#16 made by Nour omar corrected by laith sorour date 17/11

Transcription

1 Lipid metabolism 2 #16 made by Nour omar corrected by laith sorour date 17/11

2 Keton Bodies Ketone bodies: acetone, -hydroxybutyrate, and acetoacetate formed principally in the liver mitochondria. can be used as a fuel in most tissues and organs. Formation occurs when the amount of acetyl-coa produced is excessive compared to the amount of oxaloacetate available to react with it, because it is being used in gluconeogenesis during high intake of lipids and low intake of carbohydrates diabetes not suitably controlled strenuous exercise starvation *Ketone bodies are formed in the liver. However, the liver does not use keton bodies for itself. They are transported into other organs. *Ketone bodies are important source of energy in brain and muscle in case of starvation and severe (strenuous) exercise (because there is no glucose). * Fats are burned in the flame of carbohydrate: تحرق الدهون في نار الكربوهيدرات *When there is increased fat intake and less carbohydrate intake this lead to formation of large amount of Acetyl-coA because fatty acids degradation occur and oxaloacetate is not available (because there is no glucose so it s used in gluconeogenesis). When there is an accumulation of Acetyl-coA: some of which enter the citric acid cycle and the other form ketone bodies there for keton bodies are formed in the mitochondrial matrix beside citric acid cycle. Also beta oxidation of fatty acids occur in mitochondrial matrix (thus these three processes: keton body formation & citric acid cycle & beta oxidation of fatty acids occur beside each other in the mitochondrial matrix). The presence of carbohydrate help in consumption of Acetyl-coA: وجود الكربوهيدرات يساعد في استهالك ال Acetyl-coA لذلك ينصح بتناول الحلوى بعد الطعام)الكنافة بعد المنسف.(

3 The presence of high level of Acetyl-coA and the absence of oxaloacetate lead to another pathway which is keton bodies formation. In case of starvation there is a degradation of fats, so accumulation of Acetyl-coA, thus diabetes is not suitably controlled. Brain and muscles prefer ketone bodies in starvation because there is no glucose. *ketone bodies enter the brain directly unlike the glucose which needs insulin, because of that we give Alzheimer patients coconut which have a lot of ketone bodies. HS- CoA 2 CH 3 C-SCo A Acetyl-CoA CH 3 CCH 2 C- SCoA Acetoacetyl-CoA Ketone bodies include: CH 3 -C- CH 2 -C - Acetoacetate C 2 NADH NAD + + H + CH 3 -C- CH 3 Acetone H CH 3 -CH-CH 2 - C - -Hydroxybutyrate 1-Acetoacetate. 2-Acetone. 3-Beta- Hydroxybutyrat e. #Acetone is smelled in the breathe of uncontrolled diabetes patients. (Acetone smell smell). is rotten apple رائحة التفاح المتعفن # Acetoacetate & beta-hydroxybutyrate are liked source of energy. Q: Which tissues can use Keton bodies? A: Brain, skeletal muscles & Heart. Q: Why cannot RBCs and Liver use keton bodies for Energy production? A: RBCs does not contain mitochondria at all & liver lacks some enzymes used for ketone body formation. Heart muscle and the renal cortex use acetoacetate in preference to glucose. Glucose is the major fuel for the brain and red blood cells in well-nourished people on a balanced diet. However, the brain adapts to the utilization of acetoacetate during starvation and diabetes. In prolonged starvation, 75% of the fuel needs of the brain are met by ketone bodies.

4 The Heart usually uses fatty acids, but when there is no fatty acids the heart uses keton bodies because the heart does not use Glucose. اكيد في حكمة من هاد الموضوع ان القلب ال يستخدم ال glucose حتى ال يتنافس الbrain \ heart على نفس المصدر و ايضا ال heart يحتاج تزويد مستمر بالطاقة. *last source of energy finished is F.A *hypoglycemia leads to coma -CoA Transferase is absent in the liver. -Acetoacetate contain two Acetyl-CoA molecules so it is a good source of energy. -As we said before liver transport keton bodies to other organs (Heart, brain &muscles). Fatty Acid Biosynthesis Biosynthesis is not the exact reversal of oxidation Biosynthetic reactions occur in the cytosol

5 Fatty acid biosynthesis; (reversal of oxidation) ccur in the cytosol. All biosynthesis reactions occurred in cytosol. The starting point of fatty acid synthesis is citrate (with acetyl CA and oxaloacetate) The end product of fatty acid oxidation is the starting substrate of fatty acid synthesis. *Anabolic reactions take place in the cytosol

