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Electron Transfer Pathways in Cholesterol Synthesis

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Lipids

Abstract

Cholesterol synthesis in the endoplasmic reticulum requires electron input at multiple steps and utilizes both NADH and NADPH as the electron source. Four enzymes catalyzing five steps in the pathway require electron input: squalene monooxygenase, lanosterol demethylase, sterol 4α-methyl oxidase, and sterol C5-desaturase. The electron-donor proteins for these enzymes include cytochrome P450 reductase and the cytochrome b5 pathway. Here I review the evidence for electron donor protein requirements with these enzymes, the evidence for additional electron donor pathways, and the effect of deletion of these redox enzymes on cholesterol and lipid metabolism.

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References

  1. Risley JM (2002) Cholesterol biosynthesis: lanosterol to cholesterol. J Chem Educ 79:377–384

    Article  CAS  Google Scholar 

  2. Sharpe LJ, Brown AJ (2013) Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). J Biol Chem 288:18707–18715

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Porter FD, Herman GE (2011) Malformation syndromes caused by disorders of cholesterol synthesis. J Lipid Res 52:6–34

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Kanungo S, Soares N, He M, Steiner RD (2013) Sterol metabolism disorders and neurodevelopment—an update. Dev Disabil Res Rev 17:197–210

    Article  PubMed  Google Scholar 

  5. Seeger MA, Paller AS (2014) The role of abnormalities in the distal pathway of cholesterol synthesis in the congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome. Biochim Biophys Acta 1841:345–352

    Article  CAS  PubMed  Google Scholar 

  6. Canueto J, Giros M, Gonzalez-Sarmiento R (2014) The role of the abnormalities in the distal pathway of cholesterol biosynthesis in the Conradi–Hunermann–Happle syndrome. Biochim Biophys Acta 1841:336–344

    Article  CAS  PubMed  Google Scholar 

  7. Woollett LA (2008) Where does fetal and embryonic cholesterol originate and what does it do? Annu Rev Nutr 28:97–114

    Article  CAS  PubMed  Google Scholar 

  8. Jeong J, McMahon AP (2002) Cholesterol modification of hedgehog family proteins. J Clin Invest 110:591–596

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Mann RK, Beachy PA (2004) Novel lipid modifications of secreted protein signals. Annu Rev Biochem 73:891–923

    Article  CAS  PubMed  Google Scholar 

  10. Li L, Porter TD (2007) Hepatic cytochrome P450 reductase-null mice reveal a second microsomal reductase for squalene monooxygenase. Arch Biochem Biophys 461:76–84

    Article  CAS  PubMed  Google Scholar 

  11. Pandey AV, Fluck CE (2013) NADPH P450 oxidoreductase: structure, function, and pathology of diseases. Pharmacol Ther 138:229–254

    Article  CAS  PubMed  Google Scholar 

  12. Altuve A, Wang L, Benson DR, Rivera M (2004) Mammalian mitochondrial and microsomal cytochromes b(5) exhibit divergent structural and biophysical characteristics. Biochem Biophys Res Commun 314:602–609

    Article  CAS  PubMed  Google Scholar 

  13. Enoch HG, Strittmatter P (1979) Cytochrome b5 reduction by NADPH-cytochrome P-450 reductase. J Biol Chem 254:8976–8981

    CAS  PubMed  Google Scholar 

  14. Shen AL, O’Leary KA, Kasper CB (2002) Association of multiple developmental defects and embryonic lethality with loss of microsomal NADPH-cytochrome P450 oxidoreductase. J Biol Chem 277:6536–6541

    Article  CAS  PubMed  Google Scholar 

  15. Otto DM, Henderson CJ, Carrie D, Davey M, Gundersen TE, Blomhoff R, Adams RH, Tickle C, Wolf CR (2003) Identification of novel roles of the cytochrome p450 system in early embryogenesis: effects on vasculogenesis and retinoic Acid homeostasis. Mol Cell Biol 23:6103–6116

