Lipolysis, Fatty Acid Oxidation and Ketone Bodies Biochemistry Lecture Notes PDF

‫ الخميس‬: ‫احمد سالم‬# BIOCHEMISTRY ‫ﻟﺠﻨﺔ اﻟﻄﺐ اﻟﺒﺸﺮي‬ ‫اﻟﻔﺮﻳﻖ اﻟﻌﻠﻤﻲ‬ Done By: Abdalrahman Qutami & Abdulrahman Eswed & Ghaleb Saleh & Yazid Salameh & Mosa'b Ankeer &. Rakan Khraisha ...

‫ الخميس‬: ‫احمد سالم‬# BIOCHEMISTRY ‫ﻟﺠﻨﺔ اﻟﻄﺐ اﻟﺒﺸﺮي‬ ‫اﻟﻔﺮﻳﻖ اﻟﻌﻠﻤﻲ‬ Done By: Abdalrahman Qutami & Abdulrahman Eswed & Ghaleb Saleh & Yazid Salameh & Mosa'b Ankeer &. Rakan Khraisha  ‫ ﻟﺠﻨﺔ اﻟﻄﺐ اﻟﺒﺸﺮي‬- ‫اﻟﻔﺮﻳﻖ اﻟﻌﻠﻤﻲ‬ Bi chem stry Lipolysis, fatty acid oxidation and ketone bodies ‫ﻣﻦ اﻫﻢ ﻣﺤﺎﺿﺮات ﻣﺎدة اﻟﻔﺎﻳﻨﻞ‬ ‫ أﺳﻮد‬: ‫اﻟﺴﻼﻳﺪات‬ Adipose tissues and energy stores ‫ أﺣﻤﺮ‬: ‫اﻟﺘﻔﺮﻳﻎ‬ ‫ ﺑﻨﻔﺴﺠﻲ‬: ‫ﺷﺮح اﺿﺎﻓﻲ‬ Types of adipose tissue. ‫ﻻ ﻳﺴﺤﺐ ﻣﺎء ﻛﺜﻴﺮ ﻟﺬﻟﻚ ﻧﺴﺘﻄﻴﻊ ﺗﺨﺰﻳﻦ ﻛﻤﻴﺔ ﻃﺎﻗﺔ ﻛﺒﻴﺮة ﺑﻤﺴﺎﺣﺔ ﻗﻠﻴﻠﺔ‬ White adipose tissue: mainly concerned with energy storage Has very few mitochondria ‫ﻻ‬، hydrophobic ‫ اﻟﺬي ﻳﻌﺘﺒﺮ‬،TAG ‫ﺑﺴﺒﺐ اﺣﺘﻮاﺋﻪ ﻋﻠﻰ ﻛﻤﻴﺔ ﻛﺒﻴﺮة ﻣﻦ‬ TAG makes 80% of it onidation.‫ﻳﺤﺘﺎج إﻟﻰ ﺳﺤﺐ اﻟﻜﺜﻴﺮ ﻣﻦ اﻟﻤﺎء‬ Brown adipose tissue: involved in thermogenesis uncoupling in ETC & oxidative Numerous mitochondria, cytochromes → brown colour phosphorylation Important in new-borns and hibernating animals - = + Thermogenesis Process in which heat is liberated by uncoupling oxidation from phosphorylation → energy is released as heat Not ATP Occurs due to presences of uncoupling protein (thermogenin) ‫ﻻ داﻋﻲ ﻟﺤﺪوث ﻫﺬه اﻟﻌﻤﻠﻴﺔ ﻓﻲ ﺣﺎل ﻋﺪم ﻣﺮور ﻓﺘﺮة‬ Process of mobilization of stored fats ‫ﻃﻮﻳﻠﺔ ﻋﻠﻰ ﺗﻨﺎول اﻟﺸﺨﺺ ل وﺟﺒﺔ دﺳﻤﺔ‬ Lipolysis: process of appearance of FAs in blood during fasting is due to ‫ﻳﺠﺐ ﻋﻠﻴﻨﺎ اﻟﺘﻔﺮﻳﻖ ﺑﻴﻦ ﻣﺼﻄﻠﺤﻴﻦ ﻣﻬﻤﻴﻦ ﺟﺪا‬: WA T mobilization of fat stores.. 1-lipolysis :is the break down of fats(TAG),into glycerol and FA and then FA moves into blood (mobilization) during fasting, this process - happens in white adipose tissue. This is via hydrolytic release of FAs from glycerol in TAG TAG ‫ ﻣﻦ اﻫﻢ ﻣﺼﺎدر ال‬white adipose tissue ‫وﻳﻌﺘﺒﺮ ال‬ ‫ﻣﻬﻢ‬ 2-B-oxidation:is the break down of Fatty acids Initiated by hormone sensitive lipase (removes FAs from carbon 1 and/or carbon 3 of TAG) ‫ واﺣﺪة ﻣﺮﺗﺒﻄﺔ ﺑﺬرة‬FA ‫ ﻋﻠﻰ إزاﻟﺔ ﺳﻠﺴﻠﺔ‬Hormone sensitive lipase ‫ﻳﻌﻤﻞ‬ glycerol ‫ ﻣﻦ‬3 ‫ أو‬1 ‫اﻟﻜﺮﺑﻮن رﻗﻢ‬ Additional lipases remove the remaining FAs from diacylglycerol or monoacylglycerol ‫اﻻﻫﻢ‬ The gain : glycerol + (Diacylglycerol lipase) 3 FFAs · O O free fatty acid O(monoacylglycerol lipase)  ‫ ﻟﺠﻨﺔ اﻟﻄﺐ اﻟﺒﺸﺮي‬- ‫اﻟﻔﺮﻳﻖ اﻟﻌﻠﻤﻲ‬ Bi chem stry Lipolysis, fatty acid oxidation and ketone bodies Regulation of hormone sensitive lipase Hormone sensitive lipase is a phosphorylated enzyme (needs phosphate to be activated) Fasting kinase ‫ ﻋﻦ ﻃﺮﻳﻖ اﻧﺰﻳﻢ ﻳﺴﻤﻰ‬phosphorylation ‫وﻳﺤﺪث ﻟﻪ‬ - Regulation of hormone sensitive lipase: ‫ ﻋﻠﻰ‬insulin ‫ﻳﻌﻤﻞ ال‬، ‫ﻟﻤﺎ ﺗﺘﻨﺎول وﺟﺒﺔ‬-١ cAMP ‫ ﻋﻦ ﻃﺮﻳﻖ ﺗﺤﻮﻳﻞ‬inactivation of kinase ‫ ﻣﻦ ﺧﻼل ﺗﺤﻔﻴﺰ اﻻﻧﺴﻮﻟﻴﻦ اﻧﺰﻳﻢ‬AMP ‫إﻟﻰ‬ phosphodiesterase glucagon and ‫ﻓﻲ ﺣﺎﻟﺔ اﻟﺼﻴﺎم ﻳﺤﺪث زﻳﺎدة ﻓﻲ‬-٢ ‫ﻓﻴﻌﻤﻠﻮا ﻋﻠﻰ‬، noradrenaline release activation of ‫ ﺛﻢ‬activation of kinase hormone sensitive lipase ‫ﻟﻮ ﺷﺨﺺ ﺣﺎب ﻳﻀﻌﻒ ﻻزم ﻳﺼﻮم‬ Fatty acids are stored in adipose tissue as TAG TAG are the major fuel storage reserve. Lipolysis is the hydrolysis of stored TAG in adipose tissue into glycerol and FA Make lipids (TAG) Gluconeogenesis(make glucose)  ‫ ﻟﺠﻨﺔ اﻟﻄﺐ اﻟﺒﺸﺮي‬- ‫اﻟﻔﺮﻳﻖ اﻟﻌﻠﻤﻲ‬ Bi chem stry Lipolysis, fatty acid oxidation and ketone bodies Fatty acids oxidation F.As not simple lipid The main pathway for FA oxidation is present in the mitochondria and known as β-oxidation Most imp. FA oxidation pathway is B-oxidation B-oxidation ‫ ﻻزم ﺑﺎﻟﻨﺎ ﻳﺮوح ﻋﻠﻰ‬FA oxidation ‫ﻓﻲ اﻻﻣﺘﺤﺎن ﻓﻲ ﺣﺎل اﻧﺬﻛﺮ‬ Other specified pathways are: α-oxidation of FA ‫أﻗﻞ أﻫﻤﻴﺔ‬ ω-oxidation ‫ ﺗﺬﻛﺮ اﻧﻪ ﻳﺘﻜﻮن ﻣﻦ‬،TAG ‫ﻓﻲ اﻻﻣﺘﺤﺎن اذا ﺳﺄل ﻋﻦ ﻣﻘﺪار اﻟﻄﺎﻗﺔ اﻟﻨﺎﺗﺠﺔ ﻣﻦ ﺗﻜﺴﻴﺮ‬ 3FAs ‫ و‬glycerol β-oxidation of fatty acids Site: All cells containing mitochondria Steps: Individual enzymes,not complex as in FA synthesis Several enzymes, known collectively as «FA oxidase» are found in the - mitochondrial matrix adjacent to citric acid cycle Steps: acetyl COA and acyl CoA ‫ﻳﺠﺐ أن ﻧﻔﺮق ﺑﻴﻦ‬ ii Acetyl Co-A : CO-A+‫ﺗﺘﻜﻮن ﻣﻦ ﻛﺮﺑﻮﻧﺘﻴﻦ‬ 1- Activation of FA to acyl-CoA - Acyl CO-A: FA ‫ إﻟﻰ‬CO-A ‫ﺗﺘﻜﻮن ﻣﻦ إﺿﺎﻓﺔ‬ => F A G.. 2-Transport of acyl-CoA through mitochondrial membrane by the * carnitine shuttle d 3-Oxidation of acyl-CoA inside the mitochondrial matrix (NADH,FADH2) ‫ﻹﻧﺘﺎج ﺑﻄﺎرﻳﺎت‬ 1- Activation of FA ّ 2ATP ‫ ﻟﺬﻟﻚ ﻧﻌﺘﺒﺮ ﻛﺎﻧﻪ ﺗﻢ اﺳﺘﻬﻼك‬AMP ‫ إﻟﻰ‬ATP ‫ﺣﻮﻟﻨﺎ ﻣﻦ‬ Coenzyme required: CoASH CH3-R-COOH - Energy required: ATP which W converted into AMP & PPi (pyrophosphate) 73. You are breaking two high energy phosphate bounds(one of them is (7.kcal and the other is 6.6kcal which doesn't consider high energy phosphate bond ,but relatively we consider it as high energy phosphate bond )  ‫ ﻟﺠﻨﺔ اﻟﻄﺐ اﻟﺒﺸﺮي‬- ‫اﻟﻔﺮﻳﻖ اﻟﻌﻠﻤﻲ‬ Bi chem stry Lipolysis, fatty acid oxidation and ketone bodies PPi The PPi is hydrolyzed by inorganic pyrophosphatase with the loss of further high-energy phosphates So, the total loss, two “high” energy - phosphates. Fate of activated FAs If energy charge of cell is low Activated acyl coA will be moved to mitochondrial matrix by carnitine shuttle - → FA oxidation If energy charge of cell is high FA synthesis is favoured → movement of activated acyl coA is inhibited and it is used O for TAG or membrane lipid