Characterization, Modes of Synthesis, and Pleiotropic Effects of Hypocholesterolemic Compounds – A Review
TL;DR: Major natural sources as well as synthetic and biological routes of synthesis of these compounds are reviewed in a concise manner and various HMG-CoA analogues including statins have been reviewed specifically.
Abstract: Studies on the various cholesterol-lowering agents is one of the important areas in clinical research. Identifica- tion and characterization of potential molecules from various sources have been carried out in the past and their relation- ship with the enzymes which are involved in the cholesterol cascade is gaining interest. In this review, we have high- lighted various inhibitors involved in the cholesterol cascade as well as cholesterol-lowering agents, viz., tocotrienol, flavonoids, phytosterols, phytostanols, statins, DADS, and synthetic compounds. The mechanism of action and characteri- zation of these hypocholesterolemic compounds are discussed in this communication. Major natural sources as well as synthetic and biological routes of synthesis of these compounds are reviewed in a concise manner. Especially, various HMG-CoA analogues including statins have been reviewed specifically. In this respect, researchers have identified 2,3- oxidosqualene cyclase-lanosterol synthase (lanosterol syn- thase, oxidosqualene-lanosterol cyclase, lanosterol synthase, 2,3-oxidosqualene-lanosterol cyclase, human lanosterol syn- thase (EC 5.4.99.7)) having a molecular weight of 83 kDa, catalyzing the highly selective cyclization reaction from the substrate 2,3-oxidosqualene (squalene 2,3-epoxide, squalene 2,3-oxide, (S)-squalene-2,3-epoxide, 2,3-epoxisqualene, oxidosqualene) into lanosterol, as an appropriate step for the inhibition of cholesterol biosynthesis (3). Oxidosqualene cyclase inhibitors (OSCI) arrest the downstream of 2,3- oxidosqualene which helps to stimulate epoxysterols to
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TL;DR: In this article, the authors investigated the possible mechanisms for the use of phenolic extracts from grapefruit peels in the management/prevention of cardiovascular complications and found that the phenolic contents of the extracts were investigated using HPLC-DAD.
39 citations
TL;DR: The phenolic compounds and volatile compounds which have been linked with the biological activities of the peels have been characterized and the bioactive compounds of citrus peels and the mechanisms for the biological Activities are looked at.
Abstract: Citrus peels, which are an environmental menace in many developing countries have been in use in folk medicine for the management of some degenerative conditions, though there was limited information on the mechanism of such medicinal properties. These medicinal properties also promote the peels as functional foods; since they are generally regarded as safe and are consumed in some countries in forms of candies, wines, infusions and additives. Studies on the mechanisms for the antioxidant, anti-diabetic, cardioprotective, neuroprotective and anticancer activities of the peels have established the intereaction with some key enzymes relevant to the management of such diseases. The phenolic compounds and volatile compounds which have been linked with the biological activities of the peels have been characterized. This review looks at the bioactive compounds of citrus peels and the mechanisms for the biological activities of the peels.
23 citations
Cites background from "Characterization, Modes of Synthesi..."
...The inhibition of HMG-CoA reductase by phenolic compounds is both competitive with HMG-CoA and non-competitive with NADPH (Sung et al. 2004a, b; Seenivasan et al. 2011)....
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TL;DR: In this article, the authors characterized the soluble free and bound phenolic compounds from shaddock peels and investigated their effect on 3-hydroxy-methyl-3-glutaryl coenzyme A reductase (HMG-CoA) and glutathione-linked enzymes in colon (Caco-2) cells.
10 citations
TL;DR: The estimation of Lovastatin produced by Monascus purpureus and pure lovastatin was attempted by UV-visible spectrophotometer as well as HPLC, and HPLC analysis consistently gave reliable results for the estimation of lovastsatin under all the experimental conditions studied.
Abstract: Development of a novel method for the quantification of lovastatin is an interesting problem in the analytical field. In the literature, many reports use spectrophotometric method for the quantification of lovastatin. However, the analysis of fermentation broth containing lovastatin appears to be inaccurate using spectrophotometric method. Hence, the estimation of lovastatin produced by Monascus purpureus and pure lovastatin was attempted by UV-visible spectrophotometer as well as HPLC. It was observed that the analogues and/or intermediates of lovastatin synthesized in the fermentation broth and the products of fermentation caused superimposition effect on the absorption spectrum. Phosphate is a medium constituent for the production of lovastatin by the organism which contributed significantly to the superimposition of absorption spectrum. On the other hand, HPLC analysis consistently gave reliable results for the estimation of lovastatin under all the experimental conditions studied.