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Finn RD, McLaughlin LA, Hughes C, Song C, Henderson CJ, Roland Wolf C (2011) Cytochrome b5 null mouse: a new model for studying inherited skin disorders and the role of unsaturated fatty acids in normal homeostasis. Transgenic Res 20:491–502

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Giordano SJ, Kaftory A, Steggles AW (1994) A splicing mutation in the cytochrome b5 gene from a patient with congenital methemoglobinemia and pseudohermaphrodism. Hum Genet 93:568–570

    Article  CAS  PubMed  Google Scholar 

  18. Hegesh E, Hegesh J, Kaftory A (1986) Congenital methemoglobinemia with a deficiency of cytochrome b5. N Engl J Med 314:757–761

    Article  CAS  PubMed  Google Scholar 

  19. Kok RC, Timmerman MA, Wolffenbuttel KP, Drop SL, de Jong FH (2010) Isolated 17,20-lyase deficiency due to the cytochrome b5 mutation W27X. J Clin Endocrinol Metab 95:994–999

    Article  CAS  PubMed  Google Scholar 

  20. Idkowiak J, Randell T, Dhir V, Patel P, Shackleton CH, Taylor NF, Krone N, Arlt W (2012) A missense mutation in the human cytochrome b5 gene causes 46, XY disorder of sex development due to true isolated 17,20 lyase deficiency. J Clin Endocrinol Metab 97:E465–E475

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Porter TD (2012) New insights into the role of cytochrome P450 reductase (POR) in microsomal redox biology. Acta Pharm Sin B 2:100–104

    Article  Google Scholar 

  22. Gu J, Weng Y, Zhang QY, Cui H, Behr M, Wu L, Yang W, Zhang L, Ding X (2003) Liver-specific deletion of the NADPH-cytochrome P450 reductase gene: impact on plasma cholesterol homeostasis and the function and regulation of microsomal cytochrome P450 and heme oxygenase. J Biol Chem 278:25895–25901

    Article  CAS  PubMed  Google Scholar 

  23. Henderson CJ, Otto DM, Carrie D, Magnuson MA, McLaren AW, Rosewell I, Wolf CR (2003) Inactivation of the hepatic cytochrome P450 system by conditional deletion of hepatic cytochrome P450 reductase. J Biol Chem 278:13480–13486

    Article  CAS  PubMed  Google Scholar 

  24. Mutch DM, Klocke B, Morrison P, Murray CA, Henderson CJ, Seifert M, Williamson G (2007) The disruption of hepatic cytochrome p450 reductase alters mouse lipid metabolism. J Proteome Res 6:3976–3984

    Article  CAS  PubMed  Google Scholar 

  25. Finn RD, Henderson CJ, Scott CL, Wolf CR (2009) Unsaturated fatty acid regulation of cytochrome P450 expression via a CAR-dependent pathway. Biochem J 417:43–54

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Porter TD, Banerjee S, Stolarczyk EI, Zou L (2011) Suppression of cytochrome P450 reductase (POR) expression in hepatoma cells replicates the hepatic lipidosis observed in hepatic POR-null mice. Drug Metab Dispos 39:966–973

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Riddick DS, Ding X, Wolf CR, Porter TD, Pandey AV, Zhang QY, Gu J, Finn RD, Ronseaux S, McLaughlin LA, Henderson CJ, Zou L, Fluck CE (2013) NADPH-cytochrome P450 oxidoreductase: roles in physiology, pharmacology, and toxicology. Drug Metab Dispos 41:12–23

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Wang XJ, Chamberlain M, Vassieva O, Henderson CJ, Wolf CR (2005) Relationship between hepatic phenotype and changes in gene expression in cytochrome P450 reductase (POR) null mice. Biochem J 388:857–867

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Weng Y, DiRusso CC, Reilly AA, Black PN, Ding X (2005) Hepatic gene expression changes in mouse models with liver-specific deletion or global suppression of the NADPH-cytochrome P450 reductase gene. Mechanistic implications for the regulation of microsomal cytochrome P450 and the fatty liver phenotype. J Biol Chem 280:31686–31698

