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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

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

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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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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 -> 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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Enzymes of β-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 -> 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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Transport of Acetyl-CoA from the Mitochondria-> Cytosol

Glycolysis

FA synthesis

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Activation of Acetyl and Malonyl in Synthesis

Activation for Synthesis Activation for Degradation

reactive unit

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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 -> 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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Fatty Acid Synthesis -> Pathway Integration

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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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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 -> Hormones

Localization of Lipid Metabolism

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Aspirin + Ibuprofen block enzyme

Eicosanoides

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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 -> 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