Fatty Acid Metabolism

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Fatty Acid Metabolism
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Free Energy of Oxidation of Carbon Compounds
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Metabolic Motifs
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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

• Triacylglycerols are concentrated energy stores
• Utilization of FAs in 3 stages of processing
  (TAG -gt 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

An adipocyte cell stores triacylglycerols in the
cytoplasm
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Utilization of Fatty Acids requires 3 Stages of
Processing

1. Lipids (Triacylglycerols) are mobilizes -gt broken
   down to fatty acids glycerol
2. Fatty acids activated and transported into
   mitochondria
3. Fatty acids are broken down to acetyl-CoA -gt
   citric acid cycle

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Dietary Lipids are Broken Down by Pancreatic
Lipase and Transported through the Lymph System
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Dietary Lipids are Broken Down by Pancreatic
Lipase and Transported through the Lymph System
Packed together with Apoprotein B-48 -gtto 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 -gt Insulin inhibits
lipolysis Protein Kinase A phosphorylates
(activates) -gt Perilipin HS lipase Perilipin
(fat droplet associated protein) -gt restructures
fat to make it more accessible for lipase Free
fatty acids and glycerol are released into the
blood stream -gt bound by serum albumin -gt serves
as carrier in blood
Muscle cells
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Glycerol can be converted to Pyruvate or Glucose
in the Liver !!! Conversion of Glucose -gt
Glycerol possible !!!
Intermediates in Glycolysis ands Glyconeogensesis
Convertion of Glucose -gt Acetyl-CoA -gt Fatty
acid -gt Fat possible !!! Convertion of Fat -gt
fatty acids -gt Acety-CoA -gt Glucose impossible !!!
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1. Fatty Acid Activation - Fatty Acid Degradation
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2. Transport of Fatty Acids into the Mitochondria
Symptoms for deficiency of carnitine mild
muscle cramping -gt weakness -gt death
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Fatty Acid Oxidation (ß-Oxidation Pathway) in the
Mitochondria

• 4 Steps in one round
• Oxidation -gt introduction of double bond between
  a-ß carbon, generation of FADH2
• Hydration of double bound
• Oxidation of hydroxy (OH) group in ß- position,
  generation of NADH
• Thiolysis -gt cleavage of 2 C units (acetyl CoA)

Other oxidations -gt ?-Oxidation in the
endoplasmatic rediculum of liver and kidney
many C-10 to C-12 carbons,
normally not the main
oxidation pathway -gt if problems with
ß-oxidation -gt a-Oxidation in peroxisomes on
branched FA (branch on ß-carbon)
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Fatty Acid Oxidation (ß-Oxidation Pathway) in the
Mitochondria

• Acyl CoA Dehydrogenase
• chain-length specific
• FA with C-12 to C-18 -gt long-chain isozyme
• FA with C-14 to C-4 -gt medium-chain isozyme
• FA with C-4 and C-6 -gt short-chain isozyme

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First 3 Rounds in Degradation of Palmitate (C-16)
Complete oxidation of Palmitate -gt 106
ATP Complete oxidation of Glucose -gt 30 ATP
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Fatty Acid Oxidation in Peroxisomes
Peroxisome in liver cell
Fatty acid oxidation stops at Octanyl-CoA (C-8)
-gt may serve to shorten long chain to make them
better suitable for ß-Oxidation in
mitochondria In Peroxisomes Flavoprotein Acyl
CoA dehydrogenase transfers electrons (not FADH2)
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Fatty Acid Oxidation in Peroxisomes
Catalase
regeneration in cytosol
Acetyl-CoA produced in the peroxisomes -gt used as
precursors and not for energy consumption
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Enzymes of ß-oxidation
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Oxidation of Monounsaturated FA and FA with
odd-numbered double bonds
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Oxidation of Polyunsaturated Fatty Acids
- 1 acetyl CoA
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Oxidation of Odd-Chain Fatty Acids -gt Propionyl
CoA
In lipids from many plants and marine organisms
Reaction requires Vitamin B12 (Cobalamin)
Citric acid cycle
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Oxidation of Odd-Chain Fatty Acids -gt Propionyl
CoA
Vitamin B12 Animals and plants cannot produce
B12 -gt produced by a few species of bacteria
living in the intestine Deficiency-gt failure to
absorb vitamine (not enough of the protein that
facilitates uptake) -gt reduced red blood cells,
reduced level of hemoglobin, impairment of
central nervous system
Reaction requires Vitamin B12 (Cobalamin)
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Ketone Bodies
Acetyl-CoA
Keton Bodies
- 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)
-gt just if enough Oxaloacetat present !!!
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Why do we form Ketone Bodies?

