The mevalonate pathway in C. elegans

Lipids in Health and Disease

Marc Pilon¹  Manish Rauthan¹ 

[1] Department of Cell and Molecular Biology, University of Gothenburg, S-405 30 Gothenburg, Sweden

关键词: protein prenylation;    cholesterol;    dolichol;    coenzyme Q;    statin;    mevalonate pathway;    C. elegans;   

Others  :  1212346
DOI  :  10.1186/1476-511X-10-243

 received in 2011-11-08, accepted in 2011-12-28,  发布年份 2011

【 摘 要 】

The mevalonate pathway in human is responsible for the synthesis of cholesterol and other important biomolecules such as coenzyme Q, dolichols and isoprenoids. These molecules are required in the cell for functions ranging from signaling to membrane integrity, protein prenylation and glycosylation, and energy homeostasis. The pathway consists of a main trunk followed by sub-branches that synthesize the different biomolecules. The majority of our knowledge about the mevalonate pathway is currently focused on the cholesterol synthesis branch, which is the target of the cholesterol-lowering statins; less is known about the function and regulation of the non-cholesterol-related branches. To study them, we need a biological system where it is possible to specifically modulate these metabolic branches individually or in groups. The nematode Caenorhabditis elegans (C. elegans) is a promising model to study these non-cholesterol branches since its mevalonate pathway seems very well conserved with that in human except that it has no cholesterol synthesis branch. The simple genetic makeup and tractability of C. elegans makes it relatively easy to identify and manipulate key genetic components of the mevalonate pathway, and to evaluate the consequences of tampering with their activity. This general experimental approach should lead to new insights into the physiological roles of the non-cholesterol part of the mevalonate pathway. This review will focus on the current knowledge related to the mevalonate pathway in C. elegans and its possible applications as a model organism to study the non-cholesterol functions of this pathway.

【 授权许可】

   
2011 Rauthan and Pilon; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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【 参考文献 】

