____________ are a class of compounds containing a long hydrocarbon chain and a terminal carboxylate group.
Where is the beta carbon located?
Carboxylate carbon is #1. Then next carbon is alpha, and the third carbon is the beta carbon.
Fatty acids usually contain an (odd/even) number of carbon atoms.
Even. Typically between 14 and 24.
True/False: The double bonds in polyunsaturated fatty acids are adjacent to each other.
False. They are separated by at least one methylene group (-CH2-).
What is the major fuel storage in the body?
Esterified fatty acids (in the form of triacylglycerols)
Which yields more ATP per weight, triacylglycerols or glycogen?
Triacylglycerols yield about 2.5 times more ATP per weight on complete oxidation.
True/False: Most tissues utilize fatty acids as a fuel.
Which tissue does not utilize fatty acids as an energy source? Why not?
The brain does not use fatty acids as an energy source because fatty acids do not cross the blood-brain barrier. Also red blood cells do not use fatty acids as an energy source because they lack mitochondria, the site of fatty acid oxidation.
Where are fatty acids oxidized?
In the mitochondria.
Describe the essential features of beta-oxidation.
A mitochondrial pathway in which two-carbon fragments are successively removed from the carboxyl end of the fatty acyl-CoA, producing Acetyl-CoA, NADH, and FADH2.
What enzyme is responsible for hydrolysis of triacylglycerol?
After hormonse-sensitive lipase hydrolyzes triacylglycerol to fatty acids, the fatty acids are released into the blood where they bind to...?
Describe the mechanism of the mobilization of triacylglycerides stored in adipose tissue.
A hormone binds its receptor, activates adenylyl cyclase, increases cAMP, activates PKA, phosphorylates/activates triacylglycerol lipase.
Once in the bloodstream, how do fatty acids enter cells?
Fatty acids are transported inside the cell by fatty acid transporters.
In the cells fatty acids are conjugated with __________ to form ___________ for beta-oxidation.
CoA; fatty acyl-CoA
__________ is a protein that coats the lipid droplet in an adipocyte.
PKA phosphorylates and activates the lipase. Regarding fatty acid oxidation, what else does PKA phosphorylate?
What is the effect of phoshorylating perilipin?
Phosphorylated perilipin promotes translocation of hormone-sensitive lipase to the lipid droplet making fatty acid hydrolysis by the enzyme possible. Dephosphorylated perilipin blocks lipase access to triacylglycerol.
What is the overall effect glucagon, epinephrine, and ACTH on triacylglycerol metabolism?
They induce the release of free fatty acids from triglycerides in adipose tissue.
How do glucagon, epinephrine, and ACTH induce the release of free fatty acids from triglycerides in adipose tissue?
They increase intracellular cAMP thereby activating PKA, which phosphorylates fatty acid lipase and perilipin.
What is the overall effect of insulin on triacylglycerol metabolism?
Insulin inhibits fatty acid lipase by promoting its dephosphorylated state.
What are the three main stages of fatty acid oxidation?
1. Activation of fatty acids to fatty-acyl-CoA by acyl-CoA synthetases
2. Transport of fatty acyl-CoA to the mitochondrial matrix by the carnitine shuttle
3. Beta-oxidation of fatty acids
What enzyme activates fatty acids to fatty acyl-CoA?
acyl-CoA synthetases (thiokinases)
Where is the fatty acid activation enzyme, acyl-CoA synthetase, located?
In the outer mitochondrial membrane and endoplasmic reticulum (ER)
The formation of fatty acyl-CoA requires energy. Where does this energy come from?
The hydrolysis of TWO high energy bonds in ATP (i.e. ATP goes to AMP and 2 Pi).
What is the rate-limiting step of beta-oxidation?
The carnitine shuttle that transports the fatty acyl-CoA across the mitochondrial membranes.
For a fatty acyl-CoA to get into the mitochondrial matrix, first, the ________ is transferred from ________ to _________.
Acyl group is transferred from CoA to carnitine.
Why must the acyl group be removed from fatty acyl-CoA and attached to carnitine to enter the matrix?