10 citations
TL;DR: Predicted specific substrate utilization and product excretion rates have been correlated well with the experimental observations, which validate the proposed metabolic pathway developed from metabolic footprinting data.
8 citations
References
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28 Nov 2003
TL;DR: Current literature suggests that phytosterols are safe when added to the diet, and measured absorption and plasma levels are very small, but increasing the aggregate amount ofphytosterol consumed in a variety of foods may be an important way of reducing population cholesterol levels and preventing coronary heart disease.
Abstract: ▪ Abstract Phytosterols are cholesterol-like molecules found in all plant foods, with the highest concentrations occurring in vegetable oils. They are absorbed only in trace amounts but inhibit the absorption of intestinal cholesterol including recirculating endogenous biliary cholesterol, a key step in cholesterol elimination. Natural dietary intake varies from about 167–437 mg/day. Attempts to measure biological effects in feeding studies have been impeded by limited solubility in both water and fat. Esterification of phytosterols with long-chain fatty acids increases fat solubility by 10-fold and allows delivery of several grams daily in fatty foods such as margarine. A dose of 2 g/day as the ester reduces low density lipoprotein cholesterol by 10%, and little difference is observed between Δ5-sterols and 5α-reduced sterols (stanols). Phytosterols can also be dispersed in water after emulsification with lecithin and reduce cholesterol absorption when added to nonfat foods. In contrast to these suppleme...
604 citations
"Characterization, Modes of Synthesi..." refers background in this paper
...Also, these compounds were efficacious in the treatment of cardiovascular disease (CVD), Alzheimer’s disease, renal disease, cancer, bone fracture, allergic encephalomyelitis, multiple sclerosis, immune-mediated neurological disorders, and also diabetes [15, 27, 32, 35, 39, 62, 66-69]....
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...Food items exhibit oxidative stability when phytostanol esters are present as a constituent [62, 67, 68]....
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TL;DR: The use of statins can lead to a reduction in coronary events related to hypercholesterolemia, but the relationship between benefit and risk, and any possible interaction with other drugs, must be taken into account.
Abstract: Hypercholesterolemia is considered an important risk factor in coronary artery disease. Thus the possibility of controlling de novo synthesis of endogenous cholesterol, which is nearly two-thirds of total body cholesterol, represents an effective way of lowering plasma cholesterol levels. Statins, fungal secondary metabolites, selectively inhibit hydroxymethyl glutaryl-coenzyme A (HMG-CoA) reductase, the first enzyme in cholesterol biosynthesis. The mechanism involved in controlling plasma cholesterol levels is the reversible inhibition of HMG-CoA reductase by statins, related to the structural similarity of the acid form of the statins to HMG-CoA, the natural substrate of the enzymatic reaction. Currently there are five statins in clinical use. Lovastatin and pravastatin (mevastatin derived) are natural statins of fungal origin, while symvastatin is a semi-synthetic lovastatin derivative. Atorvastatin and fluvastatin are fully synthetic statins, derived from mevalonate and pyridine, respectively. In addition to the principal natural statins, several related compounds, monacolins and dihydromonacolins, isolated fungal intermediate metabolites, have also been characterized. All natural statins possess a common polyketide portion, a hydroxy-hexahydro naphthalene ring system, to which different side chains are linked. The biosynthetic pathway involved in statin production, starting from acetate units linked to each other in head-to-tail fashion to form polyketide chains, has been elucidated by both early biogenetic investigations and recent advances in gene studies. Natural statins can be obtained from different genera and species of filamentous fungi. Lovastatin is mainly produced by Aspergillus terreus strains, and mevastatin by Penicillium citrinum. Pravastatin can be obtained by the biotransformation of mevastatin by Streptomyces carbophilus and simvastatin by a semi-synthetic process, involving the chemical modification of the lovastatin side chain. The hypocholesterolemic effect of statins lies in the reduction of the very low-density lipoproteins (VLDL) and LDL involved in the translocation of cholesterol, and in the increase in the high-density lipoproteins (HDL), with a subsequent reduction of the LDL- to HDL-cholesterol ratio, the best predictor of atherogenic risk. The use of statins can lead to a reduction in coronary events related to hypercholesterolemia, but the relationship between benefit and risk, and any possible interaction with other drugs, must be taken into account.
388 citations
"Characterization, Modes of Synthesi..." refers background in this paper
...rosuvastatin, atorvastatin, pitavastatin, and cerivastatin) which are prepared by a series of chemical reactions and have low inhibition constant (Ki) values than the statins derived by the fermentation route [15, 45, 46, 65]....
