Cholesterol is synthesized from acetyl-CoA in most tissues. The rate-limiting step is the conversion of HMG-CoA to mevalonic acid by HMG-CoA reductase. Mevalonic acid is then modified to form isoprenoid units which condense to form squalene. Squalene cyclizes to form lanosterol, which is then modified to form cholesterol through removal of methyl groups and movement of double bonds. Cholesterol synthesis is regulated by feedback inhibition of HMG-CoA reductase.
Cholesterol is synthesized from acetyl-CoA in most tissues. The rate-limiting step is the conversion of HMG-CoA to mevalonic acid by HMG-CoA reductase. Mevalonic acid is then modified to form isoprenoid units which condense to form squalene. Squalene cyclizes to form lanosterol, which is then modified to form cholesterol through removal of methyl groups and movement of double bonds. Cholesterol synthesis is regulated by feedback inhibition of HMG-CoA reductase.
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Cholesterol is synthesized from acetyl-CoA in most tissues. The rate-limiting step is the conversion of HMG-CoA to mevalonic acid by HMG-CoA reductase. Mevalonic acid is then modified to form isoprenoid units which condense to form squalene. Squalene cyclizes to form lanosterol, which is then modified to form cholesterol through removal of methyl groups and movement of double bonds. Cholesterol synthesis is regulated by feedback inhibition of HMG-CoA reductase.
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m Cholesterol is present in tissues and in plasma either as free
cholesterol or as a storage form, combined with a long-chain
fatty acid as cholesteryl ester.
m Cholesterol is an amphipathic lipid and as such is an essential
structural component of membranes and of the outer layer of plasma lipoproteins.
m It is synthesized in many tissues from acetyl-CoA and
m Is the precursor of all other steroids in the body such as
. m As a typical product of animal metabolism, cholesterol occurs in foods of animal origin such as egg yolk, meat, liver, and brain.
m Plasma low-density lipoprotein (LDL) is the
vehicle of uptake of cholesterol and cholesteryl ester into many tissues.
m Free cholesterol is removed from tissues by
plasma high-density lipoprotein (HDL) and transported to the liver, where it is eliminated from the body either in unchanged form or after conversion to bile acids in the process known as reverse cholesterol transport. m Cholesterol is a major constituent of allstones.
m Pathologically is a main causing factor in the
genesis of atherosclerosis of vital arteries, causing cerebrovascular, coronary, and peripheral vascular disease.
m 2therosclerosis is due to deposition of
cholesterol in the lumen of arteries m A little more than half the cholesterol of the body arises by synthesis (about 700 mg/d), and the rest is provided by the average diet.
m The liver and intestine account for approximately 10%
each of total synthesis in humans.
m Virtually all tissues containing nucleated cells are
capable of cholesterol synthesis, which occurs in the endoplasmic reticulum and the cytosol.
m 2cetyl-Co2 s the ource of 2ll Carbon 2toms in
Cholesterol ¦ynthesis of cholesterol occurs in the cytoplasm of most tissues, but the liver, intestine, adrenal cortex, and steroidogenic reproductive tissues are the most active. ¦ynthesis of cholesterol involve followin steps:- 1. Acetate, via acetyl CoA, is the initial precursor for cholesterol synthesis, leading in two steps to Co2. 2. Conversion of Co2 to mevalonic acid is catalyzed by the key regulatory enzyme, Co2 reductase. m a. This is the rate-limitin step of cholesterol synthesis. m b. HMG CoA reductase is heavily reulated by several mechanisms. m M 0xpression of the HMG CoA reductase gene is controlled by a steroldependent transcription factor, which increases enzyme synthesis in response to low cholesterol levels. m Mnsulin up-regulates the gene and lucaon down-regulates it m M0nzyme activity is controlled by reversible phosphorylation /dephosphorylation in response to 2, ie, cholesterol synthesis is suppressed when energy levels are low. . evalonic acid is then modified by phosphorylation and decarboxylation, and several molecules of it are condensed to form cholesterol in a complex series of eight reactions. m The biosynthesis of cholesterol may be divided into five steps:
(1) ¦ynthesis of mevalonate occurs from acetyl- CoA
(Figure 1).
(2) Isoprenoid units are formed from mevalonate by loss of
CO2 (Figure 2).
(3) ¦ix isoprenoid units condense to form squalene.
(4) ¦qualene cyclizes to give rise to the parent steroid,
lanosterol.
(5) Cholesterol is formed from lanosterol (Figure 3).
tep 1²Biosynthesis of evalonate: m HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) is formed by the reactions used in mitochondria to synthesize ketone bodies .
m Initially, two molecules of acetyl-CoA condense to form acetoacetyl-
CoA catalyzed by cytosolic thiolase.
m Acetoacetyl-CoA condenses with a further molecule of acetyl-CoA
catalyzed by -Co2 synthase to form HMG-CoA, which is reduced to mevalonate by NADPH catalyzed by -Co2 reductase.
m This is the principal regulatory or rate limiting step in the pathway of
cholesterol synthesis and is the site of action of the most effective class of cholesterol-lowering drugs, the HMG-CoA reductase inhibitors (statins) (Figure below). m tep 2²Formation of soprenoid nits:
m Mevalonate is phosphorylated sequentially by ATP
by three kinases, and after decarboxylation the active isoprenoid unit, isopentenyl diphosphate, is formed. Figure (2) m tep ²ynthesis of ix soprenoid nits Form ualene:
m Isopentenyl diphosphate is isomerized by a shift of the double bond
to form dimethylallyl diphosphate, then condensed with another molecule of isopentenyl diphosphate to form the ten-carbon intermediate eranyl diphosphate (Figure 2).
m A further condensation with isopentenyl diphosphate forms farnesyl
diphosphate.
m Two molecules of farnesyl diphosphate condense at the
diphosphate end to form s ualene.
m Initially, inorganic pyrophosphate is eliminated, forming presqualene
diphosphate, which is then reduced by NADPH with elimination of a further inorganic pyrophosphate molecule. m tep ²Formation of anosterol from s ualene m ¦qualene can fold into a structure that closely resembles the steroid nucleus (Figure 3). m Before ring closure occurs, squalene is converted to squalene 2,3-epoxide by s ualene epoxidas in the endoplasmic reticulum. m The methyl group on C14 is transferred to C13 and that on C8 to C14 as cyclization occurs, catalyzed by oxidos ualene is a lanosterol cyclase. m tep ²Formation of Cholesterol:
m The formation of cholesterol from lanosterol takes place
in the membranes of the endoplasmic reticulum and involves changes in the steroid nucleus and side chain (Figure below). m The methyl groups on C14 and C4 are removed to form 14-desmethyl lanosterol and then zymosterol.
m The double bond at C8±C9 is subsequently moved to
C5±C6 in two steps, forming desmosterol.
m Finally, the double bond of the side chain is reduced,
producing cholesterol. m The above figure explain - Biosynthesis of cholesterol. The numbered positions are those of the steroid nucleus and the open and solid circles indicate the fate of each of the carbons in the acetyl moiety of acetyl-CoA. m Asterisks: Refer to labeling of squalene in above Figure