1 Fatty Acid Metabolism
Dec 22, 2015
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Naming of Fatty Acids
- Fatty acids differ in length and degree of saturation (number of double bonds)
- Double bonds can be in cis or trans
- in biological system double bonds are generally in cis conformation
- Fatty acids are ionized at physiological pH
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Fatty Acid Metabolism
An adipocyte cell stores triacylglycerols in the cytoplasm
- Triacylglycerols are concentrated energy stores
- Utilization of FAs in 3 stages of processing (TAG -> FA; transport of FA; degradation of FA)
- certain FAs require additional steps for degradation (unsaturated FA, odd-chain FA)
- FA synthesis and degradation done by different pathways
- Acetyl-CoA Carboxylase plays key role in controlling FA metabolism
- Elongation and saturation of FAs are done by additional enzymes
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Utilization of Fatty Acids requires 3 Stages of Processing:
1. Lipids (Triacylglycerols) are mobilizes -> broken down to fatty acids + glycerol
2. Fatty acids activated and transported into mitochondria
3. Fatty acids are broken down to acetyl-CoA -> citric acid cycle
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Dietary Lipids are Broken Down by Pancreatic Lipase and Transported through the Lymph System
Packed together with Apoprotein B-48 ->to give Chylomicrons (180-500 nm in diameter)
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Mobilisation of Triacylglycerols That are Stored in Adipocyte Cells
Lipolysis inducing hormones: Epinephrine, glucagon (low blood glucose level), adrenocorticotropic homones -> Insulin inhibits lipolysis
Protein Kinase A phosphorylates (activates) -> Perilipin + HS lipase
Perilipin (fat droplet associated protein) -> restructures fat to make it more accessible for lipase
Free fatty acids and glycerol are released into the blood stream -> bound by serum albumin -> serves as carrier in blood
Muscle cells
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Intermediates in Glycolysis ands Glyconeogensesis
Glycerol can be converted to Pyruvate or Glucose in the Liver !!!
Conversion of: Glucose -> Glycerol possible !!!
Convertion of: Glucose -> Acetyl-CoA -> Fatty acid -> Fat possible !!!Convertion of: Fat -> fatty acids -> Acety-CoA -> Glucose impossible !!!
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2. Transport of Fatty Acids into the Mitochondria
Symptoms for deficiency of carnitine: mild muscle cramping -> weakness -> death
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Fatty Acid Oxidation (β-Oxidation Pathway) in the Mitochondria
4 Steps in one round:
1. Oxidation -> introduction of double bond between α-β carbon, generation of FADH2
2. Hydration of double bound
3. Oxidation of hydroxy (OH) group in β- position, generation of NADH
4. Thiolysis -> cleavage of 2 C units (acetyl CoA)
Other oxidations:
-> ω-Oxidation: in the endoplasmatic rediculum of liver and kidney many C-10 to C-12 carbons, normally not the main oxidation pathway -> if problems with β-oxidation
-> α-Oxidation: in peroxisomes on branched FA (branch on β-carbon)
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Fatty Acid Oxidation (β-Oxidation Pathway) in the Mitochondria
Acyl CoA Dehydrogenase:
- chain-length specific
- FA with C-12 to C-18 -> long-chain isozyme
- FA with C-14 to C-4 -> medium-chain isozyme
- FA with C-4 and C-6 -> short-chain isozyme
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First 3 Rounds in Degradation of Palmitate (C-16):
Complete oxidation of Palmitate -> 106 ATP
Complete oxidation of Glucose -> 30 ATP
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Fatty Acid Oxidation in Peroxisomes
Peroxisome in liver cell
Fatty acid oxidation stops at Octanyl-CoA (C-8) -> may serve to shorten long chain to make them better suitable for β-Oxidation in mitochondria
In Peroxisomes: Flavoprotein Acyl CoA dehydrogenase transfers electrons (not FADH2)
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Fatty Acid Oxidation in Peroxisomes
Acetyl-CoA produced in the peroxisomes -> used as precursors and not for energy consumption
Catalase
regeneration in cytosol
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Oxidation of Odd-Chain Fatty Acids -> Propionyl CoA
Citric acid cycleReaction requires Vitamin B12 (Cobalamin)
In lipids from many plants and marine organisms
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Oxidation of Odd-Chain Fatty Acids -> Propionyl CoA
Reaction requires Vitamin B12 (Cobalamin)
Vitamin B12 :Animals and plants cannot produce B12 -> produced by a few species of bacteria living in the intestineDeficiency-> failure to absorb vitamine (not enough of the protein that facilitates uptake) -> reduced red blood cells, reduced level of hemoglobin, impairment of central nervous system
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Ketone Bodies
Keton Bodies
Acetyl-CoA
- Ketone bodies are formed in the liver from acetyl-CoA
- Keton bodies are an important source of energy
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Utilization of Ketone Bodies as Energy Source
Citric acid cycle (Oxaloacetat)
Can be used as energy source (broken down in ATP) -> just if enough Oxaloacetat present !!!
