Cholesterol biosynthesis (Homo sapiens)
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Description
Cholesterol is synthesized de novo from from acetyl CoA. The overall synthetic process is outlined in the figure below. Enzymes whose regulation plays a major role in determining the rate of cholesterol synthesis in the body are highlighted in red, and connections to other metabolic processes are indicated. The transformation of lanosterol into cholesterol requires multiple steps, including the removal of three methyl groups, the reduction of one double bond and the migration of another. These reactions may not occur in a single fixed order in the body, so the linear pathway laid out here following the work of Gaylor and colleagues (Gaylor 2002) is an oversimplification of the process that occurs in vivo. Defects in several of the enzymes involved in this process are associated with human disease and have provided useful insights into the regulatory roles of cholesterol and its synthetic intermediates in human development (Herman 2003; Song et al. 2005).
Source:Reactome.
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- Gaylor JL.; ''Membrane-bound enzymes of cholesterol synthesis from lanosterol.''; PubMed Europe PMC Scholia
History
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External references
DataNodes
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Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| 14DMLANOL | Arrow | R-HSA-194674 (Reactome)  | ||
| 14DMLANOL | Arrow | R-HSA-194698 (Reactome) | ||
| 4,4DMCHOLtrienol | Arrow | R-HSA-194678 (Reactome) | ||
| 4,4DMCHOLtrienol | R-HSA-194641 (Reactome) | |||
| 4,4DMCHOLtrienol | R-HSA-194698 (Reactome) | |||
| 4,4DMCHtOL | R-HSA-194674 (Reactome) | |||
| 4C4MZYMOL | Arrow | R-HSA-194641 (Reactome) | ||
| 4C4MZYMOL | R-HSA-194642 (Reactome) | |||
| 4CZYMOL | Arrow | R-HSA-194669 (Reactome) | ||
| 4CZYMOL | R-HSA-194718 (Reactome) | |||
| 4MZYMOL | Arrow | R-HSA-194689 (Reactome) | ||
| 4MZYMOL | R-HSA-194669 (Reactome) | |||
| 7dhDESOL | Arrow | R-HSA-195664 (Reactome) | ||
| 7dhDESOL | R-HSA-196402 (Reactome) | |||
| ACA-CoA | R-HSA-191323 (Reactome) | |||
| ADP | Arrow | R-HSA-191380 (Reactome) | ||
| ADP | Arrow | R-HSA-191414 (Reactome) | ||
| ADP | Arrow | R-HSA-191422 (Reactome) | ||
| ARV1 | mim-catalysis | R-HSA-5250531 (Reactome) | ||
| ATP | R-HSA-191380 (Reactome) | |||
| ATP | R-HSA-191414 (Reactome) | |||
| ATP | R-HSA-191422 (Reactome) | |||
| Ac-CoA | R-HSA-191323 (Reactome) | |||
| CHOL | Arrow | R-HSA-196417 (Reactome) | ||
| CHOL | Arrow | R-HSA-5250531 (Reactome) | ||
| CHOL | R-HSA-5250531 (Reactome) | |||
| CHdOL | Arrow | R-HSA-195690 (Reactome) | ||
| CHdOL | R-HSA-195664 (Reactome) | |||
| CO2 | Arrow | R-HSA-191414 (Reactome) | ||
| CO2 | Arrow | R-HSA-194642 (Reactome) | ||
| CO2 | Arrow | R-HSA-194718 (Reactome) | ||
| CYP51A1 | mim-catalysis | R-HSA-194678 (Reactome) | ||
| CoA-SH | Arrow | R-HSA-191323 (Reactome) | ||
| CoA-SH | Arrow | R-HSA-191352 (Reactome) | ||
| DESMOL | Arrow | R-HSA-196402 (Reactome) | ||
| DESMOL | R-HSA-196417 (Reactome) | |||
| DHCR24 | mim-catalysis | R-HSA-196417 (Reactome) | ||
| DHCR7 | mim-catalysis | R-HSA-196402 (Reactome) | ||
| DMAPP | Arrow | R-HSA-191382 (Reactome) | ||
| DMAPP | R-HSA-191322 (Reactome) | |||
| EBP | mim-catalysis | R-HSA-195690 (Reactome) | ||
| FAPP | Arrow | R-HSA-191303 (Reactome) | ||