Because the inner membrane is impermeable to CoA.
What enzyme catalyzes the transfer of the acyl group of fatty acyl-CoA to carnitine?
Carnitine polmitoyltransferase-I (CPT-I)
The acyl-carnitine is transferred from the intermembrane space into the matrix in exchange for free carnitine by what inner membrane enzyme?
What is the function of the inner membrane enzyme carnitine polmitoyltransferase II (CPT-II)?
Catalyzes the transfer of the acyl group from acylcarnitine to CoA in the matrix, thus regenerating free carnitine and finishing the shuttle of acyl-CoA into the matrix.
What intermediate in fatty acid synthesis inhibits CPT-1, thus preventing fatty acid oxidation in the fed state?
Does the carnitine shuttle of fatty acids from the cytosol to the mitochondria require the hyrolysis of ATP?
Does the activation of a free fatty acid in the cytosol by conversion to the fatty acyl-CoA derivative require ATP hydrolysis?
Where does the exchange of acylcarnitine and free carnitine occur?
Across the inner mitochondrial membrane.
Beta-oxidation of FA is a sequence of ___ reactions carried out by the fatty acid oxidase system (how many?).
What is the first step of the beta-oxidation pathway?
The acyl-CoA is (alpha-beta carbon) dehydrogenated by acyl-CoA dehydrogenase. FAD is reduced to FADH2.
In the second step of beta-oxidation, H2O is added to the double bond from the first step. What enzyme catalyzes the second step?
What is the third step of beta-oxidation?
The oxidation of the beta-hydroxyacyl-CoA to a ketone. NAD+ is reduced to NADH.
What enzyme catalyzes the oxidation of the beta-carbon hydroxyl to a ketone?
What is the 4th step of beta-oxidation?
The thiolytic cleavage of the 2-carbon Acetyl-CoA (catalyzed by thiolase)
Each FADH2 yielded from beta-oxidation yields ~___ ATP.
Each NADH yielded from beta-oxidation yields ~___ ATP.
Oxidation of each ___________ from beta-oxidation through the TCA yields ~10 ATP.
The total ATP yield from the oxidation of palmitate is ~____ ATP.
106 ATP per mole
How do short-chain (2-4C) and medium-chain (4-12C) fatty acids enter the mitochondrial matrix?
How do long-chain (12-20C) fatty acids enter the mitochondria?
The carnitine cycle.
How are odd-chain fatty acids oxidized?
Beta-oxidation proceeds from the carboxyl end. Propionyl CoA is formed by the last thiolase cleavage reaction and is metabolized in the TCA cycle.
How are unsaturated fatty acids oxidized?
Beta-oxidation requires several additional enzymes, both to shift the position and to change the geometry of the double bond.
Which produces more ATP: oxidation of saturated fatty acids or unsaturated fatty acids?
Oxidation of saturated fatty acids yields more FADH and ATP than unsaturated.
Ketone bodies are formed from what precursor?
What intermediate in ketogenesis is also an intermediate in cholesterol synthesis?
Where is the pool of HMG-CoA for use in ketogenesis located?
In the mitochondria.
What three substances are collectively known as the ketone bodies?
Acetoacetate, acetone, beta-hydroxybutyrate
Which ketone body is converted into the other two?
Acetoacetate can convert into acetone or beta-hydroxybutyrate.
Describe the conversion of acetoacetate into acetone.
Spontaneous, loss of CO2.
Describe the conversion of acetoacetate into beta-hydroxybutyrate.
Catalyzed by beta-hydroxybutyrate dehydrogenase. NADH is oxidized to NAD+.
What is reflected in the radio of beta-hydroxybutyrate/acetoacetate?
The intramitochondrial [NADH/NAD+] ratio.
Ketogenesis occurs in the ________ when there is a (high/low) rate of fatty acid oxidation.
Ketone bodies are exported from the liver and used as an energy source for...(what tissues)?
Heart, brain (as well as kidney and skeletal muscle)
During prolonged fasting, triacylglycerol in adipose tissue is hydrolyzed and __________ and __________ are released into the blood.
