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Biochem 1 > Fatty Acid Oxidation and Ketone Bodies > Flashcards

Fatty Acid Oxidation and Ketone Bodies Flashcards

1
Q

Describe long chain fatty acid oxidation?

A
  1. FA-binding proteins transport FA across the plasma membrane to the cell cytosol
  2. Fatty acyl-CoA synthetase activates FA to FA-CoAs
  3. Carnitine transports the activated fatty acyl group into the mitochondria
  4. Beta-oxidation (cleavage) of FA in mitochondria yields NADH, FAD(2H) and acetyl-CoA
  5. In the liver, Acetyl CoA is converted to ketone bodies when Acetyl CoA is elevated
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2
Q

How is the release of FA from adipose tissue initiated?

A

In fasted stated (or times of metabolic need) there is low insulin/high glucagon

This activates cAMP which activates protein kinase

Protein kinase activates lipase which degrades TG into FA and glycerol

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3
Q

How are long chain FA transported into the cytosol of the cell?

How they they get from the cytosol to the mitochondria?

A
  1. Long chain FA are transported to the blood bound to albumin
  2. FA-binding proteins (FaBP) transport FA across the plasma membrane to the cell cytosol
  3. Fatty acyl-CoA synthetase activates FA to FA-CoAs

4 Carnitine transports the activated fatty acyl group into the mitochondria

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4
Q

How are fatty acids activated?

A

FA + ATP + fatty acyl CoA synthase –>
Fatty acyl AMP (enzyme bound) loses AMP –> Fatty acyl CoA

Hydrolysis of pyrophosphate helps drive the formation of fatty acyl CoA

Fatty Acyl CoA is the starting material of beta oxidation

Fatty Acyl CoA contains a high energy thioester bond

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5
Q

What is the fate of fatty acyl CoA compounds?

A
  1. Targeted for degradation in mitochondrial beta-oxidation for energy
  2. Incorporated into storage triacylglycerol’s
  3. Incorporated into membrane lipids as phospholipids and sphingolipids
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6
Q

How is carnitine involved in FA oxidation?

A

Long chain FA transport into mitochondria requires carnitine

Carnitine is obtained from the diet or synthesized from the side chain of lysine

Carnitine palmitoyl transferases (CPT) catalyze reversible transfer of a long-chain fatty acyl group from the fatty acyl-CoA to the hydroxyl group of carnitine

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7
Q

Describe the role of carnitine in the outer mitochondrial membrane

A

CPTI converts fatty acyl CoA to Fatty Acyl Carnitine

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8
Q

Describe the role of carnitine in the inner mitochondrial membrane

A

Fatty acyl carnitine is transported across the IMME

CPTII converts Fatty Acyl Carnitine to Fatty Acyl CoA

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9
Q

What is beta oxidation spiral/pathway?

A
  • Oxidation occurs at the beta carbon on fatty acyl CoA
  • Beta oxidation spiral - oxidation of the beta carbon and cleavage of the alpha-beta bond in fatty acyl CoA
  • One cycle of beta oxidation produces: acetyl CoA. FADH2, NADH, Fatty acyl CoA (n-2)
  • Oxidation of palmitoyl CoA (16C) requires 7 cycles of beta oxidation
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10
Q

What happens after beta oxidation?

A
  • Electrons from oxidation of the beta carbon conserved in FADH2 and NADH
  • FADH2 and NADH enter ETC to generate ATP
  • Acetyl CoA enters the TCA to generate NADH, FADH2 and GTP
  • Spiral repeats until all carbons are converted to acetyl CoA
  • Oxidation of Palmitoyl CoA (C16) produces: 7 FADH2, 7 NADH, 8 Acetyl CoA’s
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11
Q

What are 4 additional pathways of fatty acid oxidation?

A
  1. Beta-oxidation of unsaturated fatty acids - major pathway
  2. Beta-oxidation of odd-carbon FA - propionyl CoA is a product
  3. Peroxisomal oxidation of very long-chain FA (>20C) and branched-chain FA
  4. Omega-oxidation of unsaturated FA
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12
Q

Describe beta oxidation of unsaturated fatty acids?

A
  • Approximately 1/2 of FA in human diet are unsaturated (cis bonds)
  • Oleate and linoleate are the most common
  • Cis double bonds are converted to trans
  • Lineolate (an essential FA) is a polyunsaturated FA
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13
Q

Describe beta-oxidation of odd-carbon FA

A

LOOK AT SLIDE 13

  • Successive spirals of B-oxidation cleave each of the bonds and produce acetyl Co-A except for the three
    Carbons at the w-end which produces propionyl-CoA
  • Carboxylation of propionyl CoA yields methyl malonyl-CoA
  • methyl malonyl-CoA is converted to succinyl Co-A (in a vitamin B-12 dependent reaction) which enters the TCA cycle
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14
Q

Describe peroxisomal oxidation of FA

A

LOOK AT DIAGRAM ON SLIDE 15
This is only for very long chain Fa and can’t be done in the mitochondria

It is not coupled to ATP synthesis - Instead, it generated peroxide which is converted to water and oxygen by catalase found in the peroxisomes