| FAPP | R-HSA-191405 (Reactome) | |||
| FDFT:Mg2+ | mim-catalysis | R-HSA-191402 (Reactome) | ||
| FDFT:Mg2+ | mim-catalysis | R-HSA-191405 (Reactome) | ||
| FDPS,GGPS1 | mim-catalysis | R-HSA-191303 (Reactome) | ||
| FDPS,GGPS1 | mim-catalysis | R-HSA-191322 (Reactome) | ||
| GPP | Arrow | R-HSA-191322 (Reactome) | ||
| GPP | R-HSA-191303 (Reactome) | |||
| H+ | Arrow | R-HSA-194642 (Reactome) | ||
| H+ | Arrow | R-HSA-194718 (Reactome) | ||
| H+ | R-HSA-191299 (Reactome) | |||
| H+ | R-HSA-191352 (Reactome) | |||
| H+ | R-HSA-191402 (Reactome) | |||
| H+ | R-HSA-194632 (Reactome) | |||
| H+ | R-HSA-194641 (Reactome) | |||
| H+ | R-HSA-194669 (Reactome) | |||
| H+ | R-HSA-194674 (Reactome) | |||
| H+ | R-HSA-194678 (Reactome) | |||
| H+ | R-HSA-194689 (Reactome) | |||
| H+ | R-HSA-194698 (Reactome) | |||
| H+ | R-HSA-195664 (Reactome) | |||
| H+ | R-HSA-196402 (Reactome) | |||
| H+ | R-HSA-196417 (Reactome) | |||
| H2O | Arrow | R-HSA-191299 (Reactome) | ||
| H2O | Arrow | R-HSA-194641 (Reactome) | ||
| H2O | Arrow | R-HSA-194669 (Reactome) | ||
| H2O | Arrow | R-HSA-194678 (Reactome) | ||
| H2O | Arrow | R-HSA-195664 (Reactome) | ||
| H2O | R-HSA-191323 (Reactome) | |||
| HCOOH | Arrow | R-HSA-194678 (Reactome) | ||
| HMGCR dimer | mim-catalysis | R-HSA-191352 (Reactome) | ||
| HMGCS1 | mim-catalysis | R-HSA-191323 (Reactome) | ||
| HSD17B7 | mim-catalysis | R-HSA-194632 (Reactome) | ||
| HSD17B7 | mim-catalysis | R-HSA-194689 (Reactome) | ||
| IDI1 or 2 | mim-catalysis | R-HSA-191382 (Reactome) | ||
| IPPP | Arrow | R-HSA-191414 (Reactome) | ||
| IPPP | R-HSA-191303 (Reactome) | |||
| IPPP | R-HSA-191322 (Reactome) | |||
| IPPP | R-HSA-191382 (Reactome) | |||
| LBR | mim-catalysis | R-HSA-194674 (Reactome) | ||
| LNSOL | Arrow | R-HSA-191366 (Reactome) | ||
| LNSOL | R-HSA-194678 (Reactome) | |||
| LSS | mim-catalysis | R-HSA-191366 (Reactome) | ||
| MSMO1 | mim-catalysis | R-HSA-194641 (Reactome) | ||
| MSMO1 | mim-catalysis | R-HSA-194669 (Reactome) | ||
| MVA5P | Arrow | R-HSA-191380 (Reactome) | ||
| MVA5PP | Arrow | R-HSA-191422 (Reactome) | ||
| MVA5PP | R-HSA-191414 (Reactome) | |||
| MVA5P | R-HSA-191422 (Reactome) | |||
| MVA | Arrow | R-HSA-191352 (Reactome) | ||
| MVA | R-HSA-191380 (Reactome) | |||
| MVD dimer | mim-catalysis | R-HSA-191414 (Reactome) | ||
| MVK dimer | mim-catalysis | R-HSA-191380 (Reactome) | ||
| NAD+ | R-HSA-194642 (Reactome) | |||
| NAD+ | R-HSA-194718 (Reactome) | |||
| NADH | Arrow | R-HSA-194642 (Reactome) | ||
| NADH | Arrow | R-HSA-194718 (Reactome) | ||
| NADP+ | Arrow | R-HSA-191299 (Reactome) | ||
| NADP+ | Arrow | R-HSA-191352 (Reactome) | ||
| NADP+ | Arrow | R-HSA-191402 (Reactome) | ||
| NADP+ | Arrow | R-HSA-194632 (Reactome) | ||
| NADP+ | Arrow | R-HSA-194641 (Reactome) | ||
| NADP+ | Arrow | R-HSA-194669 (Reactome) | ||
| NADP+ | Arrow | R-HSA-194674 (Reactome) | ||
| NADP+ | Arrow | R-HSA-194678 (Reactome) | ||
| NADP+ | Arrow | R-HSA-194689 (Reactome) | ||
| NADP+ | Arrow | R-HSA-194698 (Reactome) | ||
| NADP+ | Arrow | R-HSA-195664 (Reactome) | ||
| NADP+ | Arrow | R-HSA-196402 (Reactome) | ||
| NADP+ | Arrow | R-HSA-196417 (Reactome) | ||
| NADPH | R-HSA-191299 (Reactome) | |||
| NADPH | R-HSA-191352 (Reactome) | |||
| NADPH | R-HSA-191402 (Reactome) | |||
| NADPH | R-HSA-194632 (Reactome) | |||
| NADPH | R-HSA-194641 (Reactome) | |||