• [1]Bentinger M, Tekle M, Dallner G: Coenzyme Q--biosynthesis and functions. Biochemical and biophysical research communications 2010, 396:74-79.
• [2]Demierre MF, Higgins PD, Gruber SB, Hawk E, Lippman SM: Statins and cancer prevention. Nat Rev Cancer 2005, 5:930-942.
• [3]Mehta NG, Mehta M: Overcoming multidrug-resistance in cancer: statins offer a logical candidate. Medical hypotheses 2010, 74:237-239.
• [4]Shimabukuro-Vornhagen A, Glossmann J, Liebig T, Scheid C, von Bergwelt-Baildon M: The use of statins in hematopoietic stem cell transplantation. Current stem cell research & therapy 2009, 4:260-265.
• [5]Willey JZ, Elkind MS: 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in the treatment of central nervous system diseases. Archives of neurology 2010, 67:1062-1067.
• [6]Morck C, Olsen L, Kurth C, Persson A, Storm NJ, Svensson E, Jansson JO, Hellqvist M, Enejder A, Faergeman NJ, Pilon M: 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.
• [7]Miziorko HM: Enzymes of the mevalonate pathway of isoprenoid biosynthesis. Archives of biochemistry and biophysics 2011, 505:131-143.
• [8]Yochem J, Hall DH, Bell LR, Hedgecock EM, Herman RK: Isopentenyl-diphosphate isomerase is essential for viability of Caenorhabditis elegans. Molecular genetics and genomics: MGG 2005, 273:158-166.
• [9]Persson BC, Esberg B, Olafsson O, Bjork GR: Synthesis and function of isopentenyl adenosine derivatives in tRNA. Biochimie 1994, 76:1152-1160.
• [10]Jenner L, Romby P, Rees B, Schulze-Briese C, Springer M, Ehresmann C, Ehresmann B, Moras D, Yusupova G, Yusupov M: Translational operator of mRNA on the ribosome: how repressor proteins exclude ribosome binding. Science 2005, 308:120-123.
• [11]Lemieux J, Lakowski B, Webb A, Meng Y, Ubach A, Bussiere F, Barnes T, Hekimi S: Regulation of physiological rates in Caenorhabditis elegans by a tRNA-modifying enzyme in the mitochondria. Genetics 2001, 159:147-157.
• [12]Chen C, Tuck S, Bystrom AS: Defects in tRNA modification associated with neurological and developmental dysfunctions in Caenorhabditis elegans elongator mutants. PLoS genetics 2009, 5:e1000561.
• [13]Ashton E, Windebank E, Skiba M, Reid C, Schneider H, Rosenfeldt F, Tonkin A, Krum H: Why did high-dose rosuvastatin not improve cardiac remodeling in chronic heart failure? Mechanistic insights from the UNIVERSE study. International journal of cardiology 2011, 146:404-407.
• [14]Folkers K, Langsjoen P, Willis R, Richardson P, Xia LJ, Ye CQ, Tamagawa H: Lovastatin decreases coenzyme Q levels in humans. Proceedings of the National Academy of Sciences of the United States of America 1990, 87:8931-8934.
• [15]Hihi AK, Gao Y, Hekimi S: Ubiquinone is necessary for Caenorhabditis elegans development at mitochondrial and non-mitochondrial sites. The Journal of biological chemistry 2002, 277:2202-2206.
• [16]Jonassen T, Larsen PL, Clarke CF: A dietary source of coenzyme Q is essential for growth of long-lived Caenorhabditis elegans clk-1 mutants. Proceedings of the National Academy of Sciences of the United States of America 2001, 98:421-426.
• [17]Ewbank JJ, Barnes TM, Lakowski B, Lussier M, Bussey H, Hekimi S: Structural and functional conservation of the Caenorhabditis elegans timing gene clk-1. Science 1997, 275:980-983.
• [18]Asencio C, Rodriguez-Aguilera JC, Ruiz-Ferrer M, Vela J, Navas P: Silencing of ubiquinone biosynthesis genes extends life span in Caenorhabditis elegans. The FASEB journal: official publication of the Federation of American Societies for Experimental Biology 2003, 17:1135-1137.
• [19]Gavilan A, Asencio C, Cabello J, Rodriguez-Aguilera JC, Schnabel R, Navas P: C. elegans knockouts in ubiquinone biosynthesis genes result in different phenotypes during larval development. BioFactors 2005, 25:21-29.
• [20]Cristina D, Cary M, Lunceford A, Clarke C, Kenyon C: A regulated response to impaired respiration slows behavioral rates and increases lifespan in Caenorhabditis elegans. PLoS genetics 2009, 5:e1000450.
• [21]Kirchman PA, Kim S, Lai CY, Jazwinski SM: Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae. Genetics 1999, 152:179-190.
