the genomes of Caenorhabditis elegansCaenorhabditis briggsae.
      ,
      • Aguinaldo A.M.
      • Turbeville J.M.
      • Linford L.S.
      • Rivera M.C.
      • Garey J.R.
      • Raff R.A.
      • Lake J.A.
      Evidence for a clade of nematodes, arthropods and other moulting animals.
      ,
      • Bird D.M.
      • Jones J.T.
      • Opperman C.H.
      • Kikuchi T.
      • Danchin E.G.
      Signatures of adaptation to plant parasitism in nematode genomes.
      ,
      • Welander P.V.
      • Coleman M.L.
      • Sessions A.L.
      • Summons R.E.
      • Newman D.K.
      Identification of a methylase required for 2-methylhopanoid production and implications for the interpretation of sedimentary hopanes.
      ,
      • Lee A.K.
      • Banta A.B.
      • Wei J.H.
      • Kiemle D.J.
      • Feng J.
      • Giner J.L.
      • Welander P.V.
      C-4 sterol demethylation enzymes distinguish bacterial and eukaryotic sterol synthesis.
      ). In C. elegans, anaerobiosis-related genes are expressed during the dauer stage, and lipid metabolism is furthermore reduced (
      • Dulovic A.
      • Streit A.
      RNAi-mediated knockdown of daf-12 in the model parasitic nematode Strongyloides ratti.
      ). It is therefore tempting to consider C4-methylsterols of auxotrophic worms as endogenous signals, analogous to what has been proposed for mammals or plants (
      • Darnet S.
      • Schaller H.
      Metabolism and biological activities of 4-methyl-sterols.
      ,
      • Witherspoon D.J.
      • Robertson H.M.
      Neutral evolution of ten types of mariner transposons in the genomes of Caenorhabditis elegansCaenorhabditis briggsae.
      ,
      • Aguinaldo A.M.
      • Turbeville J.M.
      • Linford L.S.
      • Rivera M.C.
      • Garey J.R.
      • Raff R.A.
      • Lake J.A.
      Evidence for a clade of nematodes, arthropods and other moulting animals.
      ,
      • Bird D.M.
      • Jones J.T.
      • Opperman C.H.
      • Kikuchi T.
      • Danchin E.G.
      Signatures of adaptation to plant parasitism in nematode genomes.
      ,
      • Welander P.V.
      • Coleman M.L.
      • Sessions A.L.
      • Summons R.E.
      • Newman D.K.
      Identification of a methylase required for 2-methylhopanoid production and implications for the interpretation of sedimentary hopanes.
      ,
      • Lee A.K.
      • Banta A.B.
      • Wei J.H.
      • Kiemle D.J.
      • Feng J.
      • Giner J.L.
      • Welander P.V.
      C-4 sterol demethylation enzymes distinguish bacterial and eukaryotic sterol synthesis.
      ,
      • Dulovic A.
      • Streit A.
      RNAi-mediated knockdown of daf-12 in the model parasitic nematode Strongyloides ratti.
      ,
      • Chen L.
      • Ma M.Y.
      • Sun M.
      • Jiang L.Y.
      • Zhao X.T.
      • Fang X.X.
      • Man Lam S.
      • Shui G.H.
      • Luo J.
      • Shi X.J.
      Endogenous sterol intermediates of the mevalonate pathway regulate HMGCR degradation and SREBP-2 processing.
      ). Remarkably, steroidogenic enzymes in C.elegans are components of a sterol pathway of a different evolutionary origin than those operating in other sterol autotrophs, but with a clear functional convergence. The contributions of David Nes and his colleagues herein to our current understanding of sterol diversity and the underlying pathways by which such diversity arises represents an artful foray into this topic, and is highly recommended to the reader.

      REFERENCES

        • Zhou W.
        • Fisher P.M.
        • Vanderloop B.H.
        • Shen Y.
        • Shi H.
        • Maldonado A.J.
        • Leaver D.J.
        • Nes W.D.
        A nematode sterol C4alpha-methyltransferase catalyzes a new methylation reaction responsible for sterol diversity.
        J. Lipid Res. 2019; 61: 192-204
        • Benveniste P.
        Biosynthesis and accumulation of sterols.
        Annu. Rev. Plant Biol. 2004; 55: 429-457
      1. Schaller, H., 2010. Sterol and Steroid Biosynthesis and Metabolism in Plants and Microorganisms. In Comprehensive Natural Products II: Chemistry and Biology, Volumes 1–10. L. N. Mander and L. Hung-Wen, editors. Elsevier Science, Amsterdam. 755–787.

