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The HMG CoA reductase regulatory system involves a complex, multivalent feedback mechanism that is mediated by sterol and nonsterol end-products of mevalonate metabolism (Figure 1). These
Multivalent Control of HMG-CoA Reuductase
end-products decrease HMG CoA reductase activity by inhibiting transcription of the HMG CoA reductase gene, blocking translation of the HMG CoA reductase mRNA, and accelerating degradation of the HMG CoA reductase protein. The transcriptional effects are mediated by sterol regulatory element-binding proteins (SREBPs); membrane bound transcription factors that modulate transcription of genes encoding cholesterol biosynthetic enzymes and the low density lipoprotein receptor. The translational effects are evoked by nonsterol mevalonate-derived products through an entirely unknown mechanism. Both sterol and nonsterol end-products of mevalonate metabolism contribute to accelerated degradation of reductase and the process is mediated by the 26S proteasome.

HMG CoA reductase localizes to membranes of the endoplasmic reticulum (ER) and consists of two distinct domains (Figure2). The amino-terminal domain of 339 amino acids includes eight membrane-spanning regions that are separated by short loops; it anchors the protein to ER membranes. The carboxy-terminal domain of HMG CoA reductase, which consists of 548 amino acids, protrudes into the cytosol and exhibits all of the catalytic activity of the enzyme. The amino-terminal domain is crucial for accelerated degradation of the enzyme, which is believed to occur in ER membranes. Accelerated degradation of HMG CoA reductase is blocked by proteasome inhibitors, an action that leads to the accumulation of ubiquitinated forms of the enzyme.

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