• [22]Asencio C, Navas P, Cabello J, Schnabel R, Cypser JR, Johnson TE, Rodriguez-Aguilera JC: Coenzyme Q supports distinct developmental processes in Caenorhabditis elegans. Mechanisms of ageing and development 2009, 130:145-153.
• [23]Surmacz L, Swiezewska E: Polyisoprenoids - Secondary metabolites or physiologically important superlipids? Biochemical and biophysical research communications 2011, 407:627-632.
• [24]Skorupinska-Tudek K, Wojcik J, Swiezewska E: Polyisoprenoid alcohols--recent results of structural studies. Chemical record 2008, 8:33-45.
• [25]Swiezewska E, Danikiewicz W: Polyisoprenoids: structure, biosynthesis and function. Progress in lipid research 2005, 44:235-258.
• [26]Lehrman MA: Biosynthesis of N-acetylglucosamine-P-P-dolichol, the committed step of asparagine-linked oligosaccharide assembly. Glycobiology 1991, 1:553-562.
• [27]Cantagrel V, Lefeber DJ, Ng BG, Guan Z, Silhavy JL, Bielas SL, Lehle L, Hombauer H, Adamowicz M, Swiezewska E, et al.: SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell 2010, 142:203-217.
• [28]Denecke J, Kranz C: Hypoglycosylation due to dolichol metabolism defects. Biochimica et biophysica acta 2009, 1792:888-895.
• [29]Haeuptle MA, Hennet T: Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides. Human mutation 2009, 30:1628-1641.
• [30]Jaeken J, Carchon H: Congenital disorders of glycosylation: a booming chapter of pediatrics. Current opinion in pediatrics 2004, 16:434-439.
• [31]Kaji H, Kamiie J, Kawakami H, Kido K, Yamauchi Y, Shinkawa T, Taoka M, Takahashi N, Isobe T: Proteomics reveals N-linked glycoprotein diversity in Caenorhabditis elegans and suggests an atypical translocation mechanism for integral membrane proteins. Molecular & cellular proteomics: MCP 2007, 6:2100-2109.
• [32]Kamath RS, Fraser AG, Dong Y, Poulin G, Durbin R, Gotta M, Kanapin A, Le Bot N, Moreno S, Sohrmann M, et al.: Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 2003, 421:231-237.
• [33]Simmer F, Moorman C, van der Linden AM, Kuijk E, van den Berghe PVE, Kamath RS, Fraser AG, Ahringer J, Plasterk RHA: Genome-wide RNAi of C. elegans using the hypersensitive rrf-3 strain reveals novel gene functions. PloS Biol 2003, 1:e12.
• [34]Sonnichsen B, Koski LB, Walsh A, Marschall P, Neumann B, Brehm M, Alleaume AM, Artelt J, Bettencourt P, Cassin E, et al.: Full-genome RNAi profiling of early embryogenesis in Caenorhabditis elegans. Nature 2005, 434:462-469.
• [35]Konstantinopoulos PA, Karamouzis MV, Papavassiliou AG: Post-translational modifications and regulation of the RAS superfamily of GTPases as anticancer targets. Nat Rev Drug Discov 2007, 6:541-555.
• [36]Aspbury RA, Prescott MC, Fisher MJ, Rees HH: Isoprenylation of polypeptides in the nematode Caenorhabditis elegans. Biochim Biophys Acta 1998, 1392:265-275.
• [37]Hara M, Han M: Ras farnesyltransferase inhibitors suppress the phenotype resulting from an activated ras mutation in Caenorhabditis elegans. Proceedings of the National Academy of Sciences of the United States of America 1995, 92:3333-3337.
• [38]Nagase T, Kawata S, Tamura S, Matsuda Y, Inui Y, Yamasaki E, Ishiguro H, Ito T, Miyagawa J, Mitsui H, et al.: Manumycin and gliotoxin derivative KT7595 block Ras farnesylation and cell growth but do not disturb lamin farnesylation and localization in human tumour cells. British journal of cancer 1997, 76:1001-1010.
• [39]van der Spek E: Targeting the mevalonate pathway in multiple myeloma. Leukemia research 2010, 34:267-268.
• [40]Bar DZ, Gruenbaum Y: Reversal of age-dependent nuclear morphology by inhibition of prenylation does not affect lifespan in Caenorhabditis elegans. Nucleus 2010, 1:499-505.
• [41]Hieb WF, Rothstein M: Sterol requirement for reproduction of a free-living nematode. Science 1968, 160:778-780.
• [42]Kuervers LM, Jones CL, O'Neil NJ, Baillie DL: The sterol modifying enzyme LET-767 is essential for growth, reproduction and development in Caenorhabditis elegans. Molecular genetics and genomics: MGG 2003, 270:121-131.
• [43]Matyash V, Entchev EV, Mende F, Wilsch-Brauninger M, Thiele C, Schmidt AW, Knolker HJ, Ward S, Kurzchalia TV: Sterol-derived hormone(s) controls entry into diapause in Caenorhabditis elegans by consecutive activation of DAF-12 and DAF-16. PLoS biology 2004, 2:e280.