        • Nes W.D.
        Biosynthesis of cholesterol and other sterols.
        Chem. Rev. 2011; 111: 6423-6451
        • Tamura T.
        • Akihisa T.
        • Kokke W.
        Naturally Occurring Sterols and Related Compounds from Plants.
        in: Patterson G.W. Nes W.D. Physiology and Biochemistry of Sterols. American Oil Chemists Society, Champaign, IL1992: 172-228
        • Nakamoto M.
        • Schmit A.C.
        • Heintz D.
        • Schaller H.
        • Ohta D.
        Diversification of sterol methyltransferase enzymes in plants and a role for beta-sitosterol in oriented cell plate formation and polarized growth.
        Plant J. 2015; 84: 860-874
        • Bouvier-Nave P.
        • Husselstein T.
        • Desprez T.
        • Benveniste P.
        Identification of cDNAs encoding sterol methyl-transferases involved in the second methylation step of plant sterol biosynthesis.
        Eur. J. Biochem. 1997; 246: 518-529
        • Husselstein T.
        • Gachotte D.
        • Desprez T.
        • Bard M.
        • Benveniste P.
        Transformation of Saccharomyces cerevisiae with a cDNA encoding a sterol C-methyltransferase from Arabidopsis thaliana results in the synthesis of 24-ethyl sterols.
        FEBS Lett. 1996; 381: 87-92
        • Gold D.A.
        • Grabenstatter J.
        • de Mendoza A.
        • Riesgo A.
        • Ruiz-Trillo I.
        • Summons R.E.
        Sterol and genomic analyses validate the sponge biomarker hypothesis.
        Proc. Natl. Acad. Sci. USA. 2016; 113: 2684-2689
        • Morck C.
        • Olsen L.
        • Kurth C.
        • Persson A.
        • Storm N.J.
        • Svensson E.
        • Jansson J.O.
        • Hellqvist M.
        • Enejder A.
        • Faergeman N.J.
        Statins inhibit protein lipidation and induce the unfolded protein response in the non-sterol producing nematode Caenorhabditis elegans.
        Proc. Natl. Acad. Sci. USA. 2009; 106: 18285-18290
        • Hannich J.T.
        • Entchev E.V.
        • Mende F.
        • Boytchev H.
        • Martin R.
        • Zagoriy V.
        • Theumer G.
        • Riezman I.
        • Riezman H.
        • Knolker H.J.
        Methylation of the sterol nucleus by STRM-1 regulates dauer larva formation in Caenorhabditis elegans.
        Dev. Cell. 2009; 16: 833-843
        • Vance J.E.
        Transfer of cholesterol by the NPC team.
        Cell Metab. 2010; 12: 105-106
        • Darnet S.
        • Rahier A.
        Plant sterol biosynthesis: identification of two distinct families of sterol 4α-methyl oxidases.
        Biochem. J. 2004; 378: 889-898
        • Darnet S.
        • Schaller H.
        Metabolism and biological activities of 4-methyl-sterols.
        Molecules. 2019; 24: E451
        • Witherspoon D.J.
        • Robertson H.M.
        Neutral evolution of ten types of mariner transposons in the genomes of Caenorhabditis elegansCaenorhabditis briggsae.
        J. Mol. Evol. 2003; 56: 751-769
        • Aguinaldo A.M.
        • Turbeville J.M.
        • Linford L.S.
        • Rivera M.C.
        • Garey J.R.
        • Raff R.A.
        • Lake J.A.
        Evidence for a clade of nematodes, arthropods and other moulting animals.
        Nature. 1997; 387: 489-493
        • Bird D.M.
        • Jones J.T.
        • Opperman C.H.
        • Kikuchi T.
        • Danchin E.G.
        Signatures of adaptation to plant parasitism in nematode genomes.
        Parasitology. 2015; 142(Suppl 1): S71-S84
        • Welander P.V.
        • Coleman M.L.
        • Sessions A.L.
        • Summons R.E.
        • Newman D.K.
        Identification of a methylase required for 2-methylhopanoid production and implications for the interpretation of sedimentary hopanes.
        Proc. Natl. Acad. Sci. USA. 2010; 107: 8537-8542
        • Lee A.K.
        • Banta A.B.
        • Wei J.H.
        • Kiemle D.J.
        • Feng J.
        • Giner J.L.
        • Welander P.V.
        C-4 sterol demethylation enzymes distinguish bacterial and eukaryotic sterol synthesis.
        Proc. Natl. Acad. Sci. USA. 2018; 115: 5884-5889
        • Dulovic A.
        • Streit A.
        RNAi-mediated knockdown of daf-12 in the model parasitic nematode Strongyloides ratti.
        PLoS Pathog. 2019; 15: e1007705
        • Chen L.
        • Ma M.Y.
        • Sun M.
        • Jiang L.Y.
        • Zhao X.T.
        • Fang X.X.
        • Man Lam S.
        • Shui G.H.
        • Luo J.
        • Shi X.J.
        Endogenous sterol intermediates of the mevalonate pathway regulate HMGCR degradation and SREBP-2 processing.
        J. Lipid Res. 2019; 60: 1765-1775

      Linked Article

      • A nematode sterol C4α-methyltransferase catalyzes a new methylation reaction responsible for sterol diversity
        Journal of Lipid ResearchVol. 61Issue 2
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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).
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