    Article  CAS  PubMed  Google Scholar 

  30. Miller WL (1986) Congenital adrenal hyperplasia. N Engl J Med 314:1321–1322

    CAS  PubMed  Google Scholar 

  31. Fluck CE, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge CF, Jabs EW, Mendonca BB, Fujieda K, Miller WL (2004) Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nat Genet 36:228–230

    Article  PubMed  Google Scholar 

  32. Huang N, Pandey AV, Agrawal V, Reardon W, Lapunzina PD, Mowat D, Jabs EW, Van Vliet G, Sack J, Fluck CE, Miller WL (2005) Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. Am J Hum Genet 76:729–749

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Schmidt K, Hughes C, Chudek JA, Goodyear SR, Aspden RM, Talbot R, Gundersen TE, Blomhoff R, Henderson C, Wolf CR, Tickle C (2009) Cholesterol metabolism: the main pathway acting downstream of cytochrome P450 oxidoreductase in skeletal development of the limb. Mol Cell Biol 29:2716–2729

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Laue K, Pogoda HM, Daniel PB, van Haeringen A, Alanay Y, von Ameln S, Rachwalski M, Morgan T, Gray MJ, Breuning MH, Sawyer GM, Sutherland-Smith AJ, Nikkels PG, Kubisch C, Bloch W, Wollnik B, Hammerschmidt M, Robertson SP (2011) Craniosynostosis and multiple skeletal anomalies in humans and zebrafish result from a defect in the localized degradation of retinoic acid. Am J Hum Genet 89:595–606

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Ono T, Ozasa S, Hasegawa F, Imai Y (1977) Involvement of Nadph-cytochrome C-reductase in rat-liver squalene epoxidase system. Biochim Biophys Acta 486:401–407

    Article  CAS  PubMed  Google Scholar 

  36. Ono T, Takahashi K, Odani S, Konno H, Imai Y (1980) Purification of squalene epoxidase from rat liver microsomes. Biochem Biophys Res Commun 96:522–528

    Article  CAS  PubMed  Google Scholar 

  37. Ono T, Nakazono K, Kosaka H (1982) Purification and partial characterization of squalene epoxidase from rat liver microsomes. Biochim Biophys Acta 709:84–90

    Article  CAS  PubMed  Google Scholar 

  38. Lamb DC, Kelly DE, Manning NJ, Kaderbhai MA, Kelly SL (1999) Biodiversity of the P450 catalytic cycle: yeast cytochrome b5/NADH cytochrome b5 reductase complex efficiently drives the entire sterol 14-demethylation (CYP51) reaction. FEBS Lett 462:283–288

    Article  CAS  PubMed  Google Scholar 

  39. Laden BP, Tang Y, Porter TD (2000) Cloning, heterologous expression, and enzymological characterization of human squalene monooxygenase. Arch Biochem Biophys 374:381–388

    Article  CAS  PubMed  Google Scholar 

  40. Lepesheva GI, Waterman MR (2007) Sterol 14alpha-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms. Biochim Biophys Acta 1770:467–477

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Keber R, Motaln H, Wagner KD, Debeljak N, Rassoulzadegan M, Acimovic J, Rozman D, Horvat S (2011) Mouse knockout of the cholesterogenic cytochrome P450 lanosterol 14alpha-demethylase (Cyp51) resembles Antley-Bixler syndrome. J Biol Chem 286:29086–29097

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Bellamine A, Mangla AT, Nes WD, Waterman MR (1999) Characterization and catalytic properties of the sterol 14alpha-demethylase from Mycobacterium tuberculosis. Proc Natl Acad Sci USA 96:8937–8942

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Lamb DC, Kaderbhai NN, Venkateswarlu K, Kelly DE, Kelly SL, Kaderbhai MA (2001) Human sterol 14alpha-demethylase activity is enhanced by the membrane-bound state of cytochrome b(5). Arch Biochem Biophys 395:78–84

    Article  CAS  PubMed  Google Scholar 

  44. Richard G, Bale SJ (1993) Autosomal recessive congenital ichthyosis. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K (eds) GeneReviews(R). Seattle (WA)