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...synthetic statins, R2 is either methyl or hydroxyl group [45]....
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TL;DR: Insight is provided into the genetic basis for tocotrienol biosynthesis in plants and the ability to enhance the antioxidant content of crops by introduction of an enzyme that redirects metabolic flux is demonstrated.
Abstract: Tocotrienols are the primary form of vitamin E in seeds of most monocot plants, including cereals such as rice and wheat. As potent antioxidants, tocotrienols contribute to the nutritive value of cereal grains in human and livestock diets. cDNAs encoding homogentisic acid geranylgeranyl transferase (HGGT), which catalyzes the committed step of tocotrienol biosynthesis, were isolated from barley, wheat and rice seeds. Transgenic expression of the barley HGGT in Arabidopsis thaliana leaves resulted in accumulation of tocotrienols, which were absent from leaves of nontransformed plants, and a 10- to 15-fold increase in total vitamin E antioxidants (tocotrienols plus tocopherols). Overexpression of the barley HGGT in corn seeds resulted in an increase in tocotrienol and tocopherol content of as much as six-fold. These results provide insight into the genetic basis for tocotrienol biosynthesis in plants and demonstrate the ability to enhance the antioxidant content of crops by introduction of an enzyme that redirects metabolic flux.
376 citations
Additional excerpts
...Subsequent methylation and cyclization of the 2-methyl-6geranylgeranyl benzoquinol resulted in the synthesis of tocotrienol similar to tocopherol synthesis [53]....
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TL;DR: The physiological activities of tocotrienol suggest it to be superior than alpha-tocopherol in many situations, indicating that tocotrianol may serve as an effective agent in the prevention and/or treatment of cardiovascular disease and cancer.
356 citations
"Characterization, Modes of Synthesi..." refers background in this paper
...Also, these compounds were efficacious in the treatment of cardiovascular disease (CVD), Alzheimer’s disease, renal disease, cancer, bone fracture, allergic encephalomyelitis, multiple sclerosis, immune-mediated neurological disorders, and also diabetes [15, 27, 32, 35, 39, 62, 66-69]....
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...The role of tocotrienols in the prevention of CVD and cancer may have significant clinical implications [27, 66]....
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...3 fold per 10 g of -tocotrienol Both in vitro and in vivo [16, 25-27, 28]...
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..., hypocholesterolemic and antioxidant activity [16, 27, 51]....
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TL;DR: The target protein with an inhibitor that showed cholesterol lowering in vivo opens the way for the structure-based design of new OSC inhibitors, and the complex with the reaction product lanosterol gives a clear picture of the way in which the enzyme achieves product specificity in this highly exothermic cyclization reaction.
Abstract: In higher organisms the formation of the steroid scaffold is catalysed exclusively by the membrane-bound oxidosqualene cyclase (OSC; lanosterol synthase). In a highly selective cyclization reaction OSC forms lanosterol with seven chiral centres starting from the linear substrate 2,3-oxidosqualene. Valuable data on the mechanism of the complex cyclization cascade have been collected during the past 50 years using suicide inhibitors, mutagenesis studies and homology modelling. Nevertheless it is still not fully understood how the enzyme catalyses the reaction. Because of the decisive role of OSC in cholesterol biosynthesis it represents a target for the discovery of novel anticholesteraemic drugs that could complement the widely used statins. Here we present two crystal structures of the human membrane protein OSC: the target protein with an inhibitor that showed cholesterol lowering in vivo opens the way for the structure-based design of new OSC inhibitors. The complex with the reaction product lanosterol gives a clear picture of the way in which the enzyme achieves product specificity in this highly exothermic cyclization reaction.
305 citations
"Characterization, Modes of Synthesi..." refers background in this paper
...7)) having a molecular weight of 83 kDa, catalyzing the highly selective cyclization reaction from the substrate 2,3-oxidosqualene (squalene 2,3-epoxide, squalene 2,3-oxide, (S)-squalene-2,3-epoxide, 2,3-epoxisqualene, oxidosqualene) into lanosterol, as an appropriate step for the inhibition of cholesterol biosynthesis [3]....
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...Some examples for this group of drugs are Ro 48-8071, 2,3:22,23-dioxido squalene and 24,25-epoxycholesterol, 4-piperidinopyridine, 4-piperdinopyrimides, quinuclidine, and umbelliferone aminoalkyl derivatives [3-7]....
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