1. Dr.S.Chakravarty M.D.

3. Carbohydrates

4. Fats

5. 36+-/ Proteins recycling

6. 3 Stages Of Metabolism 1 2 3

7. Krebs cycle, tricarboxylic acid cycle The citric acid cycle (Krebs cycle, tricarboxylic acid cycle) is a sequence of reactions in mitochondria that oxidizes the acetyl moiety of acetyl-CoA and reduces coenzymes that are reoxidized through the electron transport chain, linked to the formation of ATP.

8. The citric acid cycle is the final common pathway for the oxidation of carbohydrate, lipid, and protein because glucose, fatty acids, and most amino acids are metabolized to acetyl- CoA or intermediates of the cycle. It is a source of reduced co-enzymes that provide the substrates for the respiratory chain. It is both catabolic and anabolic (amphibolic). contd..

9. It also has a central role in gluconeogenesis, lipogenesis, and interconversion of amino acids. – So, components of the cycle have a direct or indirect controlling effects in key enzymes of other pathways. Many of these processes occur in most tissues, but the liver is the only tissue in which all occur to a significant extent. – The repercussions are therefore profound when, for example, large numbers of hepatic cells are damaged as in acute hepatitis or replaced by connective tissue (as in cirrhosis). Very few, if any, genetic abnormalities of citric acid cycle enzymes have been reported; such abnormalities would be incompatible with life or normal development.

11. E1 - Thiamine pyro phosphate (TPP) (B1) E2 – Lipoic acid Co-enzyme-A – (Pantothenic acid) E3 – NAD – Niacin (B3) FAD – Riboflavin (B2) The Enzyme subunits Tender – Thiamine Loving - Lipoamide Care -CoASH For – (FAD)Riboflavin Nancy- NAD (Niacin) 3 Enzymes:- 1)PDH, 2)α-KGDH(TCA cycle) 3)Branc hed keto acid dehydrogenase

12. How does Pyruvate enter mitochondria? Symport along with H+ ions

13. PDH is IRREVERSIBLE ( Fats cannot be converted to glucose.) COMMITTED STEP in oxidation of glucose. ENERGETICS :- 1 NADH IS GENERATED = 2.5 ATP REGULATION :- – End product as well as covalent modification – Phosphorylation of enzyme by a kinase decreases the activity and dephosphorylation decreases the activity.

14. Regulation of PDH enzyme: 1. Regulation by end product inhibition (Allosteric )

15. 2. Regulation by Covalent modification : PDH kinase – inactivation of enzyme PDH Phosphatase - activation

17. Tissues :- All tissues Subcellular site :- Mitochondrial Matrix

18. Enzyme bound ATP Substrate level phosphorylation NADH FADH 2 NADH Thiamin, lipoate, FAD

20. OAA is viewed as a catalyst, which enters into the cycle, causes complete oxidation of acetyl CoA, and is regenerated in the end without any loss.

22. 1)Final common oxidative pathway

23. 2)Fat is burnt on the wick of carbohydrates Oxidation of fats need the help of Oxaloacetate which enters into the cycle and is regenerated in the end. The major source of OAA is Pyruvate. (Carbohydrate)

24. ) Excess carbohydrates are converted to neutral fats via citrate and ATP-citrate lyase but not vice versa because Pyruvate dehydrogenase step is irreversible. 3) Excess carbohydrates are converted to neutral fats via citrate and ATP-citrate lyase but not vice versa because Pyruvate dehydrogenase step is irreversible. T IRREVERSIBLE P

25. 4)Amphibolic ( Catabolic and Anabolic ) 4)Amphibolic ( Catabolic and Anabolic ) GABA HEME FATTY ACIDS, STEROLS gluconeogenesis 5) TCA cycle plays an important role in Gluconeogenesis, Transmination and Deamination.

26. 6) Anaplerotic ( filling – up) reactions -> As shown before,TCA cycle acts as precursors of biosynthetic pathways, e.g Heme. So, there is constant efflux of carbon units from the cycle.To counterbalance the loss, filling up reactions are necessary. Eg. - Pyruvate to Oxaloacetate(PYRUVATE CARBOXYLASE) ( most important) -- Phosphoenolpyruvate to Oxaloacetate (PEP CARBOXYLASE) --Pyruvate to Malate (Malic enzyme) 7) Metabolic traffic regulator - -All metabolisms end in TCA. -Availability or lack of intermediates govern the directions of pathways converging or going out of TCA.

27. Regulation of Iso-Citrate dehydrogenase: Isocitrate Dehydrogenase ATP NADH (-) Iso-citrate Alpha ketoglutarate (-) Accumulation of Citrate In well fed state: Inhibit Glycolysis Enters fatty acid synthesis In well fed state, increase in ATP and NADH will inhibit isocitrate dehydrogenase leading to accumulation of citrate. citrate will enter cytosol and inhibit Glycolysis and activates fatty acid synthesis.

28. Regulation of citric acid cycle Citrate synthase Iso-citrate dehydrogenase Alpha keto glutarate dehydrogenase

29. Aconitase – is inhibited by fluoroacetate (non- competitive inhibition)  -ketoglutarate dehydrogenase is inhibited by Arsenite (non-competitive inhibition) Succinate dehydrogenase is inhibited by Malonate (competitive inhibition)

30. Which of the following is required for cholesterol synthesis in hepatocytes? A. Citrate shuttle B. Glycerphosphate shuttle C. Malate-Aspartate shuttle D. Carnitine shuttle E. Adenine nucleotide shuttle