BIOCHEMISTRY AND HUMAN NUTRITION

Module 3. Metabolism

Lesson 20
FATTY ACID OXIDATION

20.1 Introduction

• The yield of completely burning fatty acids is approximately 9000 calories per gram. The yield of burning carbohydrates and proteins is approximately 4000 calories per gram only.
• This is the result of the fact that fatty acids are more reduced than carbohydrates and proteins.
• Fatty acids are because of their non-polar character (not soluble in water) stored in a water free form. Carbohydrates and proteins in contrast, do bind water when stored. Because of this 1 gram of fat contains six times more energy than 1 gram glycogen in which water is bound.
• Most fatty acids are degraded by the sequential removal of two-carbon fragments from the carboxyl end of fatty acids. During this process, referred to as β-oxidation, acetyl-CoA is formed as the bond between the α- and β-carbon atoms is broken. β-Oxidation is so named because the β-carbon of fatty acids is oxidized. β-oxidation occurs primarily within mitochondria.

20.2 Hydrolysis of Triglycerides

• The first event in the use of fat as energy source is the hydrolysis (i.e break down by water) of triglycerides by the enzymes that are called lipases. This process is also called lipolysis. Lipases convert triglycerides into glycerol and fatty acids as below.

Fig. 20.1 Hydrolysis by lipases of triglycerol in glycerol and fatty acids.

• The activity of lipase in fat cells is regulated by hormones like epinephrine and glucagon. These hormones activate the enzyme adenylate cyclase which produces cAMP from ATP. This cAMP activates the enzyme protein kinase A (PKA). The enzyme PKA phosphorylates the lipase enzyme and gets activated because of this phosphorylation.
• The hormone insulin inhibits the hydrolysis of triglycerids. Glycerol, that by the breakdown of triglyceride arise, is phosphorylated by glycerolkinase and is then oxidised by glycerol phosphate dehydrogenase to dihydroxyacetone phosphate. This is an intermediary of the glycolysis and will be broken down further in the glycolysis.

20.3 Fatty Acid Activation and Transport Across the Mitochondrial Membrane

Before β-Oxidation begins, each fatty acid is activated in a reaction with ATP and CoA. Fatty acids undergo for ATP dependent acylation reaction to form fatty acyl-CoA. This activation process is catalyzed by acyl-CoA synthetase in the cytosol.

Fig. 20.2 Activation of fatty acid

The enzyme acyl CoA synthetase has been bound at the outer membrane of the mitochondria. Hydrolysis of pyrophosphate moves the reaction in forward direction.

20.3.1 Translocation of long-chain activated fatty acids into the mitochondrial matrix

Transport of activated long chain fatty acid into the mitochondria for oxidation is brought out by carnitine mediated specialized mechanism. The acyl group is transferred by the sulphur atom of coenzyme A on the hydroxyl group of carnitine under formation of acylcarnitine. This reaction is catalysed by carnitine acyltransferase I that is bound at the outer face of the inner membrane of the mitochondria.

Fig. 20.3 Activated long-chain fatty acids are combined with carnitine.

Acylcarnitine is then moved through the inner membrane by a translocase enzyme (membrane protein). The acyl group is transferred back to coenzyme A at the matrix side (in the mitochondria) by the membrane. This reaction is catalysed by carnitine acyltransferase II. Ultimately carnitine is transported back into the inter membrane space by the enzyme translocase in exchange for a coming in of acylcarnitine.

20.4 Fatty Acid Oxidation

20.4.1 Fatty Acids are Broken by Splitting Off Always Two Carbon Atoms.

Fatty acids are broken down by repetitions of separations of parts of two carbon atoms. The reactions that repeat are oxidation, hydration, oxidation (dehydrogenation) and thiolyse. See the figure below.

Fig. 20.4 Reaction order for the breakdown of fatty acids: oxidation, hydration, oxidation and thiolyse.

The three reactions from acyl CoA to 3-ketoacyl CoA are comparable to the reactions of succinate to oxalacetate in the citric acid cycle.

20.4 Excess Acetyl CoA are Converted into Ketone Bodies

All by the fatty acid break down formed active acetyl CoA can only be sufficient fast broken down in the citric acid cycle when sufficient oxalacetate is present. By fasting or by diabetes oxalacetate is used for the gluconeogenesis. Then there is insufficient oxalacetate available to react with acetyl CoA. Under these circumstances, from two molecules of acetyl CoA one molecule of acetoacetyl CoA is formed and from that the ketone bodies are formed: acetolacetate, D-3-hydroxybutyrate and acetone.

Fig. 20.5 Two molecules acetyl CoA form one acetoacetyl CoA and from this the ketone bodies are formed

The enzymes that accelerate these reactions in the liver are (1) 3- ketothiolase, (2) hydroxymethylglutaryl CoA synthetase, (3) hydroxymethylglutaryl CoA lyase and (4) the mitochondrial enzyme D-3-hydroxybutyratedehydrogenase. Acetoacetate decarboxylates spontaneously to acetone. Acetone is a volatile compound and its smell is observed in the breath of men with diabetes or with people that fast.

The ketone bodies appear to be important energy sources, It is the primary fuels for the heart muscle and kidney. By fasting or diabetes the brains change from the use of glucose to the use of acetoacetate as fuel. Acetoacetate is activated by the transfer of the CoA of succinyl CoA to acetoacetate. Acetoacetyl CoA is then thiolysed to two molecules of acetyl CoA that go into the citric acid cycle.

Fig. 20.6 The use of acetoacetate as a fuel by TCA cycle after conversion in acetyl CoA

Humans and animals can not convert fatty acids into glucose because they cannot use the acetyl CoA to make pyruvate or oxalacetate. The both carbon atoms are taken up in the citric acid cycle, and are converted to CO₂ or acetyl CoA is converted to ketone bodies, so acetyl CoA does not provide oxaloacetate to be needed for gluconeogenesis.