Mechanism for oxygen sensing in the cholesterol synthetic pathway. The link between synthesis of cholesterol and oxygen sensing in animal cells is provided by hypoxia-induced accumulation of lanosterol and 24,25-dihydrolanosterol and -1alpha-mediated induction of Insig-1 and Insig-2. Convergence of these responses leads to rapid degradation of CoA reductase, thereby limiting synthesis of cholesterol.
Multiple mechanisms for feedback control of cholesterol synthesis converge on the rate-limiting enzyme in the pathway, 3-hydroxy-3-methylglutaryl coenzyme A reductase. This complex feedback regulatory system is mediated by sterol and nonsterol metabolites of mevalonate, the immediate product of reductase activity. One mechanism for feedback control of reductase involves rapid degradation of the enzyme from membranes of the endoplasmic reticulum (ER). This degradation results from the accumulation of sterols in ER membranes, which triggers binding of reductase to ER membrane proteins called Insig-1 and Insig-2. Insig binding leads to the recruitment of a membrane-associated ubiquitin ligase called gp78 that initiates ubiquitination of reductase. Ubiquitinated reductase then becomes extracted from ER membranes and is delivered to cytosolic 26S proteasomes through an unknown mechanism that is mediated by the gp78-associated ase Valosin-containing protein/p97 and appears to be augmented by nonsterol isoprenoids. Here, we will highlight several advances that have led to the current view of mechanisms for sterol-accelerated, ER-associated degradation of reductase. In addition, we will discuss potential mechanisms for other aspects of the pathway such as selection of reductase for gp78-mediated ubiquitination, extraction of the ubiquitinated enzyme from ER membranes, and the contribution of Insig-mediated degradation to overall regulation of reductase in whole animals.
The mevalonate pathway or HMG-CoAreductase pathway or mevalonate-dependent (MAD)route or isoprenoid pathway, is animportant present in allhigher eukaryotes and many bacteria. It is important for theproduction of (DMAPP) and (IPP), which serve as the basis for the biosynthesis of moleculesused in processes as diverse as synthesis, protein , maintenance, , , and . It is also apart of .