Fatty Acid Catabolism

C483 Spring 2013

1. Which lipid form is transported across the inner mitochondrial membrane before β-oxidation? A) Acylcarnitine. B) Fatty acyl CoA. C) Acetoacetyl CoA. D) Lysophospholipid CoA.

2. There are four steps in the β-oxidation pathway. Some reaction types are listed below. Give the proper reaction types in the order that they occur in the β-oxidation pathway.

1. Condensation 5. hydration2. Oxidation 6. phosphorylation3. Reduction 7. rearrangement4. Thiolysis A) 1, 7, 2, 2 B) 6, 3, 4, 2 C) 1, 2, 3, 4 D) 2, 5, 2, 4

3. The conversion of the laurate CoA (a 12-carbon acylCoA) to carbon dioxide via β-oxidation, the citric acid cycle and oxidative phosphorylation yield approximately ________ ATP equivalents. A) 78 B) 80 C) 82 D) 84

4. A patient is found to have a high concentration of cholesterol in the blood and deposits of cholesterol under the skin. The patient is diagnosed with familial hypercholesterolemia. What is the likely cause of this condition? A) A deficiency in insulin production by the pancreas. B) Insufficient chylomicron concentration in the blood. C) Overproduction of lysosomal lipases. D) Lack of LDL receptors on the surfaces of nonhepatic cells.

5. Ketone bodies form when ______________ is in low concentration:A) Acetyl CoAB) TriacylglycerideC) CholesterolD) oxaloacetate

Overview

• Lipids as a fuel source—diet• Beta oxidation – Mechanism– ATP production

• Ketone bodies as fuel

TAG and FA

• High energy– More reduced– Little water

content– 9 Cal/g vs 4

Cal/g for carbs• Unsaturated FA• Glycerol

Digestion• Cross from intestine into

bloodstream

Lipoprotein Metabolism

• Liver is the packaging center

• VLDL are sent out of liver• Constant cycling of LDL in

blood• Genetic cholesterol

problem: no LDL receptors in non-liver cells

• HDLs are “good cholesterol”

Utilization Stage 1:Mobilization

Hormone Sensitive Lipase

Utilization Stage 2:Transport into Matrix

• FA FA-CoA costs ATP AMP (2 ATP equivalents)

• Carnitine ester: high energy bond

• Mammals also degrade FA in peroxisome

• Major site of regulation of FA degradation

Utilization Stage 3: Beta Oxidation

• Four step process• Production of – QH2

– NADH– Acetyl CoA

Step 1: Acyl CoA Dehydrogenase

• Similar to succinate DH from citric acid cycle

• Prosthetic FAD/FADH2

• High energy electrons passed on to QH2

• 1.5 ATP

R SCoA

O

R SCoA

O

Step 2: Enoyl CoA Hydratase

• Similar to fumarate hydratase from citric acid cycle

• Addition of water• No energy

cost/productionR SCoA

O

R SCoA

O

OH

Step 3: 3-hydroxyacyl CoA DH

• Similar to malate DH from citric acid cycle

• Oxidation of secondary alcohol to ketone

• NADH production• 2.5 ATP

R SCoA

OOH

R SCoA

OO

Step 4: Thiolase

• CoA is used as a nucleophile in a “nucleophilic acyl substitution”

• FA shortened by 2 carbons• Acetyl CoA produced• 10 ATP through CAC

R SCoA

OO

HS-CoA

R SCoA

OO

SCoA

ATP Accounting

• How much ATP is netted from palmitate (16 carbons)?– Cost 2 ATP to activate to palmitate CoA– Run through beta oxidation SEVEN times• 7 QH2 = 10.5 ATP• 7NADH = 17.5 ATP

– 8 acetyl CoA produced = 80 ATP• Total: 106 ATP, or 6.625 ATP per carbon• Compare to glucose, which is 5.33 ATP per C

Processing Other FA

• Unsaturated and trans fatty acids– Enzymes can handle processing– Produce 1.5 ATP less per unsaturation (why?)

• Odd chain fatty acids– Rare, but do occur in diet– One of 2 requirements for Vitamin B12

(cobalamine) in human diet

Alternate Fate of Acetyl CoA

• Fasting, Diabetes• Glycolysis is down, gluconeogenesis is up• Oxaloacetate depleted• Citric acid cycle has diminished capacity• Acetyl CoA levels build up• Ketone bodies are formed

Ketone Bodies

• Water soluble form of lipids

• Less potential energy than FA

• Main energy source of brain in starvation

• Also used in muscle and intestine

Regulation

Answers

1. A2. D3. B4. D5. D