| NADPH | R-HSA-194669 (Reactome) | |||
| NADPH | R-HSA-194674 (Reactome) | |||
| NADPH | R-HSA-194678 (Reactome) | |||
| NADPH | R-HSA-194689 (Reactome) | |||
| NADPH | R-HSA-194698 (Reactome) | |||
| NADPH | R-HSA-195664 (Reactome) | |||
| NADPH | R-HSA-196402 (Reactome) | |||
| NADPH | R-HSA-196417 (Reactome) | |||
| NSDHL | mim-catalysis | R-HSA-194642 (Reactome) | ||
| NSDHL | mim-catalysis | R-HSA-194718 (Reactome) | ||
| O2 | R-HSA-191299 (Reactome) | |||
| O2 | R-HSA-194641 (Reactome) | |||
| O2 | R-HSA-194669 (Reactome) | |||
| O2 | R-HSA-194678 (Reactome) | |||
| O2 | R-HSA-195664 (Reactome) | |||
| PMVK | mim-catalysis | R-HSA-191422 (Reactome) | ||
| PPi | Arrow | R-HSA-191303 (Reactome) | ||
| PPi | Arrow | R-HSA-191322 (Reactome) | ||
| PPi | Arrow | R-HSA-191402 (Reactome) | ||
| PPi | Arrow | R-HSA-191405 (Reactome) | ||
| PSQPP | Arrow | R-HSA-191405 (Reactome) | ||
| PSQPP | R-HSA-191402 (Reactome) | |||
| Pi | Arrow | R-HSA-191414 (Reactome) | ||
| R-HSA-191299 (Reactome) | Squalene monooxygenase (squalene epoxidase, SE) is located on the endoplamic reticulum. It catalyzes the oxidation of squalene to squalene 2,3-epoxide. SE seems to be an important rate-limiting enzyme in cholesterol biosynthesis. | |||
| R-HSA-191303 (Reactome) | Further condensation of an isopentenyl pyrophosphate with geranyl pyrophosphate to form farnesyl pyrophosphate is catalyzed by the prenyltransferases FPP synthase and GGPP synthase. (Kavanagh et al, 2006) | |||
| R-HSA-191322 (Reactome) | The family of enzymes called prenyltransferases is involved in the biosynthesis of isoprenoids. Two members of this family are known to catalyse the sequential condensation of isopentenyl pyrophosphate to DMAPP: farnesyl pyrophosphate synthase (FPPS) and geranylgeranyl pyrophosphate synthetase (GGPPS) (Kavanaugh et al, 2006). | |||
| R-HSA-191323 (Reactome) | 3-hydroxy-3-methylglutaryl Coenzyme A synthase (HMG-CoA synthase) catalyzes the condensation of acetyl CoA with acetoacetyl CoA to produce HMG-CoA. There are two forms of this enzyme, cytosolic and mitochondrial. The cytosolic form is ubiquitous in the body and is involved in cholesterol biosynthesis and synthesis of other isoprenoid products. The mitochondrial form, found solely in the liver and kidney, is involved in the ketogenic pathway. | |||
| R-HSA-191352 (Reactome) | 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) catalyzes the four-electron reduction of HMG-CoA to mevalonate. Mevalonate concentrations in the cell are tightly controlled through the activity of HMGR, which is one of the most highly regulated enzymes known (Goldstein and Brown 1990). | |||
| R-HSA-191366 (Reactome) | Lanosterol synthase (LS) catalyzes the cyclization of squalene 2,3-epoxide to lanosterol, a reaction that forms the sterol nucleus.LS is located on the ER membrane and is active as the monomer (Ruf et al, 2004). | |||
| R-HSA-191380 (Reactome) | Mevalonate kinase (MK) catalyzes the phosphorylation of mevalonate to mevalonate-5-phosphate. | |||
| R-HSA-191382 (Reactome) | Cytosolic isopentenyl diphosphate isomerase (IPP isomerase) catalyzes an essential activation step in the isoprenoid biosynthetic pathway. It rearranges isopentenyl pyrophosphate into its highly electrophilic isomer, dimethylallyl pyrophosphate (DMAPP). IPP isomerase may also be located in human peroxisomes but it's function there is not clear. | |||
