86 Questions
What hormonal state favors the synthesis of long-chain, even-numbered saturated fatty acids?
High insulin/glucagon ratio
Which carrier is involved in transporting acyl/acetyl groups between mitochondria and cytosol during the synthesis of long-chain, even-numbered saturated fatty acids?
Citrate
Which coenzyme is used for oxidation/reduction reactions in the synthesis of long-chain, even-numbered saturated fatty acids?
NADPH
What subcellular location is primarily associated with the degradation of long-chain, even-numbered saturated fatty acids?
Mitochondria
During the synthesis of long-chain, even-numbered saturated fatty acids, what is the two-carbon donor/product?
Malonyl CoA
Which compound inhibits the synthesis of long-chain, even-numbered saturated fatty acids?
Long-chain fatty acyl CoA
Which molecule provides the highest amount of ATP during the oxidation of palmitoyl CoA?
Acetyl CoA
Which metabolic disorder is characterized by the inability to oxidize medium-chain fatty acids leading to hypoglycemia?
MCAD deficiency
How many ATP are produced from the oxidation of 7 NADH molecules during the breakdown of palmitoyl CoA?
21 ATP
What is the total energy yield from the oxidation of palmitoyl CoA after accounting for the activation energy?
129 ATP
What key intermediate is produced during the breakdown of fatty acids with an odd number of carbons?
Propionyl CoA
What leads to a significant decrease in glucose levels in patients with MCAD deficiency?
Reduced ability to oxidize medium-chain fatty acids
Which enzyme deficiency is particularly linked to sudden infant death syndrome (SIDS)?
MCAD enzyme
In the context of beta oxidation of palmitoyl CoA, what is the significance of electron transport chain in yielding ATP?
FADH2 and NADH transfer electrons to the chain, producing ATP indirectly.
Which enzyme catalyzes the transfer of the acyl group from CoA to carnitine?
Carnitine palmitoyltransferase I
What compound inhibits the entry of long-chain acyl groups into the mitochondrial matrix?
Malonyl CoA
Which tissue contains about 97% of all carnitine in the body?
Skeletal muscle
From which amino acids can carnitine be synthesized?
Lysine and methionine
Which enzyme catalyzes the transfer of the acyl group from carnitine to CoA in the mitochondrial matrix?
Carnitine palmitoyltransferase II
What is the role of carnitine-acylcarnitine translocase?
Transporting acylcarnitine into the mitochondrial matrix in exchange for free carnitine
In which tissues can carnitine synthesis occur?
Liver and kidney
Which factor decreases the CoA-requiring thiolase reaction during fatty acid oxidation?
Increasing acetyl CoA to CoA ratio
What is a primary characteristic of secondary carnitine deficiency?
Often observed in patients undergoing hemodialysis
Which condition is related to primary carnitine deficiency?
Issues with renal tubular reabsorption of carnitine
How does genetic CPT-I deficiency primarily affect the body?
By impairing the liver's ability to synthesize glucose during fasting
Which of the following is true about medium-chain fatty acids?
They are abundant in human milk
What molecule is directly produced during the first oxidation step in beta-oxidation?
FADH2
What is the net ATP yield from the complete oxidation of a palmitate molecule?
129 ATP
Which step in beta-oxidation involves a thiolytic cleavage?
Final thiolytic cleavage
What metabolic complication is NOT associated with CPT-II deficiency?
Hypoglycemia
What role does acetyl CoA play in linking fatty acid oxidation to gluconeogenesis?
It is a positive allosteric effector of pyruvate carboxylase
What dietary modification is recommended for someone with carnitine deficiency?
High in carbohydrates and low in long-chain fatty acids
Which enzyme is specifically required for the oxidation of monounsaturated fatty acids like 18:1(9) (oleic acid)?
3,2-enoyl CoA isomerase
What is a product of the initial dehydrogenation in peroxisomes during the oxidation of very-long-chain fatty acids?
FADH2
What is the side product formed when FADH2 is oxidized by molecular oxygen in the peroxisome?
H2O2
Which disorder results from the inability to transport very-long-chain fatty acids across the peroxisomal membrane?
X-linked adrenoleukodystrophy
What is the enzyme responsible for hydroxylating the α-carbon of phytanic acid in α-oxidation?
PhyH (phytanoyl CoA α-hydroxylase)
What compound is produced when the initial carbon is released as CO2 during the α-oxidation of phytanic acid?
19-carbon pristanic acid
Which enzyme deficiency causes Refsum disease?
PhyH (phytanoyl CoA α-hydroxylase)
Liver mitochondria can convert acetyl CoA into which functional ketone bodies?
Acetoacetate and 3-hydroxybutyrate
What happens to the energy output when oxidizing unsaturated fatty acids compared to saturated fatty acids?
Less energy is produced
Which enzyme is required for the oxidation of polyunsaturated fatty acids such as 18:2(9,12) (linoleic acid) in addition to the isomerase?
2,4-dienoyl CoA reductase
What activates Acetyl CoA carboxylase during fatty acid synthesis?
Insulin
Which component is NOT involved in fatty acid synthesis in the liver?
FADH2
What compound inhibits carnitine palmitoyltransferase I, preventing fatty acid degradation in mitochondria?
