Chol Flashcards
What are the main phases of cholesterol biosynthesis?
- Synthesis of Mevalonate from Acetate 2. Conversion of Mevalonate to Activated Isoprenes 3. Condensation of Activated Isoprene Units to Form Squalene 4. Conversion of Squalene to Four-Ring Steroid Nucleus
What is the role of Cyt P450 in cholesterol metabolism?
Cyt P450 enzymes function as mixed-function oxidases, facilitating hydroxylation reactions that increase water solubility of substrates.
What are the main cholesterol derivatives?
- Steroid hormones * Bile acids * Vitamin D * Cholesteryl esters
Fill in the blank: Cholesterol is synthesized from _______.
Acetyl-CoA
What is the first step in the synthesis of Mevalonate?
2 Acetyl-CoA → Acetoacetyl-CoA, catalyzed by acetyl-CoA acyl transferase.
What is the rate-limiting step in cholesterol synthesis?
Conversion of HMG-CoA to Mevalonate, catalyzed by HMG-CoA reductase.
What are the activated isoprene units produced from mevalonate?
- Δ3-isopentyl pyrophosphate * Dimethylallyl pyrophosphate
How many ATP molecules are required to create each of the six activated isoprenes?
Three ATP molecules are used.
What is the cyclization product of squalene in animals?
Lanosterol
What leads to the formation of atherosclerosis?
Pathological accumulation of cholesterol leading to obstruction of blood vessels.
What is the function of bile acids?
They aid in the digestion of fats and act as emulsifiers.
What regulates cholesterol metabolism at several levels?
- Covalent modification of HMG-CoA reductase * Transcriptional regulation of HMG-CoA gene * Proteolytic degradation of HMG-CoA reductase * Activation of ACAT * Transcriptional regulation of LDL receptor
What is familial hypercholesterolemia characterized by?
Extremely high blood levels of cholesterol due to a defective LDL receptor.
What do statin drugs inhibit?
HMG-CoA reductase
What process protects against atherosclerosis?
Reverse cholesterol transport by HDL
Fill in the blank: Steroid hormones synthesis occurs in the _______.
Mitochondria of steroidogenic tissues
What are the two classes of steroids synthesized in the adrenal gland?
- Mineralcorticoids * Glucocorticoids
What is the primary transporter of cholesterol in the blood?
Plasma lipoproteins
What happens to cholesteryl esters in terms of solubility?
They are more nonpolar than cholesterol.
What activates ACAT?
Cholesterol
What is the function of apolipoproteins?
They are specific carrier proteins that transport lipids in the blood.
True or False: Insulin leads to the phosphorylation and inactivation of HMG-CoA reductase.
False
What is the metabolic fate of cholesterol after synthesis?
- Export as bile acids * Used for membrane synthesis in liver * Used as a precursor for steroid hormones and vitamin D
What is the effect of glucagon and epinephrine on HMG-CoA reductase activity?
They lead to phosphorylation and reduce its activity.
What is the primary role of HDL in cholesterol metabolism?
To remove cholesterol from peripheral tissues and transport it to the liver.
What process increases the water solubility of substrates?
Hydroxylation
Hydroxylation makes substrates easier for transport in blood and excretion by urine.
Where does steroid hormone synthesis occur?
In mitochondria of steroidogenic tissues: placenta, ovaries, testes, and adrenal cortex
These tissues are responsible for producing steroid hormones.
What is the role of Cytochrome P450s in steroidogenic tissues?
Used to hydroxylate intermediates in the conversion of cholesterol to steroid hormones
P450s are found associated with the inner mitochondrial and microsomal membranes.
What is the function of P450 in the liver?
Hydroxylates intermediates in the conversion of cholesterol to bile acid and hydroxylates cholecalciferol to 25-hydroxycholecalciferol
This process is crucial for the metabolism of cholesterol and vitamin D.
What does hydroxylation affect in foreign compounds and drugs?
Activation or inactivation, changing its level of toxicity and solubility
Hydroxylation is important for drug metabolism.
What is the role of P450 in the kidney regarding vitamin D3?
Hydroxylates vitamin D3 to its biologically active 1,25-dihydroxylated form
This activation is essential for vitamin D’s biological functions.
What is an activated precursor in the biosynthesis of many biomolecules?
Isopentenyl pyrophosphate
This compound is involved in the synthesis of cholesterol, vitamins A, E, and K, and ubiquinone.
What is prenylation?
Anchoring of proteins to the inner surface of cellular membrane by covalent attachment to an isoprenoid
This process is important for protein localization and function within the cell.
precursor for all steroids
Cholesterol
Cholesterol Structure
27 carbon atoms
Four fused rings
• Peripheral side chain
• Only one double bond (C=C)
All of its carbon atoms are provided by
acetate
Synthesis of Mevalonate from Acetate
2 Acetyl-CoA Acetyoacetyl-CoA
– Catalyzed by acetyl-CoA acyl transferase
Acetyl-CoA + Acetoacetyl-CoA -hydroxyl--methylglutaryl-CoA HMG-CoA
– Catalyzed by HMG-CoA
synthase
HMG-CoA + 2 NADPH Mevalonate
– Catalyzed by HMG-CoA reductase
The two activated isoprenes join ———-
displacing one set of diphosphates forms
head-to-tail,
Geranyl
Six Activated Isoprene Units Condense to Form Squalene
two isoprenes join head-to-tail, Geranyl pyrophopshate
• Geranyl pyrophosphate + isopentenyl pyrophosphate
forms 15-C Farnesyl pyrophosphate
• Two farnesyl pyrophosphates join
head-to-head to form phosphate- free Squalene
Enzyme:
Two farnesyl pyrophosphates join head-to-head to form phosphate- free Squalene
Squalene synthase
Conversion of Squalene to Four-Ring Steroid Nucleus
Squalene monooxygenase
adds one oxygen from O2 to the end of the squalene chain
forms squalene 2,3-epoxide
A mixed-function oxidase
requires NADPH
correlate with atherosclerosis
Very high LDL-cholesterol
associated with heart disease
Low HDL-cholesterol levels
Statins
competitive inhibitors of
HMG-CoA reductase
