Roles of Lipids principal form of stored energy major constituents of cell membranes vitamins messengers intra and extracellular
= Oxidation of fatty acids Central energy-yielding pathway in animals. O CH 3 -C-CoA Generates acetyl-coa Generates electrons which pass through the respiratory chain driving ATP synthesis.
Sources of fatty acid fuels 1. de novo synthesis Fatty acids may be synthesized and are converted to triacylglycerols Made in liver and exported to muscle or fat cells In muscle, used as fuel; In fat cells, stored as droplets
Entry of glycerol into the glycolytic pathway The glycerol released is phosphorylated by glycerol kinase to glycerol 3- phosphate oxidized to dihydroxyacetone phosphate then converted to glyceraldehyde 3-phosphate, which is oxidized via glycolysis
Fatty acids are activated and transported into mitochondria FA oxidation enzymes are located in mitochondria Free FA cannot pass directly through the mitochondrial membranes
1. Activation of fatty acid by CoA Acyl CoA synthase Fatty acid + CoA + ATP fatty acyl-coa +AMP + PP i
2. Esterification to carnitine Then transferred to carnitine Fatty acyl-coa + carnitine Fatty acyl- carnitine + CoASH
The fatty acyl group is transferred to carnitine by carnitine transferase I on the outer face of the inner membrane The fatty acyl-carnitine ester then enters the matrix through the acyl-carnitine/carnitine transporter
3. Esterification to CoA The fatty acyl group is enzymatically transferred from carnitine to coenzyme A by carnitine acyltransferase II Regenerates fatty acyl-coa and free carnitine
Mitochondrial oxidation of fatty acids takes place in three stages These stages result in massive ATP production
b-oxidation: Oxidative removal of successive twocarbon units to form acetyl-coa starting from carboxyl end of the fatty acyl chain Also generates NADH and FADH 2 Stage 1.
Stage 2 Acetyl groups of acetyl-coa are oxidized to CO 2 in the TCA cycle NADH is also generated from the TCA cycle
Stage 3 The NADH and FADH 2 produced mitochondrial respiratory chain
The b-oxidation of saturated fatty acids has four basic steps The b-oxidation sequence is a mechanism of breaking stable bond between methylene (-CH 2 -) groups. The first three steps create a bond that is more easily broken.
Step 1 Dehydrogenation of fatty acyl-coa produces a double bond between C-2 and C-3 This double bond is in the trans configuration Yields FADH 2
Step 2 Hydration - water is added to the double bond to form b-hydroxyacyl-coa.
Step 3 b-hydroxyacyl-coa is dehydrogenated (oxidized) to form b ketoacyl-coa. (yields NADH + H + )
Step 4 b ketoacyl-coa reacts with free coenzyme A to split off the carboxyl-terminal twocarbon fragment of the original FA as acetyl CoA.
The products for one pass through b- oxidation Palmitoyl-CoA + CoA + FAD + NAD + + H 2 0 myristoyl-coa + acetyl-coa + FADH 2 + NADH + H + Myristate is a C14 fatty acid
The four steps are repeated to yield acetyl-coa and ATP The myristoyl-coa can go through another set of four b-oxidation reactions to yield a second molecule of acetyl-coa and lauryl- CoA (C-12).
The complete b-oxidation of palmitate Palmitoyl-CoA + 7CoA + 7FAD + NAD + + 7H 2 0 8acetyl-CoA + 7FAD 2 + 7NADH + 7H +
The fate of FADH 2 and NADH Each molecule of FADH 2 ---2 molecules of ATP. Each molecule of NADH delivers a pair of electrons---3 molecules of ATP.
The fate of acetyl-coa Each molecule of acetyl-coa can be oxidized to CO 2 and H 2 O by the TCA cycle to yield 12 molecules of ATP.
