cholesterol synthesis.pptx

cholesterol in biochemistry

1. Metabolism of Cholesterol Biosynthesis of Cholesterol Ass.prof.Dr. Sukayna Hussain Rashed Mosul university / College of Science / Chemistry Department Email :[email protected] 2022-2023 March 23 Ass.prof.Dr. Sukayna Hussain

2. Structure of cholesterol: The structure of cholesterol consists of four fused rings (The rings in steroids are denoted by the letters A, B, C, and D.), with the carbons numbered in the sequence, and an eight numbered, and branched hydrocarbon chain attached to the D ring . Cholesterol contains two angular methyl groups: the C-19 methyl group is attached to C-10 , and the C-18 methyl group is attached to C-13.The C-18 and C-19 methyl groups of cholesterol lie above the plane containing the four rings. March 23 Ass.prof.Dr. Sukayna Hussain

3. March 23 Ass.prof.Dr. Sukayna Hussain

4. March 23 Ass.prof.Dr. Sukayna Hussain Cholesterol Forms Free Cholesterol And Esterified Cholesterol

5. March 23 Ass.prof.Dr. Sukayna Hussain Free Cholesterol is a derived Lipid (30%) Cholesterol Ester is a simple Lipid and a body Wax. (70%) Cholesteryl Ester is a storage and excretory form of Cholesterol which is found in most tissues.

6. Functions of cholesterol 1-It is a major constituent of the plasma membrane and of plasma lipoproteins . 2-It is a precursor of bile salts . 3-It is a precursor of steroid hormones that include adrenocortical hormones, sex hormones, placental hormones. 4- Also a precursor of vitamin D3. 5- It is required for the nerve transmission. Cholesterol is widely distributed in all cells of the body but particularly abundant in nervous tissue. March 23 Ass.prof.Dr. Sukayna Hussain

7. Sources of cholesterol Cholesterol is derived from: 1- Diet (exogenous cholesterol). 2- Endogenous cholesterol, the liver and intestine account approximately 10% each of total synthesis in humans. (about 2 g/day ), and the remainder is provided by the average diet. March 23 Ass.prof.Dr. Sukayna Hussain

8. March 23 Ass.prof.Dr. Sukayna Hussain

9. March 23 Ass.prof.Dr. Sukayna Hussain Endogenous And Exogenous Sources Of Body Cholesterol A bout 1 g/day originates by bio synthesis A bout 0 . 3 g/day extracted from food 80% Endogenously produced by Liver (0.8 gram/day) 20% Exogenously comes from digestive tract (0.3 gm/day) Assume 400 mg is an intake of dietary Cholesterol per day It absorb about 50% Cholesterol 200 mg is absorbed from GIT 800 mg of Cholesterol is from de novo synthesis

10. March 23 Ass.prof.Dr. Sukayna Hussain Exogenous Sources Of Cholesterol (Animal Sterol)

11. March 23 Ass.prof.Dr. Sukayna Hussain Cholesterol Biosynthesis Is To Provide Endogenous Source of Body Cholesterol

12. March 23 Ass.prof.Dr. Sukayna Hussain Amount Of Cholesterol Biosynthesis Endogenously about 1 gm/day of Cholesterol is biosynthesized. Ingestion of excess of Carbohydrates elevates Cholesterol biosynthesis .

13. March 23 Ass.prof.Dr. Sukayna Hussain Conditions Favoring For Cholesterol Biosynthesis Biosynthesis of Cholesterol takes place: 1- In well fed condition. 2- When excess of free cellular Glucose. 3- On stimulation of Insulin. A mount of Cholesterol biosynthesis depends upon Availability of Acetyl-CoA obtained from Glucose metabolism in a well fed state.

14. March 23 Ass.prof.Dr. Sukayna Hussain Cholesterol Synthesis All 27 carbon units of Cholesterol Structure are biosynthesized using 2 carbon moiety Acetyl-CoA units , obtained from Glucose metabolism . Site of Cholesterol Biosynthesis Organs Involved For Cholesterol Biosynthesis: Liver (80% ); Intestine (10%); Skin (5%); Adrenal Cortex Ovaries , Testes , Placenta; Arterial walls (some extent). Cholesterol Synthesizing Enzymes are partly located in: Cytoplasm Endoplasmic Reticulum

15. March 23 Ass.prof.Dr. Sukayna Hussain Requirements For Cholesterol Biosynthesis Metabolic Precursor- Acetyl CoA (Obtained from excess Glucose metabolism) Enzymes ,Coenzymes and Cofactors 16 NADPH +H + (Through HMP Shunt) 36 ATPs Stages Of Cholesterol Biosynthesis Biosynthesis of Cholesterol is a very complex process To understand divided in 5 Stages Requires more than 25 steps.

