Fatty Acid Catabolism

A Angeles Chem 40

Digestion, Mobilization and Transport of Fats

Refer to our previous discussion

Fatty Acid Catabolism

About one third of our energy needs comes from dietary triacylglycerols ~80% of energy needs of mammalian heart and liver are met by oxidation of FA Fats are for long term energy needs, good storage (chemically inert) and slow delivery Fats are hydrolyzed into fatty acids and glycerol in the cytoplasm
Energy derived from glycerol ~5%

Fatty Acid Catabolism

Fats are first converted digested, transported, and delivered to cells as free fatty acids Fatty acids transported to the mitochondria where they are oxidized Each two carbon segment is converted to acetyl-CoA that can be further oxidized in the CAC

What happens to glycerol?

Glycerol can enter the glycolytic pathway

How many ATPs can we derive from 1 mol of glycerol?

Fatty Acid Catabolism

Fat (fatty acid) catabolism provides: 1. Reducing equivalents that will ultimately produce ATP 2. Acetyl-CoA that can be oxidized by the CAC ATP be converted to ketone bodies (alternate fuel source for brain and other tissues) in the liver be used for cholesterol biosynthesis act as a biosynthetic precursor

Fatty Acid Transport to the Mitochondria

-oxidation of fatty acids occurs in mitochondria Small (< 12 C) fatty acids diffuse freely across mitochondrial membranes Larger fatty acids are transported via acylcarnitine/carnitine transporter

Fatty Acid Transport to the Mitochondria

1. Fatty acid activation in the cytosol Fatty acid + CoA + ATP Fatty acyl-CoA + AMP + 2Pi

Favorable! Go=-34 kJ/mol

Fatty Acid Transport to the Mitochondria

2. Fatty acid transfer to carnitine to form fatty-acyl carnitine 3. Transport (facilitated diffusion) 4. Removal of carnitine in the matrix

This FAs fate is sealed.

Fatty Acid Transport to the Mitochondria

Oxidation of Fatty Acids

Occurs in three stages consider the oxidation of palmitate

-oxidation of Fatty Acids

STEP 1: Dehydrogenation of Fatty Acyl CoA
Formation of double bond between and carbons (oxidation) Yields 1 FADH2

-oxidation of Fatty Acids

STEP 2: Hydration of double bond
-OH is added to the carbon

-oxidation of Fatty Acids

STEP 3: Dehydrogenation at carbon
-OH carbonyl carbon (oxidation) Yields 1 NADH Priming for nucleophilic attack

-oxidation of Fatty Acids

STEP 4: Thiolysis
Yields 1 acetyl CoA + acyl CoA (n-2)

-oxidation of Fatty Acids Summary:

Every other carbon is converted to a C=O Allows nucleophilic attack by CoA-SH on remaining chain 1 CoA-SH is used for every 2 carbon segment to release acetyl-CoA Each round produces: 1 FADH2, 1 NADH, 1 Acetyl-CoA (2 in the last round)

-oxidation of Fatty Acids

How many rounds of oxidation occurs for a FA with even numbered carbons? (n/2)-1 rounds

-oxidation of Fatty Acids

How many ATPs are formed in one complete oxidation of stearic acid? Activation: -2 ATPs (the FA already has CoA, no need to subtract) 8 rounds of -oxidation: 8(1 FADH2 and 2 NADH) 9 Acetyl CoAs go into the TCA Answer: 120 ATPs Compare this energy yield with that of one glucose molecule

-oxidation of Fatty Acids

What happens if the FA is unsaturated?
Bypasses the initial dehydrogenation step Cis-isomer Trans-isomer No FADH2 yield Subtract 1.5 ATPs per unsaturation

-oxidation of Fatty Acids

Most dietary fatty acids are even-numbered Many plants and some marine organisms also synthesize odd-numbered fatty acids Propionyl-CoA forms from -oxidation of oddnumbered fatty acids Bacterial metabolism in the rumen of ruminants also produces propionyl-CoA

-oxidation of Fatty Acids

Subtract 6 ATPs in the last TCA cycle

-oxidation of Fatty Acids

How many ATPs are formed in one complete oxidation of pentadecanoic acid? Activation: -2 ATPs 6 rounds of -oxidation: 6(1 FADH2 and 2 NADH) 6 Acetyl CoAs go into the TCA 1 succinyl CoA goes into the TCA Answer: 86 ATPs

Ketone Body Production

Can we live off fatty acids alone?
Entry of acetyl-CoA into citric acid cycle requires oxaloacetate When oxaloacetate is depleted, acetyl-CoA is converted into ketone bodies

Production of ketone bodies increases during starvation

Ketone bodies are released by liver to bloodstream Organs other than liver can use ketone bodies as fuels

Ketone Body Production

Acetone can be exhaled Acetoacetate and hydroxybutyrate are transported in the blood to other tissues including the brain Too high levels of acetoacetate and -hydroxybutyrate lower blood pH dangerously (acidosis) Accumulation of ketone bodies in the bloodstream ketosis

Fatty Acid Catabolism

Synthesis
Fats are an important energy source in animals Two-carbon units in fatty acids are oxidized in a four-step oxidation process into acetyl-CoA In the process, NADH and FADH2 are formed will eventually be used in the ETC to produce ATP Acetyl-CoA formed in the liver can be either oxidized via the citric acid cycle or converted to ketone bodies that serve as fuels for other tissues