synthesis in cytosol * 2- Transport of acyl-CoA through the inner mitochondrial membrane After activation of FA to fatty acyl-CoA,: – short & medium chain FA (shorted then 12C) can penetrate the inner mitochondrial membrane for oxidation – Transport of long chain acyl-CoA requires the presence of carnitine. They are transported through the membrane as acyl-carnitine. Carnitine (β-hydroxy-γ-trimethylammoniumbutyrate), {CH3 )3N+ -CH2 -CH (OH) – CH2- COO} - is present in all tissues & in excess in muscle palmatic acid ‫ اﻟﺬي ﻧﺴﺘﻬﻠﻜﻪ ﻫﻮ‬FA ‫ ﻷن ال‬palmitoyl ‫ﻳﺴﻤﻰ‬ - Carnitine acyl (palmitoyl)transferase-1 (CAT-1 or CPT-1), present in the outer mitochondrial membrane, converts the long chain acyl-CoA to acylcarnitine - Acylcarnitine is able to penetrate the inner membrane and gain access to the β–oxidation  ‫ ﻟﺠﻨﺔ اﻟﻄﺐ اﻟﺒﺸﺮي‬- ‫اﻟﻔﺮﻳﻖ اﻟﻌﻠﻤﻲ‬ Bi chem stry Lipolysis, fatty acid oxidation and ketone bodies - Carnitine-acylcarnitine translocase acts as an inner membrane exchange transporter - Acylcarnitine is transported in exchange with Carnitine - Acylcarnitine then reacts with CoA, catalyzed by carnitine acyl (palmitoyl)transferase-2 (CAT-2 or CPT-2), and located on the inside of the inner membrane - Acyl-CoA is reformed in the mitochondrial matrix (mitosome) and carnitine is liberated fatty acyl CoA ‫ﺧﻄﻮات إدﺧﺎل‬ mitochondrial ‫ إﻟﻰ‬long :matrix ‫ ﻣﻊ ال‬fatty acyl CoA ‫دﻣﺞ‬-١ acyl ‫ ﻋﻦ ﻃﺮﻳﻖ اﻧﺰﻳﻢ ﻹﻧﺘﺎج‬carnitine ‫ وﺗﺤﻔﺰ ﻫﺬه اﻟﺨﻄﻮة ﻋﻦ‬carnitine & acyl‫( و‬CAT1 or CPT1) ‫ﻃﺮﻳﻖ اﻧﺰﻳﻢ‬ ‫ اﻟﺬي ﺑﺪوره ﻳﺴﺘﻄﻴﻊ اﻟﻮﺻﻮل‬carnitine ⑪ intermembrane space ‫إﻟﻰ‬ ③ Carnitine , ‫ إﻟﻰ‬acyl CoA Y ‫ﻳﻨﺘﻘﻞ‬-٢ mitochondrial matrix via translocase carnitine fatty ‫ إﻟﻰ‬acyl CoA ‫ﻳﺘﺤﻮل‬-٣ carnitine acyl ‫ ﻋﻦ ﻃﺮﻳﻖ‬acid CoA O ② ‫( داﺧﻞ‬palmitoyl) transferase mitochondrial matrix Info about carnitine shuttle Carnitine is primarily found in meat ‫ ﻣﻦ ﻣﺼﺎدر ﺣﻴﻮاﻧﻴﺔ ﻣﺜﻞ )اﻟﻠﻴﻪ( ﻷن ﺑﻌﺾ‬carnitine ‫ﻻزم ﻧﺤﺼﻞ ﻋﻠﻰ ال‬ skeletal or heart cells ‫اﻟﺨﻼﻳﺎ ﻻ ﺗﺴﺘﻄﻴﻊ ﺗﺼﻨﻴﻌﻪ ﻣﺜﻞ‬ It can also be synthesized from amino acids lysine and methionine Happens in liver and kidney Does not happen in skeletal muscles or heart (totally dependent on exogenous - carnitine or that distributed in blood) - - ‫ ﺑﻜﻮن ﻣﺜﺒﻂ‬FA oxidation ‫ ﻳﻜﻮن ﺷﻐﺎل‬FA synthesis ‫ﻟﻤﺎ‬ Malonyl coA inhibits CAT-1 preventing entry of long chain acyl groups from entering inner mitochondrial membrane → turn- FA oxidation off Acetyl COA carboxylase => > Malonyl Acetyl con - COA  ‫ ﻟﺠﻨﺔ اﻟﻄﺐ اﻟﺒﺸﺮي‬- ‫اﻟﻔﺮﻳﻖ اﻟﻌﻠﻤﻲ‬ Bi chem stry Lipolysis, fatty acid oxidation and ketone bodies Short and medium chain FA can cross inner mitochondrial membrane without shuttle Their oxidation is not dependent on carnitine or inhibited