Classification: Acetyl cholinesterase IFU: Alzheimers Disease.
Biochemistry: A Short Course - KOCWcontents.kocw.net/KOCW/document/2014/korea/leejinhyup/10.pdf ·...
Transcript of Biochemistry: A Short Course - KOCWcontents.kocw.net/KOCW/document/2014/korea/leejinhyup/10.pdf ·...
Biochemistry: A Short CourseSecond Edition
Tymoczko • Berg • Stryer
© 2013 W. H. Freeman and Company
CHAPTER 27Fatty Acid Degradation
Chapter 27 Outline
Fatty acids are stored in adipose tissue as triacylglycerols (TAG) in which fatty acids are linked to glycerol with ester linkages.
Adipose tissue is located throughout the body, with subcutaneous (below the skin) and visceral (around the internal organs) deposits being most prominent.
The fatty acids incorporated into triacylglycerols in adipose tissue are made accessible in three stages.
1. Degradation of TAG to release fatty acids and glycerol into the blood for transport to energy‐requiring tissues.
2. Activation of the fatty acids and transport into the mitochondria for oxidation.
3. Degradation of the fatty acids to acetyl CoA for processing by the citric acid cycle.
Triacylglycerols are stored in adipocytes as a lipid droplet.
Epinephrine and glucagon, acting through 7TM receptors, stimulate lipid breakdown or lipolysis.
Protein kinase A phosphorylates perilipin, which is associated with the lipid droplet, and hormone‐sensitive lipase.
Phosphorylation of perilipin results in the activation of adipocyte triacylglyceride lipase (ATGL). ATGL initiates the breakdown of lipids.
The glycerol released during lipolysis is absorbed by the liver for use in glycolysis or gluconeogenesis.
Upon entering the cell cytoplasm, fatty acids are activated by attachment to coenzyme A.
This two‐step reaction proceeds through an acyl adenylate intermediate.
The reaction is rendered irreversible by the action of pyrophosphatase.
After being activated by linkage to CoA, the fatty acid is transferred to carnitine, a reaction catalyzed by carnitine acyltransferase I, for transport into the mitochondria. A translocase transports the acyl carnitine into the mitochondria.
In the mitochondria, carnitine acyltransferase II transfers the fatty acid to CoA. The fatty acyl CoA is now ready to be degraded.
Muscle, kidney, and heart use fatty acids as a fuel. Pathological conditions results if the acyltransferase or the translocase are deficient.
Carnitine deficiencies can be treated by carnitine supplementation.
Fatty acid degradation consists of four steps that are repeated.
1. Oxidation of the β carbon, catalyzed by acyl CoA dehydrogenase, generates trans‐Δ2‐enoyl CoA and FADH2.
2. Hydration of trans‐Δ2‐enoyl CoA by enoyl CoA hydratase yields L‐3‐hydroxyacyl CoA.
3. Oxidation of L‐3‐hydroxyacyl CoA by L‐3‐hydroxyacyl dehydrogenase generates 2‐ketoacyl CoA and NADH.
4. Cleavage of the 3‐ketoacyl CoA by thiolase forms acetyl CoA and a fatty acid chain two carbons shorter.
Fatty acid degradation is also called β‐oxidation.
The reaction for one round of β‐oxidation is:
The complete reaction for C16 palmitoyl CoA is:
Processing of the products of the complete reaction by cellular respiration would generate 106 molecules of ATP.
β‐oxidation alone cannot degrade unsaturated fatty acids. When monounsaturated fatty acids are degraded by β‐oxidation, cis‐Δ3‐enoyl CoA is formed, which cannot be processed by acyl CoA dehydrogenase.
Cis‐Δ3‐enoyl CoA isomerase converts the double bond into trans‐Δ2‐enoyl CoA, a normal substrate for β‐oxidation.
When polyunsaturated fatty acids are degraded by β‐oxidation, cis‐Δ3‐enoyl CoA isomerase is also required. 2,4‐Dienoyl CoA is also generated, but cannot be processed by the normal enzymes.
2,4‐Dienoyl CoA is converted into trans‐Δ3‐enoyl CoA by 2,4‐dienoyl CoA reductase, and the isomerase converts this product to trans‐Δ2‐enoyl CoA, a normal substrate.
Unsaturated fatty acids with odd numbers of double bonds require only the isomerase. Even number of double bonds require both the isomerase and reductase.
β‐Oxidation of fatty acids with odd numbers of carbons generates propionyl CoA in the last thiolysis reaction.
Propionyl carboxylase, a biotin enzyme, adds a carbon to propionyl CoA to form methylmalonyl CoA
Succinyl CoA, a citric acid cycle component, is subsequently formed from methylmalonyl CoA by methylmalonyl CoA mutase, a vitamin B12 requiring enzyme.
Ketone bodies—acetoacetate, 3‐hydroxybutyrate, and acetone—are synthesized from acetyl CoA in liver mitochondria and secreted into the blood for use as a fuel by some tissues such as heart muscle.
3‐Hydroxybutyrate is formed upon the reduction of acetoacetate. Acetone is generated by the spontaneous decarboxylation of acetoacetate.
In tissues using ketone bodies, 3‐hydroxybutyrate is oxidized to acetoacetate, which is ultimately metabolized to two molecules of acetyl CoA.
Fats are converted into acetyl CoA, which is then processed by the citric acid cycle.
Oxaloacetate, a citric acid cycle intermediate, is a precursor to glucose.
However, acetyl CoA derived from fats cannot lead to the net synthesis of oxaloacetate or glucose because although two carbons enter the cycle when acetyl CoA condenses with oxaloacetate, two carbons are lost as CO2 before oxaloacetate is regenerated.
Ketone bodies are moderately strong acids, and excess production can lead to acidosis. An overproduction of ketone bodies can occur when diabetes, a condition resulting from a lack of insulin function, is untreated. The resulting acidosis is called diabetic ketosis.
If insulin is absent or not functioning, glucose cannot enter cells. All energy must be derived from fats, leading to the production of acetyl CoA.
Acetyl CoA builds up because oxaloacetate, which can be generated from glucose, is not available to replenish the citric acid cycle.
Moreover, fatty acid release from adipose tissue is enhanced in the absence of insulin function.
Glucose is the predominant fuel for the brain.
During starvation, protein degradation is initially the source of carbons for gluconeogenesis in the liver. The glucose is then released into the blood for the brain to use.
After several days of fasting, the brain begins to use ketone bodies as a fuel.
Ketone body use curtails protein degradation and thus prevents tissue failure. Moreover, ketone bodies are synthesized from fats, the largest energy store in the body.