Free fatty acids and glycerol.
The brain starts using ____________ after 2-3 days of fasting (sparing __________).
ketone bodies; glucose
To what use is the glycerol released from fatty acid oxidation?
Gluconeogenesis in the liver.
Describe the mechanism of use of glycerol for gluconeogenesis.
Free glycerol derived from hydrolysis of triglyceride in adipose tissue in used by the liver to synthesize glycerol-3-phosphate by glycerol kinase, which is converted to dihydroxyacetone phosphate.
What defect causes primary carnitine deficiency?
A defect in the plasma membrane carnitine transporter in muscle, heart and kidney (not liver).
Why does the defect in plasma membrane carnitine transporter in primary carnitine deficiency result in extremely low levels of carnitine in affected tissues and plasma?
Because the kidney fails to readsorb carnitine and it is excreted in urine.
True/False: Administration of dietary carnitine is beneficial in primary carnitine deficiency.
Describe secondary carnitine deficiency.
Often associated with inherited defects in the beta-oxidation pathway, these disorders frequently cause accumulation of acylcarnitine, which are secreted in the urine, thereby depleting the carnitine pool.
Describe secondary carnitine deficiency caused by CPT deficiency.
Most commonly mutations are in the CPTII gene. Muscle weakness with loss of myoglobin in urine (due to muscle fiber breakdown). Severe CPTII loss leads to disease in infancy. Fasting causes hypoketotic hypoglycemia, hyperammoniemia, cardiac malfunction and death.
Why does avoiding fasting relieve secondary carnitine deficiency caused by CPT deficiency?
Avoiding fasting avoids conditions where tissues require fatty acid oxidation for energy (and fatty acid oxidation is impaired).
Why does a diet supplemented by medium chain fatty acids improve secondary carnitine deficiency caused by CPT deficiency?
Medium chain fatty acids can diffuse through the mitochondria into the beta-oxidation pathway.
Describe secondary carnitine deficiency caused by Acyl-CoA dehydrogenase deficiency.
Impaired first reaction in the beta-oxidation of fatty acids manifests in the first two years of life. Vomiting, lethargy, coma. Hypoketotic hypoglycemia and dicarboxylic aciduria.
What causes hypoketotic hypoglycemia when Acyl-CoA dehydrogenase is deficient?
Reduced gluconeogenesis in the liver, increased glucose consumption in muscle, decreased formation of ketone bodies.
Why is gluconeogenesis reduced in the liver when Acyl-CoA dehydrogenase is deficient?
The block of beta-oxidation of fatty acids decreases levels of Acetyl-CoA, which leads to decreased activity of pyruvate carboxylase, in the gluconeogenesis pathway.
Why is glucose consumption increased in muscle when Acyl-CoA dehydrogenase is deficient?
Because energy cannot be derived from beta-oxidation of fatty acids.
Why is formation of ketone bodies decreased when Acyl-CoA dehydrogenase is deficient?
Because of the reduced levels of Acetyl-CoA.
What causes dicarboxylic aciduria when Acyl-CoA dehydrogenase is deficient?
Accumulation of fatty acids which enter alternative degradation pathways like omega(w)-oxidation. w-oxidation leads to excessive urinary secretion of dicarboxylic acids and their esters of glycine or carnitine.
Where does w-oxidation of fatty acids occur?
In the endoplasmic reticulum with involvement of cytochrome P450.
When does w-oxidation become the prevalent catabolic pathway?
When beta-oxidation of fatty acids is defective.
True/False: w-oxidation oxidizes the terminal methyl group, ultimately producing dicarboxylic acids.
Oxidation of very long chain fatty acids occurs preferentially where?
What is the major difference between beta-oxidation in mitochondria vs. peroxisomes?
Peroxisome Acyl-CoA dehydrogenase produces H2O2 which is consumed by catalase.
Where does alpha-oxidation occur?
Endoplasmic reticulum, mitochondria, and peroxisomes.
For what purpose is alpha-oxidation particularly important?
The catabolism of branched fatty acids such as phytanic acid.
Which type of fatty acid oxidation requires NADPH?