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Fatty Acid Metabolism

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

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slide4

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
slide6

Fatty Acid Metabolism

  • 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

An adipocyte cell stores triacylglycerols in the cytoplasm

slide8

Utilization of Fatty Acids requires 3 Stages of Processing:

  • Lipids (Triacylglycerols) are mobilizes -> broken down to fatty acids + glycerol
  • Fatty acids activated and transported into mitochondria
  • Fatty acids are broken down to acetyl-CoA -> citric acid cycle
slide10

Dietary Lipids are Broken Down by Pancreatic Lipase and Transported through the LymphSystem

Packed together with Apoprotein B-48 ->to give Chylomicrons (180-500 nm in diameter)

slide11

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

slide12

Glycerol can be converted to Pyruvate or Glucose in the Liver !!!

Conversion of: Glucose -> Glycerol possible !!!

Intermediates in Glycolysis ands Glyconeogensesis

Convertion of: Glucose -> Acetyl-CoA -> Fatty acid -> Fatpossible !!!

Convertion of: Fat -> fatty acids -> Acety-CoA -> Glucoseimpossible !!!

slide14

2. Transport of Fatty Acids into the Mitochondria

Symptoms for deficiency of carnitine: mild muscle cramping -> weakness -> death

slide15

Fatty Acid Oxidation (β-Oxidation Pathway) in the Mitochondria

  • 4 Steps in one round:
  • Oxidation -> introduction of double bond between α-β carbon, generation of FADH2
  • Hydration of double bound
  • Oxidation of hydroxy (OH) group in β- position, generation of NADH
  • 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)

slide16

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
slide17

First 3 Rounds in Degradation of Palmitate (C-16):

Complete oxidation of Palmitate -> 106 ATP

Complete oxidation of Glucose -> 30 ATP

slide18

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)

slide19

Fatty Acid Oxidation in Peroxisomes

Catalase

regeneration in cytosol

Acetyl-CoA produced in the peroxisomes -> used as precursors and not for energy consumption

slide23

Oxidation of Odd-Chain Fatty Acids -> Propionyl CoA

In lipids from many plants and marine organisms

Reaction requires Vitamin B12 (Cobalamin)

Citric acid cycle

slide24

Oxidation of Odd-Chain Fatty Acids -> Propionyl CoA

Vitamin B12 :

Animals and plants cannot produce B12 -> produced by a few species of bacteria living in the intestine

Deficiency-> 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

Reaction requires Vitamin B12 (Cobalamin)

slide25

Ketone Bodies

Acetyl-CoA

Keton Bodies

- Ketone bodies are formed in the liver from acetyl-CoA

- Keton bodies are an important source of energy

slide26

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 !!!

slide27

Why do we form Ketone Bodies?

  • 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)
slide28

Heart muscle uses preferable acetoacetate as energy source

The brain prefers glucose, but can adapt to the use of acetoacetate duringstarvation and diabetes.

High level of acetoacetate in blood -> decrease rate of lipolysis in adipose tissue.

slide29

Diabetes – Insulin Deficiency

  • Diabetes:
  • Absence of Insulin ->
  • Liver cannot absorb Glucose -> cannot provide oxaloacetate to process FA
  • No inhibition of mobilization of FA from adipose tissue
  • -> Large amount of Keton bodies produced -> drop in pH -> disturbs function in central nervous system!!!
slide30

Fatty Acids are Synthesized and Degraded by Different Pathways

Degradation (β-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 -> Acetyl-CoA
  • In the cytosol
  • Intermediates are linked to an Acyl carrier protein (ACP) complex
  • Enzymes are joined in one polypeptide chain -> FA synthase
  • The reductant is NADPH
  • Elongation by addition of malonyl ACP + release of CO2
  • Synthesis stops at palmitate (C16), additional enzymes necessary for further elongation
slide32

Activation of Acetyl and Malonyl in Synthesis

reactive unit

Activation for Synthesis

Activation for Degradation

slide35

Synthesis by Multifunctional Enzyme Complex in Eukaryotes -> Synthase

In animals: a dimer – each 3 domains with 7 activities

  • Inhibitors:
  • Antitumor drugs (synthase overexpressed in some breast cancers)
  • Antiobesity drugs
slide37

Regulation of Fatty Acid Synthesis

Acetyl Co-A -------> Malonyl Co-A

Carboxylase (key enzyme)

Global regulation

Local regulation

Allosteric stimulation by citrate

Glucagon inhibits

Insulin activates enzyme

slide39

Introduction of Double Bonds to Fatty Acids

Precursors used to generate longer unsaturated FA

Essential FA

Mammals cannot introduce double bonds beyond C-9

slide40

Desaturation and Elongation of FA

Essential FA

Mammals cannot introduce double bonds beyond C-9

Eicosanoides -> Hormones

slide42

Eicosanoides

Aspirin + Ibuprofen block enzyme

slide43

Aspirin acetylates enzyme

Inhibits enzyme by mimicking substrate or intermediate

slide44

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

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