MICROBIAL BIOTECHNOLOGY: SCOPE, TECHNIQUES CONTD..
Over 93% of the cholesterol in the human body is located in cells, where it
performs indispensable structural and metabolic roles. The remaining 7%
circulates in the plasma,where it contributes to atherosclerosis (formation of plaques on the walls of the arteries supplying the heart, the brain, and other vital organs). For delivery to tissues, plasma cholesterol is packaged in lipoprotein particles;two thirds is associated with low-density lipoprotein(LDL) and the balance with the high-density lipoprotein.
The disorder familial hypercholesterolemia occurs in one in 500 of the
population and results in elevated plasma levels of cholesterol-bearing LDL.
Male heterozygotes with dominant familial hypercholesterolemia have an
85% chance of occurrence of heart attacks (myocardial infarction) before
the age of 60. (Homozygotes of either sex die of heart disease at an early
age). A much larger number of people, who do not have familial hypercholesterolemia, have plasma levels of LDL at the upper limit of the normal
range and are also at high risk for atherosclerosis. The goal of therapy in
these subjects is to reduce the level of LDL without impairing cholesterol
delivery to cells. This is achieved by partial inhibition of cholesterol biosynthesis.
Cholesterol is a product of the isoprenoid pathway in mammals. In addition to cholesterol and other steroids, this pathway produces several key
metabolic intermediates essential to cells – dolichol, ubiquinone, the farnesyl and geranylgeranyl moieties of prenylated proteins, and the isopentenyl
side chain of isopentenyl adenine. The pathways for the synthesis of these
compounds diverge from the synthesis of cholesterol either at or before the
farnesyl diphosphate branch point. The first committed step
in cholesterol biosynthesis is the squalene synthase–catalyzed conversion
of two moles of farnesyl pyrophosphate to one mole of squalene. Therefore,
squalene synthase is an attractive target for selective inhibition of cholesterol
Screening of fungal cultures led to the discovery of three structurally
related and very potent inhibitors of squalene synthase. Zaragozic acid A
(squalestatin S1) was obtained from an unidentified fungus found
in a water sample taken from the Jalon River in Zaragoza, Spain, hence the
name. Soon after, zaragozic acids B and C were obtained from fungi isolated
elsewhere: Sporormiella intermedia,a coprophilous fungus isolated from cotton tail rabbit dung in Tucson, Arizona, and Leptodontium elatius, isolated
from wood in a forest in North Carolina, respectively.
Squalene synthase catalyzes a two-step reaction. Farnesyl pyrophosphate
is converted to presqualene diphosphate and then to squalene.The zaragozic
acids are potent inhibitors of squalene synthase competitive with farnesyl pyrophosphate. Their inhibition constants (Ki) are extraordinarily low, about 10^-11 M and they are at least 103
times more potent inhibitors of
the catalytic activity of squalene synthase than any previously described
compound. Structural comparisons suggest that the zaragozic acids bind to
squalene synthase in a manner similar to that of presqualene pyrophosphate.
Experiments in laboratory animals indicate that zaragozic acids
are promising therapeutic agents for hypercholesterolemia. They have also
proved valuable as specific inhibitors of squalene synthase in studies of the
regulation of hydroxymethylglutaryl–coenzyme A (CoA) reductase and of
other aspects of lipoprotein metabolism.
A recent study reveals that zaragozic acids have unexpected promise
in other therapeutic applications. Squalestatin was shown to cure prion infected neurons and to protect against prion neurotoxicity. Prion diseases
(or transmissible spongiform encephalopathies) are fatal neurodegenerative disorders that include kuru and Creutzfeldt–Jakob disease in humans.
In prion diseases, the normal cellular prion, PrPc is converted into a β-sheet–rich conformer, PrP
Sc, whose aggregation is believed to lead to neurodegeneration. Low concentrations of squalestatin reduced the cholesterol content of the neurons and prevented the formation of PrP Sc.These observations suggest that squalestatin is a potential drug for the treatment of prion diseases.
Cited By Kamal Singh Khadka
Msc Microbiology, TU.
Assistant Professor In PU, Pokhara Bigyan Thata Prabidhi Campus(PBTPC), PNC, NA, LA.