| R-HSA-191402 (Reactome) | In the second step, FDFT catalyzes the reduction of presqualene diphosphate to squalene (Pandit et al. 2000). | |||
| R-HSA-191405 (Reactome) | Farnesyl diphosphate farnesyltransferase (FDFT; squalene synthase) catalyzes the reductive dimerization of two farnesyl diphosphate (FPP) molecules to form squalene. This happens in two distinct steps. The first step of dimerization forms presqualene diphosphate (Pandit et al. 2000). | |||
| R-HSA-191414 (Reactome) | Mevalonate pyrophosphate decarboxylase (MPD) decarboxylates mevalonate-5-pyrophosphate (MVA5PP) into isopentenyl pyrophosphate (IPPP) while hydrolysing ATP to ADP and orthophosphate (Toth & Huwyler 1996). | |||
| R-HSA-191422 (Reactome) | Phosphomevalonate kinase (PMK) catalyzes the reversible, ATP-dependent phosphorylation of mevalonate-5-phosphate, producing mevalonate-5-pyrophosphate. | |||
| R-HSA-194632 (Reactome) | Zymosterone (cholesta-8(9),24-dien-3-one) and NADPH + H+ react to form zymosterol (cholesta-8(9),24-dien-3beta-ol) and NADP+. This reaction takes place in the endoplasmic reticulum, catalyzed by HSD17B7. Two isoforms of the enzyme due to alternative splicing have been identified but only the first has been tested for enzymatic activity (Marijanovic et al. 2003). The human enzyme has not been studied extensively; molecular details of the reaction are inferred from those worked out in studies of material from rat liver (Gaylor 2002). | |||
| R-HSA-194641 (Reactome) | 4,4-dimethylcholesta-8(9),24-dien-3beta-ol, NADPH + H+, and O2 react to form 4-methyl,4-carboxycholesta-8(9),24-dien-3beta-ol, NADP+, and H2O. This reaction, in the endoplasmic reticulum, is catalyzed by SC4MOL (C-4 methylsterol oxidase). The human enzyme has been identified based on its sequence similarity to yeast methyl sterol oxidase (ERG25) and the ability of the cloned human gene to rescue ERG25-deficient yeast cells (Li and Kaplan 1996). The mechanism and stoichiometry of the reaction have been inferred from studies of partially purified rat enzyme (Gaylor et al. 1975; Fukushima et al. 1981). | |||
| R-HSA-194642 (Reactome) | 4-methyl,4-carboxycholesta-8(9),24-dien-3beta-ol and NAD+ react to form 4-methylcholesta-8(9),24-dien-3-one, CO2, and NADH + H+. This reaction occurs in the endoplasmic reticulum, catalyzed by NSDHL (Caldas and Herman 2003). Defects in this enzyme are associated with CHILD syndrome (Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects) (Konig et al. 2000), but cholesterol biosynthesis in cells and tissues from affected individuals has not been characterized. Instead, the mechanism and stoichiometry of the reaction are inferred from biochemical studies of partially purified rat enzyme (Rahimtula and Gaylor 1972). | |||
| R-HSA-194669 (Reactome) | 4-methylcholesta-8(9),24-dien-3beta-ol, NADPH + H+, and O2 react to form 4-carboxycholesta-8(9),24-dien-3beta-ol, NADP+, and H2O. This reaction, in the endoplasmic reticulum, is catalyzed by SC4MOL (C-4 methylsterol oxidase). The human enzyme has been identified based on its sequence similarity to yeast methyl sterol oxidase (ERG25) and the ability of the cloned human gene to rescue ERG25-deficient yeast cells (Li and Kaplan 1996). The mechanism and stoichiometry of the reaction have been inferred from studies of partially purified rat enzyme (Gaylor et al. 1975; Fukushima et al. 1981). | |||
