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Pathway Description
Kandutsch-Russell Pathway (Cholesterol Biosynthesis)
Homo sapiens
Metabolic Pathway
Created: 2019-01-23
Last Updated: 2022-09-03
The Kandutsch-Russell pathway is the alternative pathway stemming from the mevalonate pathway completing cholesterol biosynthesis. The Bloch pathway and the Kandutsch-Russell pathway are both key to a functioning human body as cholesterol aids in the development of many important nutrients and hormones, such as vitamin D. Starting in the endoplasmic reticulum, lanosterol is the first compound used in this pathway, and when catalyzed by delta(24)-sterol-reductase, becomes 24,25-dihydrolanosterol. 24,25-Dihydrolanosterol is quickly converted to 4,4-dimethyl-14a-hydroxymethyl-5a-cholesta-8-en-3b-ol with the help of the enzyme lanosterol 14-alpha demethylase. This same enzyme, lanosterol 14-alpha demethylase, is also responsible for the conversion of 4,4-dimethyl-14a-hydroxymethyl-5a-cholesta-8-en-3b-ol into 4,4-dimethyl-14a-formyl-5a-cholest-8-en-3b-ol. Lanosterol 14alpha demethylase is used once more here, to push the pathway into the inner nuclear membrane, converting 4,4-dimethyl-14a-formyl-5a-cholest-8-en-3b-ol into 4,4-dimethyl-5a-cholesta-8,14-dien-3b-ol. Now located in the inner nuclear membrane, 4,4-dimethyl-5a-cholesta-8,14-dien-3b-ol is converted into 4,4-dimethyl-5a-cholesta-8-en-3b-ol through the help of a lamin-b receptor. Entering the endoplasmic reticulum membrane, methylsterol monooxygenase 1 is used to convert 4,4-dimethyl-5a-cholesta-8-en-3b-ol into 4a-hydroxymethyl-4b-methyl-5a-cholesta-8-en-3b-ol. 4a-Hydroxymethyl-4b-methyl-5a-cholesta-8-en-3b-ol then uses methylsterol monooxygenase 1 to become 4a-formyl-4b-methyl-5a-cholesta-8-en-3b-ol. Once again, methylsterol monooxygenase 1 is used to convert 4a-formyl-4b-methyl-5a-cholesta-8-en-3b-ol into 4a-carboxy-4b-methyl-5a-cholesta-8-en-3b-ol. Now using sterol-4-alpha-carboxylate 3-dehydrogenase, 4a-carboxy-4b-methyl-5a-cholesta-8-en-3b-ol is turned into 4a-methyl-5a-cholesta-8-en-3-one. This puts the pathway in the cell membrane, where a 3-keto-steroid reductase is used to convert 4a-methyl-5a-cholesta-8-en-3b-one into 4a-methyl-5a-cholesta-8-en-3-ol. Moving back into the endoplasmic reticulum membrane, methylsterol monooxygenase 1 converts 4a-methyl-5a-cholesta-8-en-3-ol into 4a-hydroxymethyl-5a-cholesta-8-en-3b-ol. Methylsterol monooxygenase is used twice more in this pathway, first converting 4a-hydroxymethyl-5a-cholesta-8-en-3b-ol into 4a-formyl-5a-cholesta-8-en-3b-ol, then converting 4a-formyl-5a-cholesta-8-en-3b-ol into 4a-carboxy-5a-cholesta-8-en-3b-ol. Now using sterol-4-alpha-carboxylate 3 dehydrogenase, 4a-carboxy-5a-cholesta-8-en-3b-ol becomes 5a-cholesta-8-en-3-one and brings the pathway back to the cell membrane. 5a-Cholesta-8-en-3-one teams up with a 3-keto-steroid reductase to create 5a-cholest-8-en-3b-ol. Then, stepping back into the endoplasmic reticulum membrane, 5a-cholest-8-en-3b-ol enlists the help of 3-beta-hydroxysteroid-delta(8),delta(7)-isomerase to produce lathosterol. Lathosterol and lathosterol oxidase work together to make 7-dehydrocholesterol . Finally, 7-dehydrocholesterol partners with 7-dehydrocholesterol reductase to create cholesterol, completing the final step in cholesterol biosynthesis.