The overall ATP yield Palmitoyl-CoA + 7CoA + 7FAD + NAD + + 7H 2 0 8acetyl-CoA + 7FAD 2 + 7NADH + 7H + becomes Palmitoyl-CoA + 23O 2 + 108P i + 131ADP CoA + 131ATP + 16CO 2 + 23H 2 O
Proprionyl-CoA is carboxylated to form D-methylmalonyl-CoA Proprionate metabolism
D-methyl-malonyl- CoA is epimerized to its L-stereoisomer L-methyl-malonyl- CoA is converted to succinyl-coa, which can enter TCA cycle.
Fatty acid oxidation is tightly regulated Fatty acid oxidation is regulated so it occur only when the need for energy requires it
Two pathways fatty acyl-coa in liver Cytosol Fatty acid synthesis Mitochondria Fatty acid oxidation The pathway taken depends on the rate of transfer of long-chain fatty acyl-coa into the mitochondria Fatty acid Triacylglycerols and phospholipids Carnitine transporter
Malonyl-CoA initiates fatty acid synthesis Glycerol-P Malonyl-CoA is the first intermediate in the cytosolic biosynthesis of long-chain fatty acids from acetyl-coa Excess glucose that cannot be oxidized or stored as glycogen is converted in the cytosol into FA for storage as triacylglycerols Glucose Pyruvate Acetyl CoA TCA cycle Fatty acyl CoA Malonyl CoA Triacylglycerol
Malonyl-CoA inhibits carnitine transferase I Malonyl-CoA Cytosol Fatty acid synthesis Mitochondria Fatty acid oxidation Fatty acid Carnitine transporter Triacylglycerols and phospholipids
Fed state Glucose Glycerol-P Triacylglycerol Glycerol Pyruvate Fatty acyl CoA Carnitine transporter Malonyl CoA Fatty acid Acetyl CoA TCA cycle Insulin, citrate
gluconeogenesis Glucose Starved state Glycerol-P Glycerol Triacylglycerol Glucagon/ epinephrine Pyruvate Carnitine transporter Fatty acyl CoA Malonyl CoA Fatty acid Acetyl CoA Ketone bodies TCA cycle
Ketone bodies The acetyl-coa formed in the liver during b-oxidation can have two fates: 1. Enter the TCA cycle 2. Converted to ketone bodies acetone, acetoacetone and b-hydroxybutyrate for export to other tissues
Ketone bodies formed in the liver 1. Condensation of two molecules of acetyl- CoA, 2. The resulting acetoacetyl-coa condenses with acetyl- CoA to form b- hydroxy-bmethylglutaryl-coa (HMG-CoA)
3. Cleavage of HMG-CoA yields acetyl-coa and acetoacetate. 4. Reduction of acetoacetate yields D-bhydroxybutyrate (do not confuse with L- b- hydroxybutyrate of the b- oxidation pathway). 5. Acetoacetate is easily decarboxylated (may be spontaneously or enzymatically) to acetone and CO 2.
Ketone bodies are exported to other organs Acetone, produced in smaller quantities than the other ketone bodies, is exhaled Acetoacetate and b-hydroxybutyrate are transported in the blood to tissues other than the liver
Ketone bodies as fuels b-hydroxybutyrate may be converted to acetyl- CoA. The acetyl-coa is Oxidized in the TCA cycle to provide much of the energy required by tissues
Ketone bodies are used under starvation conditions The brain, which preferentially uses glucose as fuel, can adapt to the use of acetoacetate or b-hydroxybutyrate under starvation conditions, when glucose is unavailable
Intertissue relationships during starvation
Summary of lipid metabolism Sources of triacylglycerols diet and stored in adipocytes Route taken by dietary triacylglycerols to muscle or fat cells Mobilization of triacylglycerols is initiated by hormones epinephrine and glucagon The products of mobilization are free fatty acid and glycerol, both are used for energy production
Summary of lipid metabolism Carnitine transporter mediates entry of fatty acids into mitochondria b-oxidation of fatty acids has four basic steps essentially fatty acid synthesis in reverse b-oxidation generates acetyl-coa, NADH and FADH 2 ATP Ketone bodies serve as fuel molecules under starvation conditions