• [44]Shim YH, Chun JH, Lee EY, Paik YK: Role of cholesterol in germ-line development of Caenorhabditis elegans. Molecular reproduction and development 2002, 61:358-366.
• [45]Merris M, Kraeft J, Tint GS, Lenard J: Long-term effects of sterol depletion in C. elegans: sterol content of synchronized wild-type and mutant populations. Journal of lipid research 2004, 45:2044-2051.
• [46]Merris M, Wadsworth WG, Khamrai U, Bittman R, Chitwood DJ, Lenard J: Sterol effects and sites of sterol accumulation in Caenorhabditis elegans: developmental requirement for 4alpha-methyl sterols. Journal of lipid research 2003, 44:172-181.
• [47]Grant B, Hirsh D: Receptor-mediated endocytosis in the Caenorhabditis elegans oocyte. Molecular biology of the cell 1999, 10:4311-4326.
• [48]Kimble J, Sharrock WJ: Tissue-specific synthesis of yolk proteins in Caenorhabditis elegans. Developmental biology 1983, 96:189-196.
• [49]Matyash V, Geier C, Henske A, Mukherjee S, Hirsh D, Thiele C, Grant B, Maxfield FR, Kurzchalia TV: Distribution and transport of cholesterol in Caenorhabditis elegans. Molecular biology of the cell 2001, 12:1725-1736.
• [50]Wustner D, Sage D: Multicolor bleach-rate imaging enlightens in vivo sterol transport. Communicative & integrative biology 2010, 3:370-373.
• [51]Chitwood DJ, Lusby WR, Lozano R, Thompson MJ, Svoboda JA: Sterol metabolism in the nematodeCaenorhabditis elegans. Lipids 1984, 19:500-506.
• [52]Scheel J, Srinivasan J, Honnert U, Henske A, Kurzchalia TV: Involvement of caveolin-1 in meiotic cell-cycle progression in Caenorhabditis elegans. Nature cell biology 1999, 1:127-129.
• [53]Yochem J, Tuck S, Greenwald I, Han M: A gp330/megalin-related protein is required in the major epidermis of Caenorhabditis elegans for completion of molting. Development 1999, 126:597-606.
• [54]Gerisch B, Antebi A: Hormonal signals produced by DAF-9/cytochrome P450 regulate C. elegans dauer diapause in response to environmental cues. Development 2004, 131:1765-1776.
• [55]Gerisch B, Weitzel C, Kober-Eisermann C, Rottiers V, Antebi A: A hormonal signaling pathway influencing C. elegans metabolism, reproductive development, and life span. Developmental cell 2001, 1:841-851.
• [56]Jeong MH, Kawasaki I, Shim YH: A circulatory transcriptional regulation among daf-9, daf-12, and daf-16 mediates larval development upon cholesterol starvation in Caenorhabditis elegans. Developmental dynamics: an official publication of the American Association of Anatomists 2010, 239:1931-1940.
• [57]Sharma KK, Wang Z, Motola DL, Cummins CL, Mangelsdorf DJ, Auchus RJ: Synthesis and activity of dafachronic acid ligands for the C. elegans DAF-12 nuclear hormone receptor. Molecular endocrinology 2009, 23:640-648.
• [58]Li J, Brown G, Ailion M, Lee S, Thomas JH: NCR-1 and NCR-2, the C. elegans homologs of the human Niemann-Pick type C1 disease protein, function upstream of DAF-9 in the dauer formation pathways. Development 2004, 131:5741-5752.
• [59]Goldstein JL, Brown MS: Regulation of the mevalonate pathway. Nature 1990, 343:425-430.
• [60]Goldstein JL, DeBose-Boyd RA, Brown MS: Protein sensors for membrane sterols. Cell 2006, 124:35-46.
• [61]Espenshade PJ, Hughes AL: Regulation of sterol synthesis in eukaryotes. Annual review of genetics 2007, 41:401-427.
• [62]Sun LP, Seemann J, Goldstein JL, Brown MS: Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteins. Proceedings of the National Academy of Sciences of the United States of America 2007, 104:6519-6526.
• [63]Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, Goldstein JL, Brown MS: Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 2002, 110:489-500.
• [64]Correll CC, Ng L, Edwards PA: Identification of farnesol as the non-sterol derivative of mevalonic acid required for the accelerated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The Journal of biological chemistry 1994, 269:17390-17393.
• [65]Jo Y, Debose-Boyd RA: Control of cholesterol synthesis through regulated ER-associated degradation of HMG CoA reductase. Critical reviews in biochemistry and molecular biology 2010, 45:185-198.
• [66]Meigs TE, Simoni RD: Farnesol as a regulator of HMG-CoA reductase degradation: characterization and role of farnesyl pyrophosphatase. Archives of biochemistry and biophysics 1997, 345:1-9.
