Fatty acids are broken down and synthesized in 2-carbon units. While there are many types of fatty acids, here we’ll focus on triacylglycerols (glycerol with 3 fatty acids attached), which are highly reduced. Their oxidations yields ~38 kJ/g, compared to carbohydrate oxidation which yields ~17 kJ/g. Triacylglycerols are also incredibly energy dnese, since they are stored in anhydrous droplets almost 100% free of H2O. In constrast, each gram of glycogen binds ~2 g of H2O. So fat stores more approximately 6 times more energy per gram than carbohydrates. Fatty acid utilization involves 3 steps: mobilization, activation/transport, and β-oxidation.
In fatty acid mobilization, hormones released during fasting states, namely epinephrine and glucagon, work through g-proteins and cAMP to open up lipid droplets to the action of lipases, yielding free fatty acids. These free fatty acids (FFAs) are then released from adipocytes into the bloodstream, where they bind with serum albumin. Serum albumin acts as a carrier to transport fatty acids to fuel-requiring tissues, whose cells take them up. The glycerol released from this process enters glycolysis via glyceraldehyde 3-phosphate (GAP).
Before being oxidized in the mitochondrial matrix to create NADH, FADH2, and acetyl-CoA, fatty acids must first be activated it cytosol. This is done by fatty acyl-CoA synthetase, with ∆G’° = -34 kJ/mol.
This activation consumes 2 ATP equivalents per fatty acid. To transport this fatty acyl-CoA accross the mitochondrial membrane, we need the carnitine shuttle. Neither CoA nor acetyl-CoA nor FA-CoA can be transported accross the inner mitochondrial membrane without it. The carnitine shuttle, shown below, first replaces CoA on the fatty acyl-CoA with carnitine, catalyzed by the enzyme carnitine acyltransferase. This commits the FA-CoA to oxidation in the mitochondrion. Second, a specific transporter shuttles FA-carnintine accross the inner membrane into the matrix. Third, carnitine acyltransferase II regenerates FA-CoA and carnitine. Fourth, carnitine is returned to the intermembrane space by the same transporter.
β-oxidation of a saturated FA-COA occurs in four steps after carnitine is replaced by CoA. First, acyl-CoA dehydrogenase catalyzes the removal of two hydrogens from the alpha and beta carbons of acyl-CoA, giving enoyl-CoA. This generates FADH2 from FAD. Second, enoyl-CoA hydratase hydrates the double bond, leaving a hydroxy group on the betea carbon, consuming one water molecule. Third, the new hydroxy group is oxidized to a carbonyl group by 3-hydroxyacyl-CoA-dehydrogenase, with NAD+ being reduced to NADH + H+. Fourth, and finally, beta-ketoacyl-CoA cleaves the C-C bond between the alpha and beta carbons, resulting in acetyl-CoA and FA-CoA that is two carbons shorter. CoA-SH is consumed in this reaction, with CoA-S ending up on the end of the FA-CoA, which undergoes subsequent rounds of
β-oxidation.
Acetyl-CoA can go into the TCA cycle or ketogenesis. Additional steps are needed if there are double bonds from unsaturated fatty acids, if there is an odd numer of carbons, or if there are branched fatty acids. Ketone bodies are basically a water-soluble, bloodstream-transportable form of acetyl units. They are synthesized by the body’s most altruistic organ, the liver, and can be consuumed as fuel by many other tissues. THe brain can adapt to using acetoacetate during starvation/diabeters and the heart prefers acetoacetat to glucose. Let us consider the liver under fasting conditions, when no glucose is being absorbed from food (liver is engaging in gluconeogenesis). β-oxidation of fatty acids mobilized from adipocytes produces acetyl-CoA in large quantities. Since gluconeogeneisis consumes oxaloacetate for gluconeogenesis, this acetyl-CoA can’t go into the TCA cycle. Instead, it is used to make ketone bodies, which are exported from the liver and serva as fuel for other tissues. This “spares” glucose, making it last longer.
Let’s calculate the ATP yield from breakdown of palmitoyl-CoA, which is the most common fatty acid in humans. β-oxidation of palmitoyl-CoA, which has a 16 carbon long chain, yields 8 acetyl-CoA’s, but also consumes 7 FAD and 7 NAD+. This means that β-oxidation of palmitoyl-CoA yields 8 acetyl-CoAs, 7 FADH2, 7 NADH. Each acetyl-CoA can make 10 ATP, for 80 ATP in total. Each NADH can be exchanged for 2.5 ATP through the ETC and Oxidative Phosphorylation, for 17.5 ATP in total. FADH2 can similaly be exchanged for 1.5 ATP each, for 10.5 total. All in all, this adds up to 108 ATP.
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Ketones can be synthesized from acetyl-CoA. Especially under fasting conditions, ketones are the preferred product of acetyl-CoA’s from FA metabolism because oxaloacetate required for entry into the TCA cycle is consumed by gluconeogenesis instead.