| R-HSA-194674 (Reactome) | 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol and NADPH + H+ react to form 4,4-dimethylcholesta-8(9),24-dien-3beta-ol and NADP+, catalyzed by LBR in the nuclear envelope. LBR protein spans the inner nuclear envelope, has an aminoterminal region with properties of a laminin receptor and a carboxyterminal domain with sequence similarity to sterol delta14-reductases (Holmer et al. 1998). Studies of material from an individual with HEM/Greenberg skeletal dysplasia indicate that LBR catalyzes the sterol delta14-reductase step of cholesterol biosynthesis in vivo. DNA sequencing revealed homozygosity for a mutant LBR allele encoding a truncated protein in the affected individual, and cells from the individual accumulated cholesta-8,14-dien-3beta-ol in culture. Transfection of wild-type LBR into the cultured cells reversed the accumulation of cholesta-8,14-dien-3beta-ol (Waterham et al. 2003). This observation is surprising because a second gene, TM7SF2, encodes an efficient sterol delta14-reductase that is localized to the endoplasmic reticulum whose expression is up-regulated in response to sterol depletion (Bennati et al. 2006). The physiological roles of LBR and TM7SF2 in vivo remain to be determined. | |||
| R-HSA-194678 (Reactome) | Lanosterol 14-alpha demethylase (CYP51A1) catalyses oxidative C14-demethylation of lanosterol (LNSOL) to 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol (4,4DMCHOLtrienol). Although the reaction is annotated here as a single concerted event, studies with purified rat enzyme indicate that the methyl group is converted successively to an alcohol and an aldehyde before being released as formate (Stromstedt et al. 1996, Strushkevich et al. 2010). | |||
| R-HSA-194689 (Reactome) | 4-methylcholesta-8(9),24-dien-3-one and NADPH + H+ react to form 4-methylcholesta-8(9),24-dien-3beta-ol and NADP+. This reaction takes place in the endoplasmic reticulum, catalyzed by HSD17B7. Two isoforms of the enzyme due to alternative splicing have been identified but only the first has been tested for enzymatic activity (Marijanovic et al. 2003). The human enzyme has not been studied extensively; molecular details of the reaction are inferred from those worked out in studies of material from rat liver (Gaylor 2002). | |||
| R-HSA-194698 (Reactome) | 4,4-dimethylcholesta-8(9),14,24-trien-3beta-ol and NADPH + H+ react to form 4,4-dimethylcholesta-8(9),24-dien-3beta-ol and NADP+, catalyzed by TM7SF2 in the endoplasmic reticulum. TM7SF2 protein has sterol delta14-reductase activity in vitro, and expression of the gene is induced by sterol starvation in human cells, as expected for a gene involved in sterol biosynthesis (Bennati et al. 2006). However, molecular studies of material from an individual with HEM/Greenberg skeletal dysplasia indicate that LBR, a protein that spans the inner nuclear membrane and has both laminin receptor and sterol delta14-reductase activities, is required for normal sterol 14delta-reductase activity in human cells. It remains to be determined whether both LBR and TM7SF2 catalyze this reaction in vivo, and whether the role of TM7SF2 is essential (Waterham et al. 2003). | |||
