Cholesterol, Steroid and Isoprenoid Biosynthesis
Cholesterol Synthesis and the Cholesterol Biosynthesis Pathway
Biosynthesis and biotransformation of cholesterol
The reaction catalyzed by HMGR is the rate limiting step of cholesterolbiosynthesis, and this enzyme is subject to complex regulatory controls asdiscussed below.
The synthesis of mevalonate from HMG-CoA, which occurs during the first segment of the pathway, is regarded as the “committed step” in cholesterol biosynthesis (Fig. 3). For this reason, much of the regulation that controls this process targets the enzyme responsible for this conversion; HMGR (3). HMGR is controlled through a variety of mechanisms to ensure that proper levels of cholesterol are maintained throughout the body. This array of methods includes the ubiquitination and subsequent degradation of the enzyme complex in the endoplasmic reticulum, inactivation via phosphorylation, or prevention of the transcription and translation of the enzyme and its mRNA (4). The importance of this enzyme and the reaction it catalyzes to the entire process of cholesterol biosynthesis makes inhibition of HMGR a rational and effective target for drugs that seek to lower blood cholesterol. By blocking the committed step of cholesterol biosynthesis, statins reduce the amount of cholesterol synthesized in a similar manner as that employed endogenously.
isoprene may be a by-product of cholesterol biosynthesis ..
The isoprenoid intermediatesof cholesterol biosynthesis can be diverted to other synthesis reactions, suchas those for dolichol (used in the synthesis of , coenzyme Q (of the pathway) or the side chain of heme-a.
Figure 4. Schematic showing the endogenous human cholesterol biosynthesis pathway. The diagram is divided into the three main steps of the process: The synthesis of the isopentenyl pyrophosphate subunit from acetyl CoA is shown in red; squalene formation from six isoprene molecules is shown in black, while the cyclization of squalene into cholesterol is shown in blue. For simplification, only the most relevant intermediates are included. A dotted box has been drawn around the step in which HMG-CoA is converted into mevalonate, as this is the most pertinent reaction to the drug described in this paper. This step is shown in more detail in Figure 3 (adapted from reference 3).
Cholesterol Biosynthesis - UMaine Chemistry Department
The biosynthesis of cholesterol in the liver and intestinal cells is a process that creates the essential lipid from acetyl CoA subunits. Much interaction and regulation exists between this endogenous synthesis process and the absorption of dietary cholesterol in the small intestine. As less cholesterol is consumed, synthesis increases in order to meet the body’s demands for the nutrient, while an increase in consumption results in the downregulation of the endogenous process (2). Canonically, the synthesis pathway is divided into three distinct segments: the synthesis of activated isoprene subunits, the condensation of these isoprene molecules to form squalene, and squalene’s cyclization into cholesterol (3) The cholesterol synthesis pathway, as divided into the three main steps listed above, is shown below (Fig. 4).
Classical pathway from acetate to isoprene units. Condensation of three acetate moieties yields HMG‐CoA. Reduction of HMG‐CoA to mevalonate by HMG‐CoA reductase is the rate‐limiting step in cholesterol biosynthesis. Phosphorylation and decarboxylation of mevalonate yields IPP and DMAPP. Small, straight arrows indicate atoms where chemistry occurs in subsequent step; curved arrows show electron flow during decarboxylation step.
Isoprene is produced by many plants, ..
The isoprene unit has the formula CH2=C ..
having a partial terpenoid structure
Isoprene - Wikipedia
which also produces cholesterol.
Statins Inhibit Isoprene Synthesis - Cholesterol
Steroids, sterols, and many other natural products all derive from isoprenoid building blocks via two common biosynthetic pathways. The subsequent processing of the structural core yields specific products that possess diverse structures and biological activities.
The importance of different isoprene compounds ..
Note that the cytoplasmic malic enzymecatalyzed reaction generates NADPH which can be used for reductive biosyntheticreactions such as those of fatty acid and cholesterol synthesis.
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