Is a Key Intermediate in Cholesterol Biosynthesis

The sequence of cholesterol biosynthesis begins with a condensation in the cytosol of two molecules of acetyl-CoA in a reaction catalyzed by thiolase (fig. 20.3). The next step requires the enzyme /3-hydroxy-/3-methylglutaryl-CoA (HMG-CoA) synthase. This enzyme catalyzes the condensation of a third acetyl-CoA with /3-ketobutyryl-CoA to yield HMG-CoA. HMG-CoA is then reduced to mevalonate by HMG-CoA reductase. The activity of this reductase is primarily responsible for control of the rate of cholesterol biosynthesis. 

HMG-CoA is an important intermediate for the biosynthesis of both cholesterol and ketone bodies (discussed 

Formation of mevalonate. The first two enzymes, thiolase and synthase, are found in both cytosol and mitochondria. The lyase that catalyzes ketone body formation is found only in the mitochondria. The reductase that catalyzes mevalonate formation is found in the endoplasmic reticulum. 3-Ketobutyryl-CoA is also known as acetoacetyl-CoA. 

The Rate of Mevalonate Synthesis Determines the Rate of Cholesterol Biosynthesis 

The thiolase and HMG-CoA synthase exhibit some regulatory properties in rat liver (cholesterol feeding causes a decrease in these enzyme activities in the cytosol but not in the mitochondria). However, the primary regulation of cholesterol biosynthesis appears to be centered on the HMG-CoA reductase reaction. HMG-CoA reductase is found on the endoplasmic reticulum, has a molecular weight of 97,092, and consists of 887 amino acids in a single polypeptide chain. The sequence of the enzyme was deduced by Michael Brown and Joseph Goldstein from the sequence of a piece of complimentary DNA (cDNA) derived from mRNA that codes for the reductase. The enzyme 

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Cytosolic HMG CoA is a key intermediate in cholesterol biosynthesis. In the endoplasmic reticulum, it is reduced to mevalonic acid by the regulatory enzyme HMG CoA reductase. 

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