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CHOLESTEROL SYNTHESIS.pptx
- 2. Group members ▪ Siphy Thindwa ▪ Emmanuel Kachali ▪ Clara Tembo ▪ Bridget Banda
- 3. Objectives ▪ Definition cholesterol and ketones ▪ Describe cholesterol synthesis pathways ▪ Describe ketogenesis ▪ Regulations of cholesterol biosynthesis
- 4. Definition ▪ Cholesterol is a waxy, fat-like substance found in all cells of the human body ▪ Cholesterol is essential for cellular structure and function ▪ It plays a crucial role as a component of cell membrane and as a precursor of steroid hormones ▪ It is synthesised in the cell cytosol and endoplasmic reticulum from acetyl-CoA.
- 5. Cholesterol biosynthesis ▪ Three molecules of acetyl –CoA are converted to the 6 – carbon mevalonic acid. ▪ The first two steps are condensation reaction leading to the formation of 3 –hydroxyl 3 –Methylglutaryl CoA (HMG –CoA) ▪ These reactions occur in cytoplasm and are catalyzed by AcetoAcetyl –CoA thiolase (Thiolase) and HMG –CoA synthase.
- 6. Gluco se Pyruvate Acetyl-CoA Acetyl-CoA + Acetyl-CoA Acetoacetyl-CoA + Acetyl-CoA Thiolase CoA SH HMG-CoA HMG synthase CoA SH Flow diagram NADH FADH2 ETC ATP
- 7. Conti… ▪ MHG –CoA is then catalyzed by HMG reductase which is a rate limiting enzyme ▪ This leads to the irreversible formation of mevalonic acid which is later converted to isopentyl pyrophosphate then to squalene. ▪ HMGR is embedded in endoplasmic reticulum. ▪ Hormones like insulin and tri –iodothyronine increases its activities
- 8. Conti… ▪ While glucagon and cortisol inhibit it. ▪ Mevalonate is phosphorylated in two reaction requiring kinases and ATP to be converted to isoprene pyrophosphate then further to isoprene units ▪ Isoprene units goes through 21 steps to be converted to squalene by a hormone called squalene synthase. ▪ Squalene is later converted to 7 –dehydrocholesterol which is finally converted to cholesterol
- 10. ketones ▪ Ketones are organic compounds that the body produces when it breaks downs fat for energy in the absence of sufficient carbohydrates ▪ They can serve as alternative source of energy for the brain and muscles when glucose levels are low, such as during fasting, starvation, Atkins die (low- carb diet), or certain medical conditions like diabetes.
- 11. Ketogenesis ❑It is the formation of ketone bodies in the liver mitochondria ❑Ketone bodies includes: ▪ Acetoacetate acid (CH3-CO-CH2-COOH) ▪ β -Hydroxybutyric acid (CH3-CHOH-COOH ▪ Acetone (CH3-CO-CH3)
- 12. Conti… ▪ Ketone bodies are formed from Acetyl CoA resulting from β oxidation of fatty acids in excess of optimal function of kreb’s cycle. ▪ Under the normal fed state, the hepatic production of acetoacetate and β hydroxybutyrate in minimal and the concentration of these compounds in the blood is very low (doe not exceed 1mg).
- 13. Conti… ▪ Most acetyl CoA fatty acid or pyruvate oxidation enter the citric cycle only if fat and carbohydrates degradation are balanced.
- 14. Steps of synthesis of ketone bodies 1. Two molecules of acetyl CoA react with each other in the presence of thiolase enzyme to form acetoacetyl CoA. 2. Condensation of acetoacetyl CoA with acetyl CoA to form 3 hydroxyl 3 methyl glutaryl CoA (HMG CoA) catalyzed by HMG CoA synthase 3. HMG CoA lyase enzyme catalyzes the cleavages of HMG CoA to acetoacetate and acetyl CoA
- 15. Conti… 4. Acetoacetate produces β –hydroxybutyrate in a reaction catalyzed by β –hydroxybutyrate dehydrogenase (β –OH butyrate –DH) in the present NADH. 5. Both acetoacetate and β –hydroxybutyrate can be transported across the mitochondrial membrane and the plasma membrane of the liver cells, enters the blood stream to be used as fuel by other cells of the body.
- 16. Conti… 6. In the blood stream, small amounts of acetoacetate are spontaneously (non –enzymatically) decarboxylated to acetone. 7. Acetone is volatile and can not be detected in the blood system 8. The odor of acetone may be detected in the breath and also in urine of a person who has high level of ketone bodies in the blood. e.g. in severe diabetic ketoacidosis while under normal conditions, acetone formation is negligible.
- 17. Gluco se Pyruvate Acetyl-CoA Acetyl-CoA + Acetyl-CoA Acetoacetyl-CoA Thiolase CoA SH HMG-CoA HMG synthase CoA SH Flow diagram Fatty Acids NADH FADH2 ETC ATP β-oxidation
- 18. HMG-CoA HMG Lyase Acetoacetate NADH NAD+ β –Hydroxybutyric DH β -hydroxybutyric Acetone Flow diagram
- 19. THE END
- 20. References • Baynes J.W. & Dominiczak M.H., (2014). Medical Biochemistry: 4th edition • Tymoczko J.L., Berg J.M., Gatto jr, & Stryer L., (2019). Biochemistry: A Short Course