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FATTY ACID OXIDATION

Yıldırım Beyazıt University Medical Faculty Biochemistry Department. FATTY ACID OXIDATION. Prof. Dr. Fatma Meriç YILMAZ fatmamericyilmaz @ hotmail .com. A Real Story.

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FATTY ACID OXIDATION

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  1. Yıldırım Beyazıt University Medical Faculty Biochemistry Department FATTY ACID OXIDATION Prof. Dr. Fatma Meriç YILMAZ fatmamericyilmaz@hotmail.com

  2. A Real Story

  3. Alexis had no previous symptoms or serious problems, and there was no reason for her family to think she has an important illness • She led a normal, active life as a second grader at Southeast Elementary School. • She took gymnastics and played soccer and softball. A Real Story

  4. Alexis stayed home from school on March 6 with the flu. • The next morning she was found in her bed, unconscious and unresponsive. • Her family took her by ambulance to the ICU at Children's Mercy Hospital, her condition continued to worsen. A Real Story

  5. She was having seizures in her brain, which was collecting fluid and continuing to swell. Her blood pressure dropped and her heart raced. There were problems with her liver and kidneys. • She didn't move. She didn't talk. She didn't cry. She didn't wake up. • The doctors had no answers. They pumped antibiotics into her system. They did everything they knew how to do however she died in a few days. • Afterwards it was understood that she had a genetic disorder which affected the oxidation of fatty acids A Real Story

  6. About one third of our energy needs comes from dietary triacylglycerols • About 80% of energy needs of mammalian heart and liver are met by oxidation of fatty acids • Efficient storage, better for slow, steady burn Oxidation of Fatty Acids is a Major Energy-Producing Pathway

  7. Fats Provide Efficient Fuel Storage • The advantage of lipids over carbohydrates • Fatty acid carry more energy per carbon because they are more reduced • Fatty acids carry less water along because they are nonpolar • Glucose and glycogen are for short-term energy needs, quick delivery • Fats are for long term (months) energy needs, good storage, slow delivery

  8. Problemsto be solvedbeforefattyacidoxidationBegins • Fatty acids are stored as parts of tryglicerides, and are bound to a glycerol molecule • Fatty acids have to be transported from fat tissue to target tissues like muscle, kidney etc. • After taken up by the target tissue they have to enter to the mitochondria because beta oxidation takes place in the mitochondria

  9. Solution • hormones trigger lipolysis in adipose tissue • epinephrine, glucagon • insulin inhibits lipolysis • Hormone sensitive lipase hydrolise trygliceride to free fatty acids and glycerol • Glycerol enters to the glycolysis or gluconeogenesis; fatty acids are released to the bloodstream to be transported to the target tissue. Problem 1: Hydrolysis of TrygliceridesintoFreeFattyAcidsandGlycerol

  10. Epinephrine : • “low energy” • Glucagon: • “low glucose” Hormones Trigger Mobilization of Stored Triacylglycerols

  11. Activation of TriacylglycerolLipase Freefattyacidsarereleasedtothebloodstream

  12. What happens to the glycerol released? • Converted to glyceraldehyde-3-PO4 • glycolysis • Gluconeogenesis

  13. What happens to the glycerol released? • Glycerol kinase activates glycerol at the expense of ATP • Subsequent reactions recover more than enough ATP to cover this cost

  14. Problem 2: Howarefreeacidstransported in thebloodstream? • Fatty acids are hydrophobic molecules which are unsoluble in water • Free fatty acids released from fat tissue to the bloodstream are transported with albumin

  15. Problem 3: FattyAcidOxidatontakesplace in theMitochondria • Smallandmediumchain (< 12 carbons) fatty acids diffuse freely across mitochondrial membranes • What must happen forlongchainfatty acids to be oxidized? • activated • transported into mitocondria

  16. A. Activation of LongChainFattyAcidsAfter a LCFA enterstothecell, it is converted in thecytosoltoitsCoAderivativeEnzyme is long-chainfattyacylCoAsynthetaseTheresult is FattyAcyl-CoATwo ATP is usedforthisactivation

  17. B. Fatty Acid Transport into Mitochondria Acyl-carnitine / CarnitineTransport: • Acylgroup is transferredfromCoAtocarnitinebycarnitineacyltransferase I (CAT I) to form acylcarnitineandfreeCoA • Acylcarnitine is transportedintothemitochondrialmatrixbytranslocasetransporter • Carnitineacyltransferase II (CAT II) formsAcylCoA in themitochondrialmatrix

  18. B. Fatty Acid Transport into Mitochondria Acyl-carnitine / CarnitineTransport: • Acylcarnitinegivesacylgroupandturnsbacktofreecarnitine form • Freecarnitine is changedwithacylcarnitinethroughtranslocase; andmovestothecytoplasmtobind a newacylgroup • MalonylCoAwhich is an intermediate in fattyacidsynthesisinhibits CAT I andpreventstheentry of longchainfattyacidsintomitochondria

  19. O α H e- e- e- e- H β H O H α H NADH FADH2 CoA β H CoA Beta Oxidation of FattyAcids Beta Oxidation converts fatty acids into several molecules of Acetyl CoA

  20. Stage 1 consists of oxidative conversion of two-carbon units into acetyl-CoA with generation of NADH and FADH2 • Stage 2 involves oxidation of acetyl-CoA into CO2 via citric acid cycle with generation NADH and FADH2 • Stage 3 generates ATP from NADH and FADH2 via the respiratory chain Stages of Fatty Acid Oxidation