  • Acetyl groups are transferred from CoA to carnitine by an acetyl carnitine transferase (CAT)
  • The peroxisomal b-oxidation spiral continues generating acetyl co-A until there are short to medium chain fatty acyl CoA
  • These are converted to carnitine derivatives by carnitine octanoyltransferase (COT)
  • These acylcarnitine diffuse from peroxisomes to mitochondria
  • They pass through the outer mitochondrial membrane and are transported through the inner mitochondrial membrane via carnitine translocase system (CAC, CPTI, CPTII)
  • They are converted back to acetyl CoA and small and medium chain fatty acyl CoA by carnitine: acyltransferases (CAT/CPTII) to directly enter the TCA cycle or to undergo further b-oxidation
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15
Q

Describe omega-oxidation of unsaturated FA

A
  • minor pathway that is used in some animals, or when beta-oxidation is defective
  • FA are oxidized at the w-carbon of the chain by enzymes in the ER
  • The dicarboxylic acids produced by w-oxidation undergo b-oxidation forming compounds with 6 to 10 carbons that enter the blood to be oxidized in mitochondria, or are excreted in urine as medium-chain dicarboxylic acids
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16
Q

How is b-oxidation regulated?

A
  1. Hormones (eg: insulin/glucagon ratio) control the supply of fatty acids in the blood
  2. CPTI inhibited by malonyl-CoA
  3. NADH, FADH2 inhibit b-oxidation
  4. Decreased ATP utilization increases NADH/FADH2
17
Q

As beta oxidation increases, FA are converted to ______

A

ketone bodies

18
Q

What are the ketone bodies are synthesized in the liver?

A

acetoacetate

beta-hydroxybutyrate

19
Q

Which tissues/cell types are not able to use ketone bodies as fuel?

A

liver

red blood cells

20
Q

What is the fate of ketone bodies in tissues after entering the blood?

A

conversion back to acetyl coA and oxidation in the TCA cycle to CO2 and H2O

21
Q

Describe the synthesis of ketone bodies

A
  1. In the liver, acetoacetyl-CoA is synthesized in the mitochondrial matrix from 2 molecules of acetyl Co-A, generated from FA oxidation by the thiolase reaction
  2. Acetoacetyl-CoA reacts with acetyl-CoA catalyzed by HMG-CoA synthase and produces 3-hydoxy-3-methylglutaryl-CoA (HMG-CoA)
  3. HMG CoA lyase catalyzes cleavage of HMG-CoA to form acetyl -CoA and acetoacetate
  4. Acetoacetate is reduced to b-hydroxybutyrate or decarboxylated to acetone
  5. Acetoacetate is a major precursor to other kb
22
Q

What happens to acetoacetate and b-hydroxybutyrate after they are formed?
What is their ratio?

A

They enter the blood directly.

1:1 in the blood

23
Q

What happens to acetone formed during the synthesis of ketone bodies?

A

it is volatile and is expired by the lungs

24
Q

How is ketone body synthesis regulated?

A

SLIDE 20

  1. Increased FA from adipose triacylglycerols increase ketone body synthesis
  2. Decreased insulin/glucagon ratio = inhibition of acetyl CoA carboxylase and decreased malonyl-CoA. This activates CPTI and allows fatty acyl-CoA to enter the b-oxidation pathway
  3. Oxidation of fatty acyl CoA to acetyl-CoA generates enough NADH and FAD(2H) to supple ATP needs of the liver and acetyl CoA is diverted from TCA cycle into ketogenesis
  4. Low levels of oxaloacetate diverts TCA cycle to malate and gluconeogenesis

5, This reduces the rate of citrate synthase reaction

25
Q

Describe the oxidation of ketone bodies as fuels

A
  • Acetoacetate and b-hydroxybutyrate ate oxidized as fuels in most tissues
    _ Oxidation occurs in the mitochondria
  • b-hydroxybutyrate is oxidized back to acetoacetate and produces ANDH
  • Acetoacetate is converted to 2 acetyl-CoA and is oxidized in the TCA cycle
  • The net energy yield from one molecule of b-hydroxybutyrate is approximately 21.5 molecules of ATP
26
Q

What happens to levels of fatty acids in the blood during fasting?

A

It increases for 2-3 days then remains relatively constant

27
Q

What happens to levels of glucose in the blood during fasting?

A

It decreases for 2-3 days then remains relatively constant

28
Q

What happens to levels of ketone bodies in the blood during fasting?

A
  • It increases markedly for up to 20-25 days
  • They rise to levels at which they can be used by the bran and other nervous tissues, thereby reducing the amount of glucose required by the brain
  • During prolonged fasting, ketone bodies may supple as much as 2/3 of energy requirements of the brain
29
Q

Describe carnitine deficiency?
Is it environmental or genetic?
What is primary carnitine deficiency?
What is secondary carnitine deficiency?

A
  • Both environmental and genetic
  • Primary carnitine deficiency - lack of a membrane transporter for carnitine
  • Secondary carnitine - results bc of other metabolic disorders
30
Q

What is Jamaican vomiting disorder?

Is it environmental or genetic?

A
  • Both environmental and genetic
  • Inhibition of carnitine activity by hypoglycin
  • Can lead to death bc of sever hypoglycemia

Biochem 1 (22 decks)

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