References
Kandutsch-Russell Pathway (Cholesterol Biosynthesis) References
Sharpe LJ, Brown AJ: Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). J Biol Chem. 2013 Jun 28;288(26):18707-15. doi: 10.1074/jbc.R113.479808. Epub 2013 May 21.
Pubmed: 23696639
Prabhu AV, Luu W, Li D, Sharpe LJ, Brown AJ: DHCR7: A vital enzyme switch between cholesterol and vitamin D production. Prog Lipid Res. 2016 Oct;64:138-151. doi: 10.1016/j.plipres.2016.09.003. Epub 2016 Sep 30.
Pubmed: 27697512
Luu W, Hart-Smith G, Sharpe LJ, Brown AJ: The terminal enzymes of cholesterol synthesis, DHCR24 and DHCR7, interact physically and functionally. J Lipid Res. 2015 Apr;56(4):888-97. doi: 10.1194/jlr.M056986. Epub 2015 Jan 31.
Pubmed: 25637936
Greeve I, Hermans-Borgmeyer I, Brellinger C, Kasper D, Gomez-Isla T, Behl C, Levkau B, Nitsch RM: The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to Alzheimer's disease-associated neurodegeneration and oxidative stress. J Neurosci. 2000 Oct 1;20(19):7345-52.
Pubmed: 11007892
Waterham HR, Koster J, Romeijn GJ, Hennekam RC, Vreken P, Andersson HC, FitzPatrick DR, Kelley RI, Wanders RJ: Mutations in the 3beta-hydroxysterol Delta24-reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis. Am J Hum Genet. 2001 Oct;69(4):685-94. doi: 10.1086/323473. Epub 2001 Aug 22.
Pubmed: 11519011
Stromstedt M, Rozman D, Waterman MR: The ubiquitously expressed human CYP51 encodes lanosterol 14 alpha-demethylase, a cytochrome P450 whose expression is regulated by oxysterols. Arch Biochem Biophys. 1996 May 1;329(1):73-81. doi: 10.1006/abbi.1996.0193.
Pubmed: 8619637
Aoyama Y, Noshiro M, Gotoh O, Imaoka S, Funae Y, Kurosawa N, Horiuchi T, Yoshida Y: Sterol 14-demethylase P450 (P45014DM*) is one of the most ancient and conserved P450 species. J Biochem. 1996 May;119(5):926-33. doi: 10.1093/oxfordjournals.jbchem.a021331.
Pubmed: 8797093
Rozman D, Stromstedt M, Waterman MR: The three human cytochrome P450 lanosterol 14 alpha-demethylase (CYP51) genes reside on chromosomes 3, 7, and 13: structure of the two retrotransposed pseudogenes, association with a line-1 element, and evolution of the human CYP51 family. Arch Biochem Biophys. 1996 Sep 15;333(2):466-74. doi: 10.1006/abbi.1996.0416.
Pubmed: 8809088
Ye Q, Worman HJ: Primary structure analysis and lamin B and DNA binding of human LBR, an integral protein of the nuclear envelope inner membrane. J Biol Chem. 1994 Apr 15;269(15):11306-11.
Pubmed: 8157662
Papoutsopoulou S, Nikolakaki E, Giannakouros T: SRPK1 and LBR protein kinases show identical substrate specificities. Biochem Biophys Res Commun. 1999 Feb 24;255(3):602-7. doi: 10.1006/bbrc.1999.0249.
Pubmed: 10049757
Duband-Goulet I, Courvalin JC: Inner nuclear membrane protein LBR preferentially interacts with DNA secondary structures and nucleosomal linker. Biochemistry. 2000 May 30;39(21):6483-8. doi: 10.1021/bi992908b.
Pubmed: 10828963
Li L, Kaplan J: Characterization of yeast methyl sterol oxidase (ERG25) and identification of a human homologue. J Biol Chem. 1996 Jul 12;271(28):16927-33. doi: 10.1074/jbc.271.28.16927.
Pubmed: 8663358
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Pubmed: 14702039
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Pubmed: 15815621
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