  21. Each pass removes one acetyl moiety in the form of acetyl-CoA • Includes four reactions Stage 1- ReactionSequence

  22. Reaction 1- Dehydrogenation of AcylCoA • First step is an oxidation • Produces a double bond, Enoyl CoA • Catalyzed by isoforms of acyl-CoA dehydrogenase (AD) on the inner mitochondrial membrane • Long-chain AD (12-18carbons) • Medium-chain AD (4-14 carbons) • Short-chain AD (4-8 carbons)

  23. Medium chain acyl coenzyme A dehydrogenase (MCAD) deficiency is assumed to be the most common inherited disorder of fatty acid oxidation. • In the classic clinical presentation, fasting precipitates acute symptoms in early infancy or childhood, mostly in combination with an increased energy need during simple infections. • Patients develop drowsiness or lethargy, which may proceed into coma or even sudden death. • Biochemically, the disease is characterized by a hypoketotic hypoglycaemia and specific metabolites can be detected in plasma and urine. MCADD

  24. Reaction2 Hydration of EnoylCoA • Second step is a hydration • Catalyzed by enoyl CoA hydratase • Removes the double bond and adds an OH group • The result is a hydroxyacyl CoA

  25. Reaction 3- Dehydrogenation of Alcohol • Third step is a second oxidation • Catalyzed by L-3-hydroxyacyl CoA dehydrogenase • Produces Ketoacyl CoA and now the fatty acid is ready for cleavage

  26. Reaction 4- Formation of AcetylCoA • Last step is cleavage of 3-ketoacyl CoA by thiol group of CoA • Fatty acid molecule is shortened by 2 carbons • Acetyl CoA formed

  27. Repeating the four-step process six more times results in the complete oxidation of palmitic acid into eight molecules of acetyl-CoA • FADH2 is formed in each cycle • NADH is formed in each cycle • Acetyl-CoA enters citric acid cycle and is further oxidizes into CO2 • This makes more GTP, NADH and FADH2 Fatty Acid Catabolism for Energy

  28. What are the products of fatty acid degradation? • For a C16 fatty acid • 8 acetyl CoA = Carbon number/2 • 7 FADH2= (Carbon number/2)-1 • 7NADH + 7 H+ = (Carbon number/2)-1 • How much energy does this generate? • 7 x 1.5 ATP = 10.5 • 7 x 2.5 ATP = 17.5 • 8 x 10 ATP = 80 • Total = 108 ATP – 2 ATP (activation) = 106 ATP Fatty Acid Catabolism for Energy

  29. NADH and FADH2 Serve as Sources of ATP

  30. Oxidation of unsaturated fatty acids provides less energy because they are less reduced than saturated fatty acids • Unsaturated fatty acids require additional steps for degradation • isomerization • shifts position and configuration of a double bond • reduction • needed to remove double bond in wrong position Oxidation of Unsaturated Fatty Acids

  31. Oxidation of Unsaturated Fatty Acids

  32. VLCFAs which include 22 carbons or more,undergo a preliminary β oxidation in peroxisomes • The shortened fatty acid diffuses to a mitochondrion for further oxidation • The initial dehydrogenation in peroxisomes is catalysed by a FAD-containing acyl CoA oxidase • Produced FADH2 is oxidized by moleculer oxygen with the production of hydrogen peroxide which is then detoxified with catalase • No ATP is produced in the peroxisomes. Oxidation of VLCFA in Peroxisomes

  33. Genetic defects, lead to accumulation of VLCFA in the blood and tissues and this accumulation causes serious neurological defects • Zellweger Syndrome is a peroxisomal biogenesis disorder • X-linked Adrenoleukodistrophy is a problem about the ability to transport VLCAFs through peroxisomal membrane DisordersAboutOxidation of VLCFAs

  34. Lorenzo's Oil is an American drama. • It is based on the true story of two parents in a relentless search for a cure for their son Lorenzo's adrenoleukodystrophy (ALD). • They finally find a therapy involving adding a certain kind of oil (actually containing two specific long chain fatty acids, isolated from canola oil and olive oil) to their son's diet. Lorenzo’sOil

  35. Most dietary fatty acids are even-numbered • Many plants and some marine organisms also synthesize odd-numbered fatty acids • The last cyle in the oxidation of odd chained fatty acids gives one acetyl CoA and one Propiony CoA which includes 3 carbons Oxidation ofFattyAcidswith an oddNumber of Carbons

  36. Oxidation of Propionyl-CoA • Proprionyl CoA is metabolized by a three-step pathway • First, propionyl CoA is carboxylated to form D-methylmalonyl CoA • D-methylmalonyl CoA is isomerised to L form • Finally carbons of L-MMA CoA are rearranged to form Succinyl CoA

  37. Ifthere is a Vitamin B12 deficiency MMA increases • MMA levelsareused in thediagnosis of Vitamin B12 deficiency Intramolecular Rearrangement in Propionate Oxidation Requires CyanoCobalamine: Coenzyme B12

  38. Summary • Fats are an important energy source in animals • Two-carbon units in fatty acids are oxidized in a four-step -oxidation process into acetyl-CoA • In the process, lots of NADH and FADH2 forms; these can yield lots of ATP in the electron-transport chain • Acetyl-CoA formed in the liver can be either oxidized via the citric acid cycle or converted to ketone bodies that serve as fuels for other tissues

  39. KEEPON STUDYING

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