MCAT Biochemistry
Cholesterol is an essential biomolecule that helps regulate membrane fluidity and serves as a precursor to steroid hormones, bile acids, and vitamin D. It is carried in the blood by lipid transporters called lipoproteins, specifically low-density lipoproteins (LDL) and high-density lipoproteins (HDL). While some cholesterol is obtained through diet, most of it is synthesized de novo in the liver and intestines. Cholesterol biosynthesis requires acetyl-CoA and energy input in the form of ATP. Since the mitochondrial membrane is relatively impermeable to acetyl-CoA, it is converted to citrate and transported across via the citrate shuttle.
In the cytoplasm, citrate is converted back to acetyl-CoA, where the cholesterol synthesis pathway begins. Acetyl-CoA is converted to HMG-CoA, and HMG-CoA is converted to mevalonic acid by HMG-CoA reductase. Mevalonic acid is further converted into cholesterol through a series of enzymatic reactions. HMG-CoA reductase is the rate-determining enzyme and is active in the membrane of the smooth endoplasmic reticulum (ER). During cholesterol biosynthesis, NADPH is utilized multiple times to provide reducing equivalents. A buildup of cholesterol provides negative feedback on HMG-CoA reductase, inhibiting the pathway, while insulin activates HMG-CoA reductase, promoting cholesterol biosynthesis.
Lesson Outline
<ul> <li>Introduction to cholesterol <ul> <li>Important biomolecule</li> <li>Regulates membrane fluidity, precursor to steroid hormones and vitamin D</li> <li>Excess cholesterol can cause arterial blockages</li> </ul> </li> <li>Cholesterol transport <ul> <li>Carried in blood by lipoproteins: LDL (low density) and HDL (high density)</li> </ul> </li> <li>Cholesterol biosynthesis <ul> <li>Mostly occurs in liver and intestines</li> <li>Pathway highlights <ul> <li>Requires acetyl-CoA and ATP</li> <li>Acetyl-CoA produced in mitochondria, then converted to citrate for transport to cytosol</li> <li>Citrate converted back to acetyl-CoA in cytoplasm</li> <li>Acetyl-CoA converted to HMG-CoA</li> <li>HMG-CoA converted to mevalonic acid by HMG-CoA reductase (rate-limiting step)</li> <li>HMG-CoA reductase active in smooth ER membrane</li> <li>NADPH required for reducing equivalents</li> </ul> </li> <li>Regulation of pathway <ul> <li>Negative feedback from excess cholesterol</li> <li>Insulin stimulates HMG-CoA reductase activity</li> </ul> </li> </ul> </li> </ul>
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FAQs
The primary source of cholesterol biosynthesis is acetyl-CoA, a molecule derived from carbohydrate, fat, and protein metabolism. The key enzymes involved in cholesterol synthesis include HMG-CoA reductase, which catalyzes the conversion of HMG-CoA to mevalonic acid, and other enzymes that facilitate the conversion of mevalonic acid to cholesterol. These enzymes require NADPH as a cofactor for proper functioning.
HMG-CoA reductase is a vital enzyme in cholesterol biosynthesis because it catalyzes the rate-limiting step in the conversion of HMG-CoA to mevalonic acid. This step is a critical checkpoint in the cholesterol synthesis pathway, and it is tightly regulated to ensure proper cholesterol levels in the body. Inhibiting HMG-CoA reductase, through drugs such as statins, can help lower cholesterol levels and provide therapeutic benefits in the management of cardiovascular diseases.
NADPH is an essential cofactor in cholesterol synthesis, providing the necessary reducing equivalents for various enzymes involved in this pathway. It acts as an electron donor, facilitating the conversion of HMG-CoA to mevalonic acid, and subsequent steps leading to the production of cholesterol. As a key player in cellular redox reactions, NADPH is also essential for maintaining an appropriate balance between oxidative and reductive processes in cells.
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