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• Acetyl-CoA (from β-oxidation) enters citric acid cycle ONLY IF enough oxaloacetate is available
• Oxaloacetate is formed (refill of citric acid cycle) by pyruvate (glucolysis)
-> Only if Carbohydrate degradation is balanced -> Acetyl Co-A from β-oxidation enters citric acid cycle !!!!
-> If not balanced -> Keton bodies are formed!!!
Consequence:
• Diabetics and if you are on a diet -> oxaloacetate is used to form glucose (gluconeogenesis) -> Acetyl-CoA (from β-oxidation) is converted into Ketone bodies !!
• Animals and humans are not able to convert fatty acids -> glucose !!!!!
• Plant can do that conversion -> Glyoxylate cycle (Acetyl Co-A -> Oxaloacetate)
Why do we form Ketone Bodies?
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Heart muscle uses preferable acetoacetate as energy source
The brain prefers glucose, but can adapt to the use of acetoacetate
during starvation and diabetes.
High level of acetoacetate in blood -> decrease rate of lipolysis in adipose tissue.
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Diabetes – Insulin Deficiency
Diabetes:
Absence of Insulin ->
1. Liver cannot absorb Glucose -> cannot provide oxaloacetate to process FA
2. No inhibition of mobilization of FA from adipose tissue
-> Large amount of Keton bodies produced -> drop in pH -> disturbs function in central nervous system!!!
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Fatty Acids are Synthesized and Degraded by Different Pathways
Degradation (β-Oxidation)
Synthesis
1. In the mitochondria matrix
2. Intermediates are linked to CoA
3. No linkage of the enzymes involved
4. The oxidants are NAD+ and FAD
5. Degradation by C2 units -> Acetyl-CoA
1. In the cytosol
2. Intermediates are linked to an Acyl carrier protein (ACP) complex
3. Enzymes are joined in one polypeptide chain -> FA synthase
4. The reductant is NADPH
5. Elongation by addition of malonyl ACP + release of CO2
6. Synthesis stops at palmitate (C16), additional enzymes necessary for further elongation
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Activation of Acetyl and Malonyl in Synthesis
Activation for Synthesis Activation for Degradation
reactive unit
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Synthesis by Multifunctional Enzyme Complex in Eukaryotes -> Synthase
Inhibitors:
- Antitumor drugs (synthase overexpressed in some breast cancers)
- Antiobesity drugs
In animals: a dimer – each 3 domains with 7 activities
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Regulation of Fatty Acid Synthesis
Acetyl Co-A -------> Malonyl Co-A
Carboxylase (key enzyme)
Insulin activates enzyme
Glucagon inhibits
Global regulation Local regulation
Allosteric stimulation by citrate
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Introduction of Double Bonds to Fatty Acids
Precursors used to generate longer unsaturated FA
Essential FA
Mammals cannot introduce double bonds beyond C-9
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Desaturation and Elongation of FA
Essential FA
Mammals cannot introduce double bonds beyond C-9
Eicosanoides -> Hormones
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Eicosanoid Hormones – local hormones
Leukotrienes (found in leukocytes): Allergic reaction -> body (immune system) releases chemicals such as histamine and leukotrines -> cause flushing, itching, hives, swelling, wheezing and loss of blood pressure
Prostaglandins: stimulate inflammation, regulate blood flow to organs, control ion transport through membranes, induce sleep