16. March 23 Ass.prof.Dr. Sukayna Hussain Stage 1. Acetyl-CoA forms HMG-CoA and Mevalonate .  Stage 2. Mevalonate forms Active Isoprenoid units(C5) Stage 3. 6 Isoprenoid units form Squalene (C30) Stage 4. Squalene is converted to Lanosterol Stage 5. Lanosterol is converted to Cholesterol(C27)

17. March 23 Ass.prof.Dr. Sukayna Hussain Overview/Outline of Cholesterol Synthesis

18. Detail steps of cholesterol Acetyl-CoA acts as a precursor of cholesterol. All 27 carbon atoms of cholesterol are derived from acetyl CoA in three stages: Stage one : Initially two molecules of acetyl-CoA condense to form Acetoacetyl -CoA catalyzed by cytosolic thiolase . Acetoacetyl-CoA condenses with a further molecule of acetyl-CoA catalyzed by HMG-CoA synthase to form HMG-CoA , that is reduced to mevalonate by NADPH catalyzed HMG-CoA reductase. March 23 Ass.prof.Dr. Sukayna Hussain

19. March 23 Ass.prof.Dr. Sukayna Hussain

20. March 23 Ass.prof.Dr. Sukayna Hussain

21. Steps of mevalonate synthesis . March 23 Ass.prof.Dr. Sukayna Hussain

22. Stage two : synthesis of Isoprenoid pyrophosphate, an activated isoprene unit that is the key building unit of cholesterol. Mevalonate in three subsequent steps is Phosphorylated with ATPs Dehydrated and Decarboxylated To form Isoprenoid unit(C5)- Isopentenyl pyrophosphate(IPP). March 23 Ass.prof.Dr. Sukayna Hussain

23. March 23 Ass.prof.Dr. Sukayna Hussain Stage 3,4, and 5 : Condensation of six molecules of Isoprenoid pyrophosphate to form Squalene. So the squalene cyclizes by oxidosqualene lanosterol cyclase reaction to produce tetracyclic product ( Lanosterol C30) is subsequently converted into cholesterol C27 .

24. March 23 Ass.prof.Dr. Sukayna Hussain

25. March 23 Ass.prof.Dr. Sukayna Hussain

26. March 23 Ass.prof.Dr. Sukayna Hussain

27. March 23 Ass.prof.Dr. Sukayna Hussain

28. March 23 Ass.prof.Dr. Sukayna Hussain Demethylation, desaturation and saturation steps convert Lanosterol to Cholesterol

29. March 23 Ass.prof.Dr. Sukayna Hussain Regulation Of Cholesterol Biosynthesis HMG-CoA Reductase Is regulatory/ key enzyme of Cholesterol Biosynthesis . This enzyme is stimulated and inhibited as per requirement of bodies need. Enzyme HMG-CoA reductase has half-life of 3 hrs. Degradation of HMG-CoA reductase depends on Cholesterol levels . Modes Of Cholesterol Regulation Hormonal Influence Covalent Modification Feedback Inhibition

30. March 23 Ass.prof.Dr. Sukayna Hussain Hormonal Regulation Insulin In well fed state: Stimulates and increases HMG CoA Reductase Increases Cholesterol Biosynthesis Glucagon and Glucocorticoids in emergency states: Inhibits HMG CoA Reductase. Decreases Cholesterol Biosynthesis.

31. March 23 Ass.prof.Dr. Sukayna Hussain

32. Degradation of cholesterol Synthesis of bile acids. Synthesis of steroid hormones. Synthesis of Vitamin D. By conversion into bile acids and bile salts-excreted in the feces. Secretion of cholesterol in bile–transported to intestine, for elimination cholesterol is converted into 7-hydroxycholesterol by 7alpha-hydroxylase. Most of 7- hydroxycholesterol is converted to cholic acid. Cholic acid can combine with: * glycine to form gly cholic acid * taurine to form tauro cholic acid Some 7-hydroxycholesterol is converted into chenodeoxycholic acid. This can form gly chenodeoxycholic acid and tauro chenodeoxycholic acid. March 23 Ass.prof.Dr. Sukayna Hussain

33. All these compounds are known as primary bile acids , and their sodium and potassium salts are known as bile salts (Bile salts are formed in liver, and are excreted through bile into intestine. Most of the bile salts entering the intestine are re-absorbed into portal blood, brought to liver, and are re-excreted into the intestine by the liver ( enterohepatic circulation of bile salts ). Finally bile salts are converted into secondary bile acids ( deoxy cholic acid and litho cholic acid), most of the lithocholic acid is excreted in the feces. March 23 Ass.prof.Dr. Sukayna Hussain

34. Detail steps of cholesterol degradation March 23 Ass.prof.Dr. Sukayna Hussain