6 First reaction is carboxylation reaction acetyl CA converted to malonyl CA... this step needs biotin, Mn+2 and ATP. -Carboxylation of acetyl-coa in the cytosol -catalyzed by acetyl-coa carboxylase -biotin is the carrier of the carboxyl group -Malonyl-CoA is key intermediate that is produced CH 3 C-SCo A Acetyl-CoA + HC 3 - ATP ADP + P i CH 2 C-SCo A Biotin, Mn 2+ C - Malonyl-CoA Step 1: priming of the system by acetyl-coa CH 3 C-SCo A + HS-ACP Acetyl-CoA CH 3 C-S-ACP + HS-CoA Acetyl-ACP CH 3 C-S-ACP Acetyl-ACP CH 3 C-SCo A Acetyl-CoA + HS-Synthase CH 3 C-S-Synthase Acetyl-Synthase + HS-Synthase CH 3 C-S-Synthase Acetyl-Synthase + HS-ACP + HS-CoA *In fatty acid degradation there is no carrier,, NADH, FADH2 and acetyl coa were released directly *Here we need carrier protein called Acyl Carrier Protein (ACP), we build(synthesize) on it fatty acid then we release it As in the glycogen we need primer called glycogenin. *Acyl carrier protein contain pantothenic acid. *In fatty acid synthesis we need NADPH (electron donor). # The main function of pentose phosphate pathway is to produce NADPH for reductive biosynthesis (cholesterol biosynthesis, fatty acid biosynthesis, hormone biosynthesis, bile. ). NTE: NADPH is an electron donor WHILE NADP is an electron carrier.

7 *Fats are stored in reduced and dehydrated form so when oxidized it gives large energy and fats become light. -Phosphopantetheine group of ACP is similar to phosphopantetheine group of CA IN STRUCTURE. The cycle now repeats on butyryl-acp CH 3 CH 2 CH 2 C-S- ACP Butyry l-acp + CH 2 C-S-ACP - C 2 Malonyl-ACP 3. condensation 4. reduction 5. dehydration 6. reduction CH 3 CH 2 CH 2 CH 2 CH 2 C- S- ACP Hexanoyl-ACP to remove palmitate (16 carbon atoms ) تستمر العملية و يحدث hydrolysis تتكر العمليه 8 مرات.

8 Sources of NADPH for Fatty Acid Synthesis First, oxaloacetate is reduced to malate by NADH. This reaction is catalyzed by a malate dehydrogenase in the cytosol. Second, malate is oxidatively decarboxylated by an NADP + -linked malate enzyme (also called malic enzyme). ne molecule of NADPH is generated for each molecule of acetyl CoA that is transferred from mitochondria to the cytosol. Hence, eight molecules of NADPH are formed when eight molecules of acetyl CoA are transferred to the cytosol for the synthesis of palmitate (doesn t come from TCA this is a new reaction) The additional six molecules of NADPH required for this process come from the pentose phosphate pathway Synthesis of Fatty Acids Repeated turns of this series of reactions occurs to lengthen the growing fatty acid chain. Hexanoyl ACP returns to condense with malonyl ACP during the third turn of this cycle. Longer products also return to condense with malonyl CoA until the chain has grown to its appropriate length (most often C16). The difference between synthesis and degradation of lipids is: Synthesis uses Acetyl-CoA WHILE degradation release Acetyl-CoA. *Precursor means the beginning *in synthesis we need malonyl CoA (an intermediate) and in degradation we don t need it *in degradation we don t need biotin\in carboxylation of synthesis we need it *degradation is oxidative process we need NAD+\FAD+ and release ATP but

9 reductive biosynthesis we need ATP and NADPH *Degradation Begins at carboxyl end and synthesis Begins at methyl end ( CH 3CH2) end *Degradation: In mitochondria, no ordered aggregate enzymes\synthesis: In cytosol, catalyzed by ordered multienzyme complex degredation intermediate: L Hydroxyacyl intermediates synthesis intermediate: D- -Hydroxyacyl-ACP intermediates Fatty Acid Synthase Inhibitors May Be Useful Drugs Mice treated with inhibitors of the condensing enzyme showed remarkable weight loss due to inhibition of feeding. The results of additional studies revealed that this inhibition is due, at least in part, to the accumulation of malonyl CoA. Thus, fatty acid synthase inhibitors are exciting candidates both as antitumor and as antiobesity drugs. Mammals lack the enzymes to introduce double bonds at carbon atoms beyond C-9 in the fatty acid chain. Hence, mammals cannot synthesize linoleate (18:2) and linolenate (18:3). Linoleate and linolenate are the two essential fatty acids Since the human body can synthesis only one double bond, Fatty acid leate (omega-9) is not essential because it can be synthesized in the human body (contain only one double bond). Arachidonic fatty acid is not essential because it can be produced from Linoleate.