30 Questions
What is the major energy reserve of the body?
TAG stored in brown adipocytes
What is the initial acceptor of fatty acids during TAG synthesis?
Dihydroxyacetone phosphate
Which enzyme is responsible for converting free glycerol to glycerol 3-phosphate in the liver?
Glycerol kinase
What is required to activate a free fatty acid before it can participate in metabolic processes?
Fatty acyl CoA synthetase
Why do adipocytes have limited ability to synthesize glycerol phosphate when plasma glucose levels are low?
Insulin activates GLUT-4
What serves as a source of heat through nonshivering thermogenesis?
TAG stored in brown adipocytes
Where does the initial dehydrogenation take place in peroxisomal β-oxidation?
Peroxisomes
What is the product when FADH2 is oxidized by O2 in peroxisomal β-oxidation?
Hydrogen peroxide (H2O2)
In peroxisomal α-oxidation, what makes phytanic acid unsuitable as a substrate for acyl CoA dehydrogenases?
Methyl group on α-carbon
Which enzyme catalyzes the initial dehydrogenation in peroxisomal β-oxidation?
Acyl CoA oxidase
What genetic defect results in the accumulation of very-long-chain fatty acids (VLCFA) in Zellweger syndrome?
Inability to target proteins to peroxisomes
What is the primary cause of secondary carnitine deficiency?
Defects in fatty acid oxidation
Why is no ATP generated during the step involving FAD-containing acyl CoA oxidase in peroxisomal β-oxidation?
Uncoupling of oxidative phosphorylation
Which organ is most affected by CPT-1 deficiency?
Liver
In acquired secondary carnitine deficiency, what can lead to the decreased availability of carnitine?
Taking valproic acid
What is the effect of CPT-II deficiency in skeletal muscle?
Muscle weakness with myoglobinemia after exercise
Why are medium-chain fatty acids especially important for individuals with carnitine deficiencies?
They do not need malonyl CoA for activation
What does the 4'-phosphopantetheine-containing acyl carrier protein (ACP) domain do during fatty acid synthesis?
Carries acyl units on its terminal thiol group for catalysis
What is the recommended dietary approach for individuals with CPT-II deficiency?
Avoid fasting and consume a high-carbohydrate, low-fat diet
What happens to the acetyl group after being transferred from acetyl CoA to the ACP domain?
It condenses with the malonyl group on ACP
Which domain is responsible for converting the 3-ketoacyl group to the corresponding saturated acyl group?
3-Ketoacyl-ACP reductase
What is the role of the condensing enzyme domain during fatty acid synthesis?
Adds two carbons from malonyl CoA to acyl acceptors
What drives the reaction in the 3-Ketoacyl-ACP synthase domain?
Decarboxylation releasing CO2
What is necessary for converting the 3-ketoacyl group to a saturated acyl group?
Dehydration step
Why are ketone bodies considered important sources of energy for peripheral tissues?
They are used in proportion to their concentration by extrahepatic tissues.
What leads to the production of ketone bodies in the liver?
Elevated hepatic acetyl CoA due to fatty acid oxidation
How do disorders of fatty acid oxidation typically present?
With hypoketosis and hypoglycemia
How do ketone bodies spare glucose during prolonged fasting?
By being used as an alternative energy source
What effect does fatty acid oxidation have on pyruvate dehydrogenase activity?
Inhibits pyruvate dehydrogenase
What is the primary role of ketone bodies in extrahepatic tissues like skeletal muscle and cardiac muscle?
To serve as an alternative energy source
Study Notes
Fatty Acid Oxidation and Synthesis
- Oxidation of a double bond at an even-numbered carbon, such as linoleic acid, requires an NADPH-dependent 2,4-dienoyl CoA reductase and an isomerase.
- Unsaturated fatty acids produce fewer reducing equivalents than saturated fatty acids during oxidation.
- Peroxisomal β-oxidation is the primary site for fatty acids ≥22 carbons in length, which undergo preliminary β-oxidation before diffusing to mitochondria for further oxidation.
Peroxisomal β-Oxidation
- FAD-containing acyl CoA oxidase catalyzes the initial dehydrogenation in peroxisomes, producing FADH2, which is oxidized by O2 to produce hydrogen peroxide (H2O2).
- No ATP is generated from this step, and catalase reduces H2O2 to H2O.
- Genetic defects in peroxisomal biogenesis or VLCFA transport lead to accumulation of VLCFA in the blood and tissues.
Peroxisomal α-Oxidation
- Branched-chain phytanic acid undergoes α-oxidation, which is not a substrate for acyl CoA dehydrogenases due to the methyl group on its α-carbon.
Ketone Bodies
- Ketone bodies are important sources of energy for peripheral tissues, being soluble in aqueous solution and produced in the liver during periods of excess acetyl CoA.
- They spare glucose, which is particularly important during prolonged periods of fasting.
- Disorders of fatty acid oxidation present with hypoketosis and hypoglycemia due to decreased acetyl CoA availability.
Ketone Body Synthesis by the Liver
- Elevated hepatic acetyl CoA inhibits pyruvate dehydrogenase and activates pyruvate carboxylase, producing OAA for gluconeogenesis rather than the TCA cycle.
- Fatty acid oxidation decreases the NAD+/NADH ratio, shifting OAA to malate.
Fatty Acid Synthesis
- The process involves the addition of two carbons from malonyl CoA to the carboxyl end of a series of acyl acceptors.
- 4'-Phosphopantetheine, a derivative of pantothenic acid (vitamin B5), carries acyl units on its terminal thiol (-SH) group and presents them to the catalytic domains of FAS during fatty acid synthesis.
Triglycerol Storage and Function
- TAG stored in white adipocytes form large oily droplets that are nearly anhydrous, serving as the major energy reserve of the body.
- TAG stored in brown adipocytes serve as a source of heat through nonshivering thermogenesis.
Glycerol 3-Phosphate Synthesis
- Glycerol 3-phosphate is the initial acceptor of fatty acids during TAG synthesis, produced from glucose in the liver and adipose tissue.
- A second pathway in the liver uses glycerol kinase to convert free glycerol to glycerol 3-phosphate.
Fatty Acid Activation
- A free fatty acid must be converted to its activated form (bound to CoA through a thioester link) before participating in metabolic processes such as TAG synthesis, catalyzed by fatty acyl CoA synthetases (thiokinases).
Carnitine Deficiency
- Secondary carnitine deficiency occurs primarily due to defects in fatty acid oxidation, leading to the accumulation of acylcarnitines excreted in the urine, decreasing carnitine availability.
- Defects in CPT-1 and CPT-II can cause mitochondrial oxidation defects, affecting the liver, cardiac, and skeletal muscle.
Learn about secondary carnitine deficiency, which can be a result of defects in fatty acid oxidation, liver disease, medication use, and mitochondrial oxidation. Understand how these factors lead to decreased carnitine availability in the body.
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