by malonyl coA & 25‫اﻟﺤﻠﻴﺐ‬ ?carnitine shuttle ‫ ﻏﻴﺮ ﻣﻌﺘﻤﺪة ﻋﻠﻰ‬diet ‫ﻛﻴﻒ ﻣﻤﻜﻦ اﻋﻄﻲ ﻟﺸﺨﺺ‬: ‫ﺳﺆال اﻣﺘﺤﺎن‬ ‫ اﻟﻲ ﻫﻢ ﻣﻮﺟﻮدﻳﻦ ﻓﻲ‬medium and short chain FA ‫ ﻳﺠﺐ ﻋﻠﻴﻨﺎ اﻟﺘﻔﻜﻴﺮ ﻓﻲ‬:‫اﻹﺟﺎﺑﺔ‬ ‫ ﻟﻜﻞ دورة‬2ATP ‫اﺳﺘﻬﻼك‬ 3-Oxidation of acyl-CoA The process is multi-cyclic & – each cycle catalyzes removal of two carbons Matrine (fromz carboxyl end of acyl coA) as active acetate - - (acetyl coA) Oxidation Ha D. & two reduced coenzymes are formed > - ‫ﻛﻞ دورة ﻳﺘﻢ إﻧﺘﺎج‬ & (FADH2 & NADH+H+ ) ‫ ﻣﻦ أﻟﻔﺎ وﺑﻴﺘﺎ ﻛﺎرﺑﻮن ﻓﺘﻜﻮن راﺑﻄﺔ ﺛﻨﺎﺋﻴﺔ ﺑﻴﻨﻬﻤﺎ‬2H ‫ﻧﺰﻋﻨﺎ‬ 1NADH and 1FADH2 Hydration- Active acetate are oxidized in citric acid cycle Beta carbon ‫ ﻋﻠﻰ‬OH ‫ﻓﻴﻪ ﻋﻨﺎ‬ & to 2 CO2 Oxidation- Reduced coenzymes produced by β-oxidation - ⑧ and citric acid cycle are oxidized by electron ‫ ﻓﺄﺻﺒﺢ ﻟﺪﻳﻨﺎ‬2C ‫ اﻻن ﻓﻘﺪﻧﺎ‬16C ‫ﻟﻮ ﺑﻠﺸﻨﺎ ﺑﻤﺮﻛﺐ‬ transport chain (ETC) for synthesis of ATP 14C ‫ ﻳﺘﻜﻮن ﻣﻦ‬fatty acyl CoA B ecarboxyl group X methyl neul ‫ وﻟﻜﻦ ﻣﻄﻠﻮب‬structures ‫ﻏﻴﺮ ﻣﻄﻠﻮب ﺣﻔﻆ ال‬: ‫ﻣﻬﻢ‬ & & ‫ﻣﻌﺮﻓﺔ اﻻﻧﺰﻳﻢ وﻣﻜﺎﻧﻪ واﻟﺘﻔﺎﻋﻞ اﻟﺬي ﻳﻌﻤﻞ ﻋﻠﻰ ﺗﺤﻔﻴﺰه‬ RE ‫ﻣﻬﻢ ﺟﺪا أﺳﺌﻠﺔ ﺣﺴﺎﺑﻴﺔ‬ If we have Palmatic acid has 16C 7cycles  Number of cycles = ‫ ﻟﺠﻨﺔ اﻟﻄﺐ اﻟﺒﺸﺮي‬- ‫اﻟﻔﺮﻳﻖ اﻟﻌﻠﻤﻲ‬ Bi chem stry (Number of carbons in FA - 2 ) /2 Number of Acetyl CoA= Number of carbons in FA /2 Number of produced ATP=Lipolysis, fatty acid oxidation and ketone bodies (10*n.Acetyl CoA) + (n. Cycles * 4) - 2 Calculation of energy yielded from complete oxidation of FA (e.g. palmitic acid): Palmitic acid is C16, saturated FA Palmitic acid is activated to palmityl-CoA = (-2 ATP). Complete oxidation of palmityl-CoA gives 8 mol of acetyl-CoA (16/2 = 8) through 7 β oxidation cycles. Each turn of β oxidation gives FADH2 & NADH+H+ which by respiratory chain give 5 ATP (old system), 4 (new system) So 7 cycles x 5 ATP = 35 ATP (old) or 7 cycles x 4 ATP = 28 ATP (new) Each acetyl-CoA by citric acid cycle gives 12 ATP (old system), so 8 acetyl-CoA x 12 ATP= 96 ATP (old system) ‫ ﻳﺤﺘﻮي‬FA ‫اﻟﺪﻛﺘﻮر ﻧﻮه إﻟﻰ وﺟﻮد ﺳﺆال ﺣﺴﺎﺑﻲ ﻓﻲ اﻻﻣﺘﺤﺎن ﻋﻠﻰ ﻫﺬة اﻟﺠﺰﺋﻴﺔ وﻟﻜﻦ ﻣﻊ‬: ‫ﻣﻬﻢ‬ The total gain : 96 + 35 = 131 ATP (old system) ‫ ﻣﺜﺎل‬،‫ﻋﻠﻰ ﻋﺪد ﻛﺮﺑﻮﻧﺎت ﻣﺨﺘﻠﻒ‬ calculate how many ATP produced by B-OXIDATION of FA composed of 14 The net gain : 131- 2 = 129 ATP (old system) carbon ,based on new system of calculation: 78acetyl COA=80ATP+6NADH=15ATP+6FADH2=9ATP-Activation of FA=2ATP ANS:92ATP Exam question: what is total net energy of complete oxidation of a fatty acid with 18 carbons (for example) New system Importance of β oxidation: 1- source of energy during fasting - 2- source of acetyl-CoA which can be converted to other important compounds as cholesterol and acetyl choline  ‫ ﻟﺠﻨﺔ اﻟﻄﺐ اﻟﺒﺸﺮي‬- ‫اﻟﻔﺮﻳﻖ اﻟﻌﻠﻤﻲ‬ Bi chem