Cholesterol
From LipidomicsWiki
Contents |
Basics
Cholesterol is an important component of the plasma membrane of eukaryotic cells. It modulates the fluidity of the membrane and is, together with sphingolipids, a main component of lipid rafts which play an important role in the regulation of signal transduction.
Cholesterol is the basis for the synthesis of Bile acids/-conjugates, steroid hormones and vitamin D.
Structures
Natural sources
Cholesterol and Cholesterol esters
Nomenclature
Biology / biochemistry
Biochemical synthesis
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Metabolism
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Enzymes/gene lists
Associated biological processes
Acetoacetyl-CoA thiolase (AA-CoA thiolase) catalyzes the conversion of acetyl-CoA to acetoacetyl-CoA in the first reaction of the cholesterol biosynthetic pathway. AA-CoA thiolase is encoded by two genes which encode a mitochondrially localized enzyme (mt AA-CoA thiolase) (Fukao et al. 1990) and a cytosolic enzyme (cyt AA-CoA thiolase) (Song et al. 1994). However, purified peroxisomes can also synthesize acetoacetyl-CoA from acetyl-CoA (Thompson et al. 1990). Analysis of the protein sequences of both AA-CoA thiolases revealed a mitochondrial targeting sequence at the carboxy terminus of the mt AACoA thiolase.
HMG-CoA synthase catalyses the second reaction in the cholesterol biosynthetic pathway, converting acetoacetyl-CoA to HMG-CoA. Similar to AA-CoA thiolase, two genes for HMGCoA synthase have been identified. One gene encodes a mitochondrial enzyme while the other encodes an enzyme originally believed to be localized to the cytosol (Ayte et al. 1990). However, subcellular fractionation studies demonstrated that HMG-CoA synthase activity was present in rat liver peroxisomes (Ayte et al. 1988). Several biochemical and immunological data indicate that a significant amount of HMG-CoA synthase is found in the peroxisomes.
HMG-CoA reductase, the rate limiting enzyme of the cholesterol biosynthetic pathway, catalyses the conversion of HMG-CoA into mevalonate. A number of studies including enzyme assays and western blotting on subcellular fractions, immunofluorescence and immunoelectron microscopy indicate that HMG-CoA reductase is located in both the endoplasmic reticulum (ER) and in peroxisomes (Engfelt et al. 1997, Kovacs et al. 2001). Furthermore, peroxisomal reductase is regulated in an independent manner from the ER reductase as demonstrated by (1) the peroxisomal HMG-CoA reductase is more resistant to inhibition by statins compared to the ER HMG-CoA reductase, (2) the rate of peroxisomal HMG-CoA reductase degradation is unaffected by the presence of mevalonate and (3) the peroxisomal reductase is not phosphorylated (Aboushadi et al. 2000). These data indicate that ER and peroxisomal HMG-CoA reductase may have separate functions in isoprenoid biosynthesis.
Mevalonate kinase (MvK) phosphorylates mevalonate in the fourth reaction of the cholesterol biosynthetic pathway. The peroxisomal localization of MvK has been conclusively demonstrated (Biardi et al. 1994).
Three enzymes catalyze the reactions required to convert mevalonate into isopentenyl diphosphate (IPP). Originally, these enzymes, phosphomevalonate kinase (PMvK), mevalonate diphosphate decarboxylase (MPD) and isopentenyl diphosphate (IPP) isomerase, were believed to be cytosolic; however, recent studies showed that they are localized to peroxisomes.
Phosphomevalonate kinase (PMvK) catalyzes the conversion of mevalonate 5-phosphate into mevalonate 5-diphosphate as the fifth reaction of the cholesterol biosynthetic pathway and is also localized to the peroxisomes.
Mevalonate diphosphate decarboxylase (MPD) catalyzes the sixth reaction of the cholesterol biosynthetic pathway in which the six carbon mevalonate diphosphate is dehydrated and decarboxylated to form isopentenyl diphosphate. Immunofluorescence studies indicate that MPD is a peroxisomal protein which requires a functional PTS-2 receptor for import into the organelle (Olivier et al. 2000). Isopentenyl diphosphate isomerase (IPP isomerase) reversibly isomerizes the double bond of IPP, contains both a putative carboxy terminal PTS-1 and an amino terminal PTS-2, which are responsible for the targeting to peroxisomes (Paton et al. 1997).
Farnesyl diphosphate synthase (FPP synthase) catalyzes two sequential 1–4 condensation reactions of isopentenyl diphosphate with the allylic diphosphates dimethylallyl diphosphate and geranyl diphosphate (Rilling et al. 1985). The product FPP is utilized in the synthesis of cholesterol, farnesylated and geranylgeranylated proteins, dolichols, coenzyme Q, and the isoprenoid moiety of heme a (Goldstein et al. 1990). FPP synthase has been identified as being predominantly peroxisomal (Krisans et al. 1994). The conversion of FPP to lanosterol is believed to occur in the ER. Squalene synthase, catalysing the first committed step of cholesterol biosynthesis, has been shown in two independent studies to be exclusively an ER protein. The subsequent conversion of lanosterol to cholesterol is proposed to take place both in peroxisomes and the ER. This hypothesis is based on several individual observations including: (1) subcellular fractionation studies revealed that the enzymes required for this conversion, dihydrolanosterol oxidase, D14-sterol reductase, c-4-sterol demethylase and D8- D7-sterol isomerase are localized in peroxisomes (Appelkvist et al. 1990) (2) peroxisomes have also been shown to accumulate biochemical intermediates between the conversion of lanosterol to cholesterol (Hashimoto et al. 1994) and (3) cholesterol is synthesized from dihydrolanosterol in isolated peroxisomes at levels equivalent to synthesis from isolated microsomes (Krisans et al. 1996). While these results are intriguing and the data suggest peroxisomal localization, further studies are necessary to delineate the subcellular localization of these proteins.
