CLINICAL CASES
317
A nsw ers
[34.1]
E. The major regulatory enzyme of cholesterol metabolism, HMG-CoA
reductase, is regulated by three distinct mechanisms. The first is phos-
phorylation by a cAMP dependent protein kinase. Phosphorylation of
HMG-CoA reductase inactivates the enzyme. The other two mecha-
nisms involve the levels of cholesterol. The degradation of the
enzyme is controlled by cholesterol levels. The half-life of HMG-
CoA reductase is regulated by cholesterol levels with high concen-
trations of cholesterol leading to a shorter half-life. The final
regulatory mechanism involves control of the expression of the
HMG-CoA reductase gene. High levels of cholesterol lead to a
decrease in the mRNA levels coding for HMG-CoA reductase.
[34.2]
B. The first step in the biosynthesis of cholesterol is the condensation
of two molecules of acetyl-CoA to form acetoacetyl-CoA. The addi-
tion of a third acetyl-CoA molecule gives rise to HMG-CoA. HMG-
CoA reductase is converted to mevalonate. HMG-CoA reductase is
the target of the statin drugs and the substrate used by this enzyme is
HMG-CoA.
[34.3]
A. Niacin is the vitamin that can be used, in high doses, to treat
hypercholesterolemia. Niacin acts to decrease VLDL and LDL
plasma levels. Its mechanism of action is not clearly understood but
probably involves inhibition of VLDL secretion, which in turn
decreases the production of LDL. Niacin inhibits the release of free
fatty acids from adipose tissue, which leads to a decrease of free fatty
acids entering the liver and decreased VLDL synthesis in the liver.
This decreases the availability of VLDL for conversion to LDL (con-
taining cholesterol esters). Niacin also increases HDL (the “good
cholesterol”) by an unknown mechanism.
B IO C H E M IS T R Y PE A R L S
HMG-CoA reductase, which catalyzes the synthesis of mevalonate
from HMG-CoA in an irreversible, rate-limiting reaction.
The enzyme 21-hydroxylase is required for the synthesis of miner-
alocorticoids and glucocorticoids.
The statins act as competitive inhibitors of the enzyme HMG-CoA
reductase.
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