  45. Miller WL, Tee MK (2015) The post-translational regulation of 17,20 lyase activity. Mol Cell Endocrinol 408:99–106

    Article  CAS  PubMed  Google Scholar 

  46. Miller WL (2012) The syndrome of 17,20 lyase deficiency. J Clin Endocrinol Metab 97:59–67

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Percy MJ, Lappin TR (2008) Recessive congenital methaemoglobinaemia: cytochrome b(5) reductase deficiency. Br J Haematol 141:298–308

    CAS  PubMed  Google Scholar 

  48. Hirono H (1980) Lipids of myelin, white matter and gray matter in a case of generalized deficiency of cytochrome b5 reductase in congenital methemoglobinemia with mental retardation. Lipids 15:272–275

    Article  CAS  PubMed  Google Scholar 

  49. Hirono H (1984) Lipids of liver, kidney, spleen and muscle in a case of generalized deficiency of cytochrome b5 reductase in congenital methemoglobinemia with mental retardation. Lipids 19:60–63

    Article  CAS  PubMed  Google Scholar 

  50. Neve EP, Nordling A, Andersson TB, Hellman U, Diczfalusy U, Johansson I, Ingelman-Sundberg M (2012) Amidoxime reductase system containing cytochrome b5 type B (CYB5B) and MOSC2 is of importance for lipid synthesis in adipocyte mitochondria. J Biol Chem 287:6307–6317

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Ogishima T, Kinoshita JY, Mitani F, Suematsu M, Ito A (2003) Identification of outer mitochondrial membrane cytochrome b5 as a modulator for androgen synthesis in Leydig cells. J Biol Chem 278:21204–21211

    Article  CAS  PubMed  Google Scholar 

  52. Plitzko B, Ott G, Reichmann D, Henderson CJ, Wolf CR, Mendel R, Bittner F, Clement B, Havemeyer A (2013) The involvement of mitochondrial amidoxime reducing components 1 and 2 and mitochondrial cytochrome b5 in N-reductive metabolism in human cells. J Biol Chem 288:20228–20237

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Colombo S, Longhi R, Alcaro S, Ortuso F, Sprocati T, Flora A, Borgese N (2005) N-myristoylation determines dual targeting of mammalian NADH-cytochrome b5 reductase to ER and mitochondrial outer membranes by a mechanism of kinetic partitioning. J Cell Biol 168:735–745

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. He M, Smith LD, Chang R, Li X, Vockley J (2014) The role of sterol-C4-methyl oxidase in epidermal biology. Biochim Biophys Acta 1841:331–335

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Byskov AG, Andersen CY, Leonardsen L (2002) Role of meiosis activating sterols, MAS, in induced oocyte maturation. Mol Cell Endocrinol 187:189–196

    Article  CAS  PubMed  Google Scholar 

  56. Keber R, Rozman D, Horvat S (2013) Sterols in spermatogenesis and sperm maturation. J Lipid Res 54:20–33

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Honjo K, Ishibashi T, Imai Y (1985) Partial purification and characterization of lathosterol 5-desaturase from rat liver microsomes. J Biochem 97:955–959

    CAS  PubMed  Google Scholar 

  58. Rossi M, D’Armiento M, Parisi I, Ferrari P, Hall CM, Cervasio M, Rivasi F, Balli F, Vecchione R, Corso G, Andria G, Parenti G (2007) Clinical phenotype of lathosterolosis. Am J Med Genet A 143:2371–2381

    Article  Google Scholar 

  59. Krakowiak PA, Wassif CA, Kratz L, Cozma D, Kovarova M, Harris G, Grinberg A, Yang Y, Hunter AG, Tsokos M, Kelley RI, Porter FD (2003) Lathosterolosis: an inborn error of human and murine cholesterol synthesis due to lathosterol 5-desaturase deficiency. Hum Mol Genet 12:1631–1641

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, 40536-0596, USA

    Todd D. Porter

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Porter, T.D. Electron Transfer Pathways in Cholesterol Synthesis. Lipids 50, 927–936 (2015). https://doi.org/10.1007/s11745-015-4065-1

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