| R-HSA-194718 (Reactome) | 4-carboxycholesta-8(9),24-dien-3beta-ol and NAD+ react to form zymosterone (cholesta-8(9),24-dien-3-one), CO2, and NADH + H+. This reaction occurs in the endoplasmic reticulum, catalyzed by NSDHL (Caldas and Herman 2003). Defects in this enzyme are associated with CHILD syndrome (Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects) (Konig et al. 2000), but cholesterol biosynthesis in cells and tissues from affceted individuals has not been characterized. Instead, the mechanism and stoichiometry of the reaction are inferred from biochemical studies of partially purified rat enzyme (Rahimtula and Gaylor 1972). | |||
| R-HSA-195664 (Reactome) | Cholesta-7,24-dien-3beta-ol, NADPH + H+, and O2 react to form cholesta-5,7,24-trien-3beta-ol, NADP+, and 2 H2O, catalyzed by SC5D. This reaction takes place in the endoplasmic reticulum. Its biochemical details are inferred from those of the reaction catalyzed by the purified rat protein (Kawata et al. 1985). The role of human SC5D in catalyzing this reaction in vivo is established from studies of patients in whom the enzyme is defective (Brunetti-Pierri et al. 2002; Krakowiak et al. 2003). | |||
| R-HSA-195690 (Reactome) | Isomerization of zymosterol to cholesta-7,24-dien-3beta-ol is catalyzed by EBP in the endoplasmic reticulum. The biochemical details of the reaction have been established through studies of purified rat EBP; the role of the human enzyme has been established through studies of patients deficient in it (Derry et al. 1999; Braverman et al. 1999). | |||
| R-HSA-196402 (Reactome) | Cholesta-5,7,24-trien-3beta-ol and NADPH + H+ react to form desmosterol and NADP+. This reaction is catalyzed by DHCR7, associated with the endoplasmic reticulum membrane. The biochemical details of the reaction are inferred from those of the reaction catalyzed by the well-studied rat enzyme (Bae et al. 1999). | |||
| R-HSA-196417 (Reactome) | Desmosterol is reduced by NADPH + H+ to form cholesterol and NADP+, catalyzed by DHCR24 associated with the endoplasmic reticulum membrane. | |||
| R-HSA-5250531 (Reactome) | Sterols such as cholesterol (CHOL) synthesised in the endoplasmic reticulum (ER) need to be efficiently transported to the plasma membrane, where 90% of the free sterol pool resides. Conversely, sterols taken up from outside the cell need to be transported back to the ER for esterification to sterol esters. The mechanisms that control this bi-directional movement of sterols are still poorly understood but a likely candidate is protein ARV1 (ARV1). Studies with mutant yeast Arv1 indicate altered intracellular sterol distribution and subsequent defects in sphingolipid metabolism. Human ARV1, a predicted sequence ortholog of yeast Arv1, complements the defects seen associated with deletion of yeast Arv1 (Tinkelenberg et al. 2000, Swain et al. 2002). | |||
| SC5D | mim-catalysis | R-HSA-195664 (Reactome) | ||
| SQLE:FAD | mim-catalysis | R-HSA-191299 (Reactome) | ||
| SQNE | Arrow | R-HSA-191402 (Reactome) | ||
| SQNE | R-HSA-191299 (Reactome) | |||
| SQOX | Arrow | R-HSA-191299 (Reactome) | ||
| SQOX | R-HSA-191366 (Reactome) | |||
| TM7SF2 | mim-catalysis | R-HSA-194698 (Reactome) | ||
| ZYMOL | Arrow | R-HSA-194632 (Reactome) | ||
| ZYMOL | R-HSA-195690 (Reactome) | |||
| ZYMONE | Arrow | R-HSA-194718 (Reactome) | ||
| ZYMONE | R-HSA-194632 (Reactome) | |||
| bHMG-CoA | Arrow | R-HSA-191323 (Reactome) | ||
| bHMG-CoA | R-HSA-191352 (Reactome) | |||
| dh4MZYMOL | Arrow | R-HSA-194642 (Reactome) | ||
| dh4MZYMOL | R-HSA-194689 (Reactome) |
