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Pathway Description
Mevalonate Pathway
Homo sapiens
Metabolic Pathway
Created: 2019-01-15
Last Updated: 2020-06-10
The Mevalonate Pathway is a necessary pathway that occurs in archaea, eukaryotes and select bacteria. It has mainly been studied with regard to cholesterol biosynthesis and how it relates to cardiovascular disease in humans, but has recently garnered attention for its many other essential roles within human pathology. The pathway begins in the cytoplasm with acetyl-CoA and acetoacetyl-CoA, which interact with acetyl-CoA acetyltransferase, coenzyme A and water to synthesize hydroxymethylglutaryl-CoA synthase. In turn, this synthase teams up with coenzyme A and a hydrogen ion in the endoplasmic reticulum to create 3-hydroxy-3-methylglutaryl-CoA. 3-Hydroxy-3-methylglutaryl-CoA then pairs with 2NADPH, 2 hydrogen ions and is catalyzed by 3-hydroxy-3-methylglutaryl-coenzyme A reductase to produce (R)-mevalonate, also producing byproducts CoA and NADP. Exiting the endoplasmic reticulum, and entering the peroxisome, (R)-mevalonate uses the help of ATP and mevalonate kinase to create mevalonic acid (5P). This piece is especially important to the human species as decreased activity of the enzyme mevalonate kinase has been found to be a direct link to two auto-inflammatory disorders: MVA and HIDS. Using phosphomevalonate kinase and ATP, the pathway re-enters the cytoplasm and mevalonic acid (5P) converts to (R)-mevalonic acid-5-pyrophosphate and ADP. (R)-mevalonic acid-5-pyrophosphate, ATP and diphosphomevalonate decarboxylase work together to create phosphate, carbon dioxide, ADP and isopentenyl pyrophosphate. Re-entering the peroxisome, isopentenyl diphosphate delta isomerase 1 is waiting to propel isopentenyl pyrophosphate into dimethylallylpyrophosphate. This pushes the pathway back into the cytoplasm, where another isopentenyl pyrophosphate molecule and the enzyme farnesyl pyrophosphate synthase create pyrophosphate and geranyl-PP. Yet another isopentenyl pyrophosphate molecules works with farnesyl pyrophosphate synthase to produce pyrophosphate and farnesyl pyrophosphate. Now in the endoplasmic reticulum membrane, 2 farnesyl pyrophosphate molecules with the help of NADPH and a hydrogen ion catalyze with squalene synthase and create squalene. This is an important first step in the specific hepatic cholesterol pathway. Remaining in the endoplasmic reticulum membrane, squalene, FMNH, oxygen and squalene monooxygenase synthesize (S)-2,3-epoxysqualene. This comes along with the byproducts of flavin mononucleotide, a hydrogen ion and water. In the final reaction within this pathway, lanesterol synthase converts (S)-2,3-epoxysqualene to lanosterin. Not pictured in this pathway, lanosterin will eventually be converted to cholesterol, an important part of many functions in the human body.
References
Mevalonate Pathway References
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Pubmed: 23696639
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Pubmed: 26758953
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Fukao T, Yamaguchi S, Kano M, Orii T, Fujiki Y, Osumi T, Hashimoto T: Molecular cloning and sequence of the complementary DNA encoding human mitochondrial acetoacetyl-coenzyme A thiolase and study of the variant enzymes in cultured fibroblasts from patients with 3-ketothiolase deficiency. J Clin Invest. 1990 Dec;86(6):2086-92. doi: 10.1172/JCI114946.
Pubmed: 1979337
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Pubmed: 1684944
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Pubmed: 14702039
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Pubmed: 1358203
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Pubmed: 7913309
Stormo C, Kringen MK, Grimholt RM, Berg JP, Piehler AP: A novel 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) splice variant with an alternative exon 1 potentially encoding an extended N-terminus. BMC Mol Biol. 2012 Sep 18;13:29. doi: 10.1186/1471-2199-13-29.
Pubmed: 22989091
Luskey KL, Stevens B: Human 3-hydroxy-3-methylglutaryl coenzyme A reductase. Conserved domains responsible for catalytic activity and sterol-regulated degradation. J Biol Chem. 1985 Aug 25;260(18):10271-7.
Pubmed: 2991281
Houten SM, Koster J, Romeijn GJ, Frenkel J, Di Rocco M, Caruso U, Landrieu P, Kelley RI, Kuis W, Poll-The BT, Gibson KM, Wanders RJ, Waterham HR: Organization of the mevalonate kinase (MVK) gene and identification of novel mutations causing mevalonic aciduria and hyperimmunoglobulinaemia D and periodic fever syndrome. Eur J Hum Genet. 2001 Apr;9(4):253-9. doi: 10.1038/sj.ejhg.5200595.
Pubmed: 11313768
Hogenboom S, Tuyp JJ, Espeel M, Koster J, Wanders RJ, Waterham HR: Mevalonate kinase is a cytosolic enzyme in humans. J Cell Sci. 2004 Feb 1;117(Pt 4):631-9. doi: 10.1242/jcs.00910.
Pubmed: 14730012
Houten SM, Kuis W, Duran M, de Koning TJ, van Royen-Kerkhof A, Romeijn GJ, Frenkel J, Dorland L, de Barse MM, Huijbers WA, Rijkers GT, Waterham HR, Wanders RJ, Poll-The BT: Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet. 1999 Jun;22(2):175-7. doi: 10.1038/9691.
Pubmed: 10369261
Chambliss KL, Slaughter CA, Schreiner R, Hoffmann GF, Gibson KM: Molecular cloning of human phosphomevalonate kinase and identification of a consensus peroxisomal targeting sequence. J Biol Chem. 1996 Jul 19;271(29):17330-4. doi: 10.1074/jbc.271.29.17330.
Pubmed: 8663599
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Pubmed: 15489334
Olivier LM, Chambliss KL, Gibson KM, Krisans SK: Characterization of phosphomevalonate kinase: chromosomal localization, regulation, and subcellular targeting. J Lipid Res. 1999 Apr;40(4):672-9.
Pubmed: 10191291
Toth MJ, Huwyler L: Molecular cloning and expression of the cDNAs encoding human and yeast mevalonate pyrophosphate decarboxylase. J Biol Chem. 1996 Apr 5;271(14):7895-8. doi: 10.1074/jbc.271.14.7895.
Pubmed: 8626466
Hinson DD, Chambliss KL, Toth MJ, Tanaka RD, Gibson KM: Post-translational regulation of mevalonate kinase by intermediates of the cholesterol and nonsterol isoprene biosynthetic pathways. J Lipid Res. 1997 Nov;38(11):2216-23.
Pubmed: 9392419
Xuan JW, Kowalski J, Chambers AF, Denhardt DT: A human promyelocyte mRNA transiently induced by TPA is homologous to yeast IPP isomerase. Genomics. 1994 Mar 1;20(1):129-31. doi: 10.1006/geno.1994.1139.
Pubmed: 8020941
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Pubmed: 15164054
Wilkin DJ, Kutsunai SY, Edwards PA: Isolation and sequence of the human farnesyl pyrophosphate synthetase cDNA. Coordinate regulation of the mRNAs for farnesyl pyrophosphate synthetase, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and 3-hydroxy-3-methylglutaryl coenzyme A synthase by phorbol ester. J Biol Chem. 1990 Mar 15;265(8):4607-14.
Pubmed: 1968462
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Pubmed: 7584026
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