stry Lipolysis, fatty acid oxidation and ketone bodies Regulation of β oxidation: (1) feeding status: Free fatty acids Fasting increases lipolysis →release of FFA from adipose tissue → ↑↑ FA in tissues → stimulation of β oxidation ‫ ﻓﻲ اﻟﺪم‬free fatty acids ‫زﻳﺎدة‬ Inhibition of hormone sensitive lipase CHO feeding → ↑ insulin → inhibition of lipolysis in adipose tissue → ↓↓ FFA in tissues → inhibition of β oxidation Rate limiting step of beta oxidation is formation of fatty acyl carnitine (catalysed by CAT1) Malonyl coA (1 st intermediate of synthesis of FA) allosterically inhibits CAT1 In fed state: ↑ insulin/glucagon ratio → fatty acid synthesis is promoted in liver (insulin - activates acetyl coA carboxylase) → ↑ malonyl coA → inhibition of CAT1 → ↓ beta oxidation In starvation: ↓ insulin/glucagon ratio → glucagon inhibits acetyl coA carboxylase → ↓ malonyl coA → release inhibition of CAT1 → ↑ beta oxidation Hormone sensitive lipase is activated by phosphorylation (glucagon) Its activity is low when insulin levels are high (im feel state) (2) Energy needs by cells: Electron transport chain ↑↑ ATP → ↓↓ respiratory chain → FADH2 and NADH+H+ remain reduced → inhibition of DH “dehydrogenases” of β oxidation ↓↓ ATP & ↑ ADP and Pi → ↑↑ respiratory chain so, FAD& NAD+ are oxidized → stimulation of DH of β oxidation  ‫ ﻟﺠﻨﺔ اﻟﻄﺐ اﻟﺒﺸﺮي‬- ‫اﻟﻔﺮﻳﻖ اﻟﻌﻠﻤﻲ‬ Bi chem stry Lipolysis, fatty acid oxidation and ketone bodies Notes: Oxidation of FA supplies NADH and ATP required for gluconeogenisis and supplies excess acetyl CoA. Activates pyruvate to oxalo-acetate Inhibits pyruvate to acetyl CO-A Acetyl CoA allosterically activates pyruvate carboxylase and inhibits pyruvate dehydrogenase. This directs pyruvate towards gluconeogenesis rather than oxidation. ً ‫ﻣﻬﻢ ﺟﺪا ﻓﻬﻢ اﻟﻌﻼﻗﺔ ﺑﻴﻨﻬﻤﺎ‬ If FA oxidation is inhibited, gluconeogenesis is inhibited. gluconeogenesis ‫ ﻟﻨﺤﺼﻞ ﻋﻠﻰ اﻟﻄﺎﻗﺔ اﻟﻼزﻣﺔ ﻟﻨﺴﺘﻜﻤﻞ‬B oxidation ‫ﻻزم ﻧﻌﻤﻞ‬ Oxidation of FA with an odd number of C atoms: Odd chain FA are oxidized by β oxidation producing acetyl-CoA but only at the ‫ﻳﺤﺪث ﻟﻪ ﺗﻜﺴﻴﺮ ﻋﻠﻰ‬، ‫ ﺗﺤﺘﻮي ﻋﻠﻰ ﻋﺪد ﻓﺮدي ﻣﻦ اﻟﻜﺎرﺑﻮﻧﺎت‬FA ‫ﻓﻲ ﺣﺎل ﻛﺎﻧﺖ ﺳﻠﺴﻠﺔ ال‬ last step one propionyl-CoA is produced‫ وﻓﻲ‬، B-OXIDATION ‫ ﻓﻲ ﻛﻞ ﻣﺮه ﻳﺤﺪث ﺗﻜﺴﻴﺮ ﺑﻌﻤﻠﻴﺔ‬2C ‫ اي ﻳﺨﺴﺮ‬acetyl CoA ‫ﺷﻜﻞ‬ propionyl CoA ‫ ﻳﺴﻤﻰ‬3C ‫اﻟﻨﻬﺎﻳﺔ ﻳﺘﺒﻘﻰ ﻣﺮﻛﺐ ﻳﺤﺘﻮي ﻋﻠﻰ‬ * Propionyl CoA can be converted to methyl malonyl CoA which is converted to succinyl-CoA → citric acid cycle → oxaloacetate →*glucose This is the only mechanism by which Fatty acids are converted to glucose - 3 C units from odd chain FA are glucogenic - Cow’s milk contains significant quantity of odd chain FAs Metabolism of propionyl-CoA ‫ﻏﻴﺮ ﻣﻄﻠﻮب‬  ‫ ﻟﺠﻨﺔ اﻟﻄﺐ اﻟﺒﺸﺮي‬- ‫اﻟﻔﺮﻳﻖ اﻟﻌﻠﻤﻲ‬ Bi chem stry Lipolysis, fatty acid oxidation and ketone bodies Metabolic disorders of FA oxidation: These include deficiency of carnitine, CPT1, CPT2 and acyl CoA dehydrogenase – → impairment of FA oxidation, fasting hypoglycemia (due to decreased gluconeogenesis as well as increased uptake of glucose by muscles and heart), muscle weakness , and fatty liver, finally produce coma and death Patients with deficiency of carnitine, CPT1, or CPT2 should avoid prolonged fasting & may benefit from the ingestion of fats rich in medium chain fatty acids alpha oxidation ‫ﻣﻌﻠﻮﻣﺎﺗﺎن ﻣﻄﻠﻮﺑﺘﺎن ﺑﺎﻟﻨﺴﺒﺔ ل‬ beta ‫ ﻳﺤﺘﻞ‬methyl group ‫ ﻟﻠﻤﺮﻛﺒﺎت اﻟﺘﻲ ﺗﺤﻮي ﻋﻠﻰ‬alpha oxidation ‫ﻳﺤﺪث‬-١ phytanic acid :‫ ﻣﺜﻞ‬Beta oxidation ‫ ﻣﻤﺎ ﻳﻤﻨﻊ‬،position α-oxidation of FA ‫ﻏﻴﺮ ﻣﻄﻠﻮب‬ refsum's disease-٢ It is a minor pathway for the oxidation of FA that have methyl group in the β carbon , e.g. phytanic acid ( found in animal and milk fats) The site of oxidation is the peroxisome of brain and liver mainly α-oxidation occurs in the α- position because the β carbon is occupied by a methyl group The α carbon is oxidized and removed as CO2, now the methyl group is at the α position (no energy produced, no coA needed) and the β carbon is free to undergo β oxidation forming propionyl→CoA in the last turn  ‫ ﻟﺠﻨﺔ اﻟﻄﺐ اﻟﺒﺸﺮي‬- ‫اﻟﻔﺮﻳﻖ اﻟﻌﻠﻤﻲ‬ Bi chem stry Lipolysis, fatty acid oxidation and ketone bodies Refsum's disease: ‫ﻣﻬﻢ ﺟﺪا ﻣﻌﺮﻓﺔ اﻋﺮاض اﻟﻤﺮض وﺳﺒﺒﻪ‬ Rare autosomal recessive disorder ‫ ﻓﻲ اﻻﻣﺘﺤﺎن‬case ‫ﺳﺆال‬ Defect in alpha oxidation Due to congenital deficiency of enzyme system of α-oxidation leading to accumulation of large amounts of phytanic acid in the brain, liver and blood A– Polyneuropathy, cerebellar ataxia, deafness and blindness occur at young age Treatment: dietary restriction to halt disease progression Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum. ω-oxidation ‫ ﻫﻲ اﻟﻤﻮﺿﻮع ﻋﻠﻴﻬﺎ إﺷﺎرة‬w-oxidation ‫اﻟﻤﻌﻠﻮﻣﺎت اﻟﻤﻄﻠﻮﺑﺔ ﻣﻦ‬ It is a minor pathway for FA oxidation * Site : in the liver endoplasmic reticulum (involves cytochrome p-450) * formation The oxidation occurs at the terminal methyl group (ω carbon)→ of a dicarboxylic acid ·. d * liberating The dicarboxylic acid is oxidized from both ends by β oxidation acetyl-CoA It ends with the formation of adipic acid (C6) which is excreted in urine. It occurs to average chain length FA (10-14 C). * It produces acetyl-CoA faster.  ‫ ﻟﺠﻨﺔ اﻟﻄﺐ اﻟﺒﺸﺮي‬- ‫اﻟﻔﺮﻳﻖ اﻟﻌﻠﻤﻲ‬ Bi chem stry Lipolysis, fatty acid oxidation and ketone bodies Omega oxidation is upregulated when beta oxidation is defective as is seen with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency Introduction- ketone bodies Acetoacetate, β-hydroxyl butyrate & acetone are collectively called ketone bodies &S S O betone bodies Ketogenesis: formation of ketone bodies (occurs in liver) is Ketolysis: utilization of ketone bodies as fuel (occurs in extrahepatic tissues) Under normal conditions, production of ketone bodies is at relatively low rate Increased ketone bodies is known as ketosis while high blood level is known as ketonemia ‫ﻳﺤﺪث ﻓﻲ ﺣﺎل ﺣﺪوث ﻣﺸﻜﻠﺔ ﻓﻲ إدﺧﺎل اﻟﺠﻠﻮﻛﻮز إﻟﻰ اﻟﺨﻼﻳﺎ‬ ‫ﺳﻴﻀﻄﺮ إﻟﻰ اﻟﻨﺰول‬، ‫ ﻋﻦ ﺣﺪ ﻣﻌﻴﻦ‬KB ‫وﻓﻲ ﺣﺎل زﻳﺎدة‬ ketoneuria ‫ وﺗﺴﻤﻰ ﻫﺬه اﻟﺤﺎﻟﺔ‬،urine‫ﻓﻲ ال‬ solabla Metabolism of ketone bodies ↳ Water Fats are burned in the fire of carbohydrates Acetyl coA formed from FAs enters Krebs → oxidised only when oxaloacetate is present (oxaloacetate comes mainly from CHO)  ‫ﺑﺎﻟﺤﺎﻻت اﻟﻨﻮرﻣﺎل ال ‪ Acetyl Co A‬اﻟﻨﺎﺗﺞ ﻣﻦ ال ‪ FA Oxidation‬ﺑﯿﺘﻔﺎﻋﻞ ﻣﻊ اﻻوﻛﺴﺎﻟﻮاﺳﯿﺘﯿﺖ وﺑﺪﺧﻠﻮا اﻟﻜﺮﺑﺲ ﺳﺎﯾﻜﻞ‬ ‫ﺑﺲ ﺑﺤﺎﻻت اﻟﻤﺠﺎﻋﺔ واﻟﺴﻜﺮي اﻻﺳﯿﺘﻞ ﻛﻮ أ ﻣﺎ رح ﯾﺘﻔﺎﻋﻞ ﻣﻊ اﻻوﻛﺴﺎﻟﻮاﺳﯿﺘﯿﺖ ورح ﯾﺤﻔﺰ اﻧﺰﯾﻢ ال ‪pyruvate‬‬ ‫‪ carboxylase‬اﻟﻠﻲ ﺑﺤﻮل اﻻوﻛﺴﺎﻟﻮاﺳﯿﺘﯿﺖ ل ﺑﯿﺮوﻓﯿﺖ ورح ﯾﺜﺒﻂ ال ‪ pyruvate dehydrogenase‬وھﯿﻚ ﺑﺰﯾﺪ ﻋﻨﺎ‬ ‫ﺗﺮﻛﯿﺰ اﻟﺒﯿﺮوﻓﯿﺖ وﺑﺼﯿﺮ ﯾﺼﻨﻊ ﻏﻠﻮﻛﻮز‬ ‫‪Ketogenesis in liver‬‬ ‫واﻻﺳﯿﺘﻞ ﻛﻮ أ ﺑﺘﻔﺎﻋﻞ ﻣﻊ اﺳﯿﺘﻞ ﻛﻮ أ ﺗﺎﻧﻲ وﺑﺴﻮوا ﻛﯿﺘﻮن ﺑﻮدﯾﺰ‬ ‫‪mitochondria‬‬ ‫اول ﻛﯿﺘﻮن ﺑﻮدي‬ ‫ﺗﺎﻟﺖ ﻛﯿﺘﻮن ﺑﻮدي‬ ‫ﺗﺎﻧﻲ ﻛﯿﺘﻮن ﺑﻮدي‬  ‫ ﻟﺠﻨﺔ اﻟﻄﺐ اﻟﺒﺸﺮي‬- ‫اﻟﻔﺮﻳﻖ اﻟﻌﻠﻤﻲ‬ Bi chem stry Lipolysis, fatty acid oxidation and ketone bodies During starvation and DM, acetyl coA takes the alternate fate of formation of ketone bodies (ketogenesis) gluconeogenesis ‫ ﻓﻲ ﻋﻤﻠﻴﺔ‬oxalo-acetate ‫ﻳﺤﺪث ﺑﺴﺒﺐ اﺳﺘﻬﻼك‬ ‫ أو ﻣﺮﺿﻰ اﻟﺴﻜﺮي ﺣﻴﺚ ﻳﺤﺘﻮي ﺟﺴﻤﻬﻢ ﻋﻠﻰ ﻣﺴﺘﻮى ﻋﺎﻟﻲ ﻣﻦ اﻟﺴﻜﺮ وﻟﻜﻦ ﺑﺴﺒﺐ وﺟﻮد ﻧﻘﺺ ﻓﻲ اﻻﻧﺴﻮﻟﻴﻦ أو ﻣﻘﺎوﻣﺔ‬،‫ﺗﺤﺪث ﻓﻲ ﺣﺎﻻت اﻟﻤﺠﺎﻋﺔ‬ ‫ ﺗﺒﺤﺚ اﻷﻧﺴﺠﺔ ﻋﻦ ﻣﺼﺪر آﺧﺮ ﻟﻠﻐﺬاء‬، ‫اﻷﻧﺴﻮﻟﻴﻦ‬ – This allows heart and skeletal muscle (to some extent, increased use in fasting) to use ketone bodies (ketolysis) as major source of energy → preserving limited glucose supply for brain -A can't penetrate B B B.. Even brain use ketone bodies as source of food after long periods of starvation,to let what's left from glucose to RBCS (can't burn anything except glucose) Ketone bodies are water soluble – Transported across inner mitochondrial membrane, blood brain barrier and cell membranes » Used as fuel for a variety of tissues including CNS » Preferred substrates for aerobic heart and muscles (to some extent, Muscles can burn fatty acids and glucose, and sometimes increased use in fasting) they prefer to burn FA especially during aerobic exercise * : ‫ﻓﻲ ﺣﺎل ﻃﻠﺐ ﻣﻨﺎ ﺷﺨﺺ ﺑﺮﻧﺎﻣﺞ ﻟﺨﺴﺎرة اﻟﻮزن ﻧﻨﺼﺤﻪ ب‬ ‫ﺻﻮم أول ﻓﺘﺮة ﻟﻔﺘﺮات ﻃﻮﻳﻠﺔ ﺣﺘﻰ ﻳﻈﻬﺮ ﻋﻠﻴﻪ ﺧﺴﺎرة اﻟﻮزن ﻓﻲ اﻟﺒﺪاﻳﺔ‬-١ Ketogenesis FA and ketone