Introduction:
Cholesterol is a vital lipid molecule essential for cell membrane structure, steroid hormone synthesis, and bile acid formation. The human body synthesizes about 1 gram of cholesterol per day, in addition to the amount obtained from diet.
Sites of Synthesis:
Cholesterol is synthesized in almost all nucleated cells, but mainly in the liver, adrenal cortex, ovaries, testes, brain, placenta, skin, and aorta. The enzymes responsible are found in the microsomes and cytosol of cells.
Precursors:
Acetyl-CoA is the primary building block for cholesterol, derived from carbohydrates, fatty acids, and amino acids. The transport of acetyl-CoA from mitochondria to cytosol occurs via the citrate shuttle, similar to fatty acid synthesis. Reducing equivalents (NADPH) are supplied by the HMP shunt (hexose monophosphate pathway).
Biosynthesis of Cholesterol
Cholesterol synthesis is a multistep process involving condensation reactions between 2-carbon and 5-carbon units, forming carbon–carbon (C–C) bonds. The pathway can be divided into several stages:
- Formation of mevalonate from acetyl-CoA
- Conversion of mevalonate to isoprenoid units
- Condensation of isoprenoid units to form squalene
- Cyclization of squalene to lanosterol
- Conversion of lanosterol to cholesterol
Stepwise Reactions of Cholesterol Biosynthesis
1. Formation of HMG-CoA
- Two molecules of acetyl-CoA condense to form acetoacetyl-CoA via thiolase.
- Another acetyl-CoA joins acetoacetyl-CoA, catalyzed by HMG-CoA synthase, to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA).
- In cholesterol synthesis, this reaction occurs in the cytosol, whereas in ketogenesis, it occurs in the mitochondria.
2. Formation of Mevalonate
HMG-CoA reductase (a rate-limiting enzyme) catalyzes the NADPH-dependent reduction of HMG-CoA to mevalonate. This is the most crucial control point of cholesterol biosynthesis.
3. Formation of Isoprenoid Units
- Mevalonate is phosphorylated by mevalonate-5-phosphotransferase to form mevalonate-5-phosphate.
- Phosphomevalonate kinase converts this to mevalonate-5-pyrophosphate.
- Pyrophosphomevalonate decarboxylase catalyzes ATP-dependent decarboxylation to yield isopentenyl pyrophosphate.
- Isopentenyl pyrophosphate isomerase converts it to dimethylallyl pyrophosphate.
4. Formation of Squalene
Condensation of five-carbon isoprenoid units leads to larger intermediates:
- Dimethylallyl pyrophosphate + Isopentenyl pyrophosphate → Geranyl pyrophosphate (10-carbon compound)
- Geranyl pyrophosphate + Isopentenyl pyrophosphate → Farnesyl pyrophosphate (15-carbon compound)
- Two farnesyl pyrophosphates condense (head-to-head) via squalene synthase to form squalene (30-carbon compound).
This process involves intermediate formation of presqualene pyrophosphate and requires NADPH for reduction.
5. Cyclization to Lanosterol
- Squalene monooxygenase (squalene epoxidase) converts squalene to squalene-2,3-epoxide using NADPH and oxygen.
- Squalene oxidocyclase cyclizes squalene-2,3-epoxide to form lanosterol, the first sterol structure in the pathway.
6. Conversion of Lanosterol to Cholesterol
Lanosterol undergoes several modifications to yield cholesterol:
- Removal of three methyl groups (one as formate, two as CO₂)
- Shifting of double bonds
- Final reduction by an NADPH-dependent reductase to form cholesterol
Alternatively, cholesterol may form through a minor pathway involving 7-dehydrocholesterol.
Other Products of Cholesterol Biosynthesis Intermediates
- Dimethylallyl pyrophosphate contributes to isopentenyl adenosine formation in tRNA.
- Farnesyl pyrophosphate serves as a precursor for ubiquinone (coenzyme Q), dolichol, and cytochrome heme groups.
- In plants, similar intermediates form carotenes, chlorophyll, and gibberellins.
- In bacteria, squalene forms hopanoids, which are stable hydrocarbons and contribute to petroleum formation.
Mevalonate-Independent Pathway
Some pathogens like Plasmodium falciparum (malaria), Mycobacterium tuberculosis (tuberculosis), and Helicobacter pylori (gastric ulcers) synthesize cholesterol through a mevalonate-independent pathway.
- It uses pyruvate and glyceraldehyde-3-phosphate as precursors instead of acetyl-CoA.
- This pathway is absent in humans, making it a potential drug target for new antimalarial and antitubercular agents.
Immediate Fate of Endogenous Cholesterol
- Newly synthesized cholesterol can exist as free cholesterol or be esterified for storage or transport.
- In liver and intestine, esterification is catalyzed by Acyl-CoA:cholesterol acyltransferase (ACAT), which attaches a fatty acid to the hydroxyl group at the 3rd carbon of cholesterol.
Regulation of Cholesterol Biosynthesis
The rate-limiting enzyme HMG-CoA reductase is the major control point of cholesterol synthesis. It is regulated by both hormonal and feedback mechanisms.
1. Hormonal Regulation
Hormones regulate HMG-CoA reductase through cAMP-mediated phosphorylation and dephosphorylation:
- Active form: Unphosphorylated HMG-CoA reductase
- Inactive form: Phosphorylated HMG-CoA reductase
Glucagon increases cAMP, activating protein kinases that phosphorylate and inactivate HMG-CoA reductase, thereby inhibiting cholesterol synthesis. Insulin decreases cAMP levels, activates phosphatases that dephosphorylate HMG-CoA reductase, and thus stimulates cholesterol synthesis.
Thyroxine increases cholesterol synthesis, while cortisol decreases it.
2. Feedback Regulation
- High intracellular cholesterol inhibits HMG-CoA reductase through allosteric inhibition.
- Dietary cholesterol intake also suppresses HMG-CoA reductase activity.
3. LDL Receptor Regulation
Cholesterol synthesis in extrahepatic tissues is indirectly regulated through LDL receptor expression:
- High intracellular cholesterol → decreases LDL receptor synthesis → reduces cholesterol uptake.
- Low intracellular cholesterol → increases LDL receptor synthesis → enhances cholesterol uptake.
4. Esterification Control
Cholesterol synthesis is also influenced by its rate of esterification through ACAT enzyme activity, which stores excess cholesterol as cholesteryl esters.
Medical Importance
- Cholesterol is the precursor for steroid hormones (cortisol, estrogen, testosterone), bile acids, and vitamin D.
- Excess cholesterol contributes to atherosclerosis and coronary artery disease.
- Inhibitors of HMG-CoA reductase, known as statins, are widely used to reduce plasma cholesterol levels.
- Pathogen-specific cholesterol pathways are potential targets for antimalarial and antitubercular drugs.
Detailed Notes:
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