• [67]Nakanishi M, Goldstein JL, Brown MS: Multivalent control of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Mevalonate-derived product inhibits translation of mRNA and accelerates degradation of enzyme. The Journal of biological chemistry 1988, 263:8929-8937.
• [68]McKay RM, McKay JP, Avery L, Graff JM: C elegans: a model for exploring the genetics of fat storage. Dev Cell 2003, 4:131-142.
• [69]Ashrafi K, Chang FY, Watts JL, Fraser AG, Kamath RS, Ahringer J, Ruvkun G: Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 2003, 421:268-272.
• [70]Yang F, Vought BW, Satterlee JS, Walker AK, Jim Sun ZY, Watts JL, DeBeaumont R, Saito RM, Hyberts SG, Yang S, et al.: An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis. Nature 2006, 442:700-704.
• [71]Winter-Vann AM, Casey PJ: Post-prenylation-processing enzymes as new targets in oncogenesis. Nature reviews Cancer 2005, 5:405-412.
• [72]Liao JK: Isoprenoids as mediators of the biological effects of statins. The Journal of clinical investigation 2002, 110:285-288.
• [73]Zhou Q, Liao JK: Pleiotropic effects of statins. - Basic research and clinical perspectives. Circulation journal: official journal of the Japanese Circulation Society 2010, 74:818-826.
• [74]Rathinam R, Berrier A, Alahari SK: Role of Rho GTPases and their regulators in cancer progression. Frontiers in bioscience: a journal and virtual library 2011, 17:2561-2571.
• [75]Bu DX, Griffin G, Lichtman AH: Mechanisms for the anti-inflammatory effects of statins. Current opinion in lipidology 2011, 22:165-170.
• [76]Miraglia E, Hogberg J, Stenius U: Statins exhibit anticancer effects through modifications of the pAkt. International journal of oncology 2011, 40:867-875.
• [77]Parvathy S, Ehrlich M, Pedrini S, Diaz N, Refolo L, Buxbaum JD, Bogush A, Petanceska S, Gandy S: Atorvastatin-induced activation of Alzheimer's alpha secretase is resistant to standard inhibitors of protein phosphorylation-regulated ectodomain shedding. Journal of neurochemistry 2004, 90:1005-1010.
• [78]Sparks DL: Alzheimer disease: Statins in the treatment of Alzheimer disease. Nature reviews Neurology 2011, 7:662-663.
• [79]Fung EC, Crook MA: Statin Myopathy: A Lipid Clinic Experience on the Tolerability of Statin Rechallenge. Cardiovascular therapeutics 2011.
• [80]Soltis DA, McMahon G, Caplan SL, Dudas DA, Chamberlin HA, Vattay A, Dottavio D, Rucker ML, Engstrom RG, Cornell-Kennon SA, et al.: Expression, purification, and characterization of the human squalene synthase: use of yeast and baculoviral systems. Archives of biochemistry and biophysics 1995, 316:713-723.
• [81]Sagami H, Morita Y, Ogura K: Purification and properties of geranylgeranyl-diphosphate synthase from bovine brain. The Journal of biological chemistry 1994, 269:20561-20566.
• [82]Brown MS, Goldstein JL: Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth. Journal of lipid research 1980, 21:505-517.
• [83]Furfine ES, Leban JJ, Landavazo A, Moomaw JF, Casey PJ: Protein farnesyltransferase: kinetics of farnesyl pyrophosphate binding and product release. Biochemistry 1995, 34:6857-6862.
• [84]Rokosz LL, Boulton DA, Butkiewicz EA, Sanyal G, Cueto MA, Lachance PA, Hermes JD: Human cytoplasmic 3-hydroxy-3-methylglutaryl coenzyme A synthase: expression, purification, and characterization of recombinant wild-type and Cys129 mutant enzymes. Archives of biochemistry and biophysics 1994, 312:1-13.
• [85]Qiu Y, Li D: Bifunctional inhibitors of mevalonate kinase and mevalonate 5-diphosphate decarboxylase. Organic letters 2006, 8:1013-1016.
• [86]Reardon JE, Abeles RH: Inhibition of cholesterol biosynthesis by fluorinated mevalonate analogues. Biochemistry 1987, 26:4717-4722.
• [87]Bergstrom JD, Bostedor RG, Masarachia PJ, Reszka AA, Rodan G: Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. Archives of biochemistry and biophysics 2000, 373:231-241.
• [88]Rogers MJ, Crockett JC, Coxon FP, Monkkonen J: Biochemical and molecular mechanisms of action of bisphosphonates. Bone 2011, 49:34-41.
• [89]Wiemer AJ, Tong H, Swanson KM, Hohl RJ: Digeranyl bisphosphonate inhibits geranylgeranyl pyrophosphate synthase. Biochemical and biophysical research communications 2007, 353:921-925.