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.