• Acetyl-CoA (from ß-oxidation) enters citric acid
  cycle ONLY IF enough oxaloacetate is available
• Oxaloacetate is formed (refill of citric acid
  cycle) by pyruvate (glucolysis)
• -gt Only if Carbohydrate degradation is balanced
  -gt Acetyl Co-A from ß-oxidation enters citric
  acid cycle !!!!
• -gt If not balanced -gt Keton bodies are formed!!!
• Consequence
• Diabetics and if you are on a diet -gt
  oxaloacetate is used to form glucose
  (gluconeogenesis) -gt Acetyl-CoA (from
  ß-oxidation) is converted into Ketone bodies !!
• Animals and humans are not able to convert fatty
  acids -gt glucose !!!!!
• Plant can do that conversion -gt Glyoxylate cycle
  (Acetyl Co-A -gt Oxaloacetate)

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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 -gt decrease rate of
lipolysis in adipose tissue.
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Diabetes Insulin Deficiency

• Diabetes
• Absence of Insulin -gt
• Liver cannot absorb Glucose -gt cannot provide
  oxaloacetate to process FA
• No inhibition of mobilization of FA from adipose
  tissue
• -gt Large amount of Keton bodies produced -gt
  drop in pH -gt disturbs function in central
  nervous system!!!

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Fatty Acids are Synthesized and Degraded by
Different Pathways
Degradation (ß-Oxidation)
Synthesis

• In the mitochondria matrix
• Intermediates are linked to CoA
• No linkage of the enzymes involved
• The oxidants are NAD and FAD
• Degradation by C2 units -gt 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 -gt 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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Transport of Acetyl-CoA from the Mitochondria-gt
Cytosol
FA synthesis
Glycolysis
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Activation of Acetyl and Malonyl in Synthesis
reactive unit
Activation for Synthesis
Activation for Degradation
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1st step in Fatty Acid Synthesis Formation of
Malonyl-CoA
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Fatty Acid Synthesis
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Synthesis by Multifunctional Enzyme Complex in
Eukaryotes -gt Synthase
In animals a dimer each 3 domains with 7
activities

• Inhibitors
• Antitumor drugs (synthase overexpressed in some
  breast cancers)
• Antiobesity drugs

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Fatty Acid Synthesis -gt Pathway Integration
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Regulation of Fatty Acid Synthesis
Acetyl Co-A -------gt Malonyl Co-A
Carboxylase (key enzyme)
Global regulation
Local regulation
Allosteric stimulation by citrate
Glucagon inhibits
Insulin activates enzyme
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Pathway Integration
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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 -gt Hormones
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Localization of Lipid Metabolism
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Eicosanoides
Aspirin Ibuprofen block enzyme
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Aspirin acetylates enzyme
Inhibits enzyme by mimicking substrate or
intermediate
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Eicosanoid Hormones local hormones
Leukotrienes (found in leukocytes) Allergic
reaction -gt body (immune system) releases
chemicals such as histamine and leukotrines -gt
cause flushing, itching, hives, swelling,
wheezing and loss of blood pressure Prostaglandin
s stimulate inflammation, regulate blood flow to
organs, control ion transport through membranes,
induce sleep