bodies ‫ ﺣﺘﻰ ﺗﺴﺘﻬﻠﻚ‬aerobic exercise ‫وﺑﻌﺪ ذﻟﻚ اﻟﺒﺪء ﺑﻌﻤﻞ‬-٢ Acetoacetate is primary ketone body ‫ﻣﻬﻢ اﻟﻤﻜﺎن‬ COA Aceloacetyl Synthesised exclusively in liver synthase mitochondria CoA HMG Synthase ‫ إﻟﻰ اﻟﻤﺮﻛﺐ رﺑﺎﻋﻲ اﻟﻜﺮﺑﻮن‬acetyl COA ‫إﺿﺎﻓﺔ‬ 4 Steps: Beta carbon O – Condensation Beta carbon binds with methyl group and hydroxy group HMG COA lyase – Production of HMG coA – Lysis – Reduction ketone body ‫ اﻫﻢ‬acetoacetate ‫ﻳﻌﺘﺒﺮ‬ – Spontaneous decarboxylation - S : gluconeogenesis : Is D H.. HMG coA synthase is rate limiting step in synthesis of ketone bodies and is present in significant quantities only in liver ‫ﻣﻬﻢ ﻣﻌﺮﻓﺔ اﻟﺘﻔﺎﻋﻼت اﻟﺘﻲ ﺗﺤﻔﺰﻫﺎ ﻫﺬه اﻻﻧﺰﻳﻤﺎت‬ - ‫وﻣﻌﺮﻓﺔ أن ﻣﻜﺎﻧﻬﻢ داﺧﻞ اﻟﻤﻴﺘﻮﻛﻨﺪرﻳﺎ‬  ‫ ﻟﺠﻨﺔ اﻟﻄﺐ اﻟﺒﺸﺮي‬- ‫اﻟﻔﺮﻳﻖ اﻟﻌﻠﻤﻲ‬ Bi chem stry Lipolysis, fatty acid oxidation and ketone bodies Ketolysis NADH ‫اﻧﺘﺠﻨﺎ ﺑﻄﺎرﻳﺔ‬ Ketone bodies are formed in liver but utilized in extrahepatic tissues Heart muscle, renal cortex sometimes prefer ketone - X * bodies to glucose as fuel Muscle can also utilize ketone bodies 1-muscles can use glucose, ketone ً B- ‫ ﻣﻦ‬ketolysis ‫داﺋﻤﺎ اﻻﻓﻀﻞ ﺑﺪاﻳﺔ‬ bodies and Fatty acids ‫ ﺣﺘﻰ ﻳﺘﻢ‬acetoacetate ‫ إﻟﻰ‬hydroxybutrate NADH ‫إﻧﺘﺎج ﺑﻄﺎرﻳﺔ‬ 2-brain essentially use glucose,but at the time of long periods of 2acetyl CoA ‫ﻓﻲ اﻟﻨﻬﺎﻳﺔ ﻳﺘﻢ إﻧﺘﺎج‬ starvation ,it can use ketone bodies 3-RBCS only use glucose Fate of ketone bodies Ketosis Causes sensitive lipase Hormone – Uncontrolled DM: most common cause of ketosis- » Glucose is plenty but deficiency of insulin → accelerated lipolysis → increased ‫أﻣﺎ ﺑﺴﺒﺐ وﺟﻮد ﻧﻘﺺ ﻓﻲ اﻻﻧﺴﻮﻟﻴﻦ أو ﺑﺴﺒﺐ ﻣﻘﺎوﻣﺔ اﻷﻧﺴﻮﻟﻴﻦ‬ acetyl CoA ‫وﻓﻲ اﻟﻨﻬﺎﻳﺔ ﺗﺬﻫﺐ اﻟﻜﻤﻴﺔ اﻟﻜﺒﻴﺮة ﻣﻦ‬ acetyl coA ketone bodies ‫ﻧﺎﺣﻴﺔ ﺗﺼﻨﻴﻊ‬ Enhanced gluconeogenesis restricts oxidation of acetyl coA in TCA as there is less oxaloacetate - > used to make glucose – Starvation: dietary supply of glucose reduced → oxaloacetate channelled to gluconeogenesis, increased lipolysis to provide fuel, excess acetyl coA converted to ketone bodies Hyperemesis in pregnancy may also lead to starvation like condition → ketosis ‫اﻟﻘﻲء اﻟﻤﻔﺮط أﺛﻨﺎء اﻟﺤﻤﻞ‬  ‫ ﻟﺠﻨﺔ اﻟﻄﺐ اﻟﺒﺸﺮي‬- ‫اﻟﻔﺮﻳﻖ اﻟﻌﻠﻤﻲ‬ Bi chem stry Lipolysis, fatty acid oxidation and ketone bodies Explanation of ketogenesis – Starvation and DM: glucagon is increased → Inhibits glycolysis Activates gluconeogenesis Insulin has opposite effect Activates lipolysis Decreases malonyl coA Stimulates ketogensis (high glucagon/ insulin ratio is ketogenic) ‫ﻣﻬﻢ‬ # ‫ ﻟﺸﺨﺺ‬management ‫اول ﺧﻄﻮة ﻟﻌﻤﻞ‬ ‫ ﻫﻲ إﻋﻄﺎءه‬ketoacidosis ‫داﺧﻞ ﻋﻠﻰ‬ 5 ‫ﻣﻤﺎ ﻳﻘﻠﻞ ﻣﻦ ﻣﺴﺘﻮى اﻟﺴﻜﺮ ﻓﻲ اﻟﺪم‬، fluids ‫وﻓﻲ ﺑﻌﺾ اﻟﺤﺎﻻت‬،‫وﺗﺤﺴﻦ ﻣﻦ وﺿﻊ اﻟﻤﺮﻳﺾ‬ fluids is ‫ﻧﻀﻄﺮ إﻟﻰ إﻋﻄﺎء اﻧﺴﻮﻟﻴﻦ وﻟﻜﻦ‬ the most important