Malonyl CoA
Where does the oxidation of very-long-chain fatty acids (VLCFA) primarily occur?
Peroxisome
Which enzyme deficiency leads to a common inborn error of metabolism causing hypoketonemia and hypoglycemia?
Medium-chain fatty acyl CoA dehydrogenase
What role does the glycerol backbone from degraded triacylglycerol play in the liver?
Gluconeogenesis
What enzyme is necessary for β-oxidation of fatty acids with an odd number of carbons to convert methylmalonyl CoA to succinyl CoA?
Methylmalonyl CoA mutase
Which compound is an allosteric activator of Acetyl CoA carboxylase?
Citrate
In what cellular location does fatty acid desaturation occur?
Endoplasmic reticulum
What is the primary regulator of the enzyme hormone-sensitive lipase in adipose tissue?
Insulin
Why are fatty acids considered important sources of energy for peripheral tissues?
They are soluble in aqueous solution and do not need to be transported as part of lipoproteins.
What leads to the production of fatty acids in the liver?
Excess acetyl CoA beyond the liver's oxidative capacity
Which enzyme's inhibition and activation are influenced by elevated hepatic acetyl CoA?
Pyruvate dehydrogenase and pyruvate carboxylase
What allows for the continued oxidation of fatty acids during ketogenesis?
Generation of free CoA
What determines the equilibrium between acetoacetate and 3-hydroxybutyrate?
The NAD+/NADH ratio
Which enzyme is the rate-limiting step in the synthesis of ketone bodies?
HMG CoA synthase
Where is HMG CoA synthase primarily active?
In the liver
What can acetoacetate spontaneously decarboxylate into?
Acetone
What happens to the NAD+/NADH ratio during fatty acid oxidation?
It decreases, pushing OAA to malate
In the context of fatty acid oxidation disorders, what are the typical metabolic presentations?
Hypoketosis and hypoglycemia
Which ketone body is produced through the reduction of acetoacetate?
3-hydroxybutyrate
What is the initial substrate for ketone body synthesis in the liver?
Fatty acids
Which enzyme reduces acetoacetate to 3-hydroxybutyrate?
3-hydroxybutyrate dehydrogenase
What condition results from the excessive accumulation of ketone bodies in the blood?
Ketoacidosis
Which of the following molecules is NOT a ketone body?
HMG-CoA
What enzyme is responsible for converting acetoacetate to acetone?
Acetoacetate decarboxylase
What initiates the synthesis of triacylglycerol in response to excess calorie intake?
Release of insulin
What symptom is NOT typically associated with ketoacidosis?
Muscle cramps
Which enzyme activity is associated with triacylglycerol degradation in a calorie-deficient diet?
Protein kinase
Which enzyme transfers CoA from succinyl CoA to acetoacetate?
Succinyl CoA:acetoacetate CoA transferase
What is the role of Malonyl CoA in the liver cytosol?
It is used to make C16 Fatty acyl CoA
Which of the following is NOT a product of HMG-CoA breakdown?
3-hydroxybutyrate
What happens to fatty acids in most tissues?
They are broken down by beta-oxidation to produce Acetyl CoA
In diabetes mellitus, what primarily triggers the increased production of ketone bodies?
Lack of insulin
What process occurs in the liver as a result of fatty acid breakdown?
Acetyl CoA can enter the TCA cycle or be converted to Acetoacetate
Which hormone stimulates triacylglycerol synthesis?
Insulin
In patients with medium-chain fatty acyl CoA dehydrogenase (MCAD) deficiency, why does fasting hypoglycemia occur?
Impaired oxidation of fatty acids less than 12 carbons in length results in decreased production of acetyl CoA, the allosteric activator of pyruvate carboxylase, a gluconeogenic enzyme, thus, glucose levels fall.
What is the specific defect in Zellweger syndrome that causes an accumulation of both very long chain fatty acids (VLCFA) and phytanic acid?
Inability to target matrix proteins to the peroxisome, thus all peroxisomal activities are affected.
Which compound is expected to be radioactively labeled when industrial workers breathe air contaminated with ¹⁴C-labeled carbon dioxide?
About one third of the carbons of newly synthesized malonyl CoA.
A teenager on a fat-free diet would be deficient in the synthesis of which lipid?
Prostaglandins
Which of the following accurately depicts the defect in X-linked adrenoleukodystrophy (X-ALD)?
Inability to transport very long chain fatty acids (VLCFA) into the peroxisome.
What is a common metabolic feature of Zellweger syndrome?
Accumulation of both VLCFA and phytanic acid
Why are ketone bodies not found in the urine of patients with medium-chain fatty acyl CoA dehydrogenase (MCAD) deficiency during hypoglycemia?
Impaired fatty acid oxidation results in insufficient acetyl CoA production for ketogenesis.
Why does a defect in fatty acid transport into peroxisomes result in the accumulation of very long chain fatty acids (VLCFA) in X-ALD?
Other cellular compartments lack enzymes for VLCFA degradation.
Study Notes
Synthesis and Degradation of Fatty Acids
-
Synthesis of Fatty Acids:
- Occurs in the liver
- Greatest flux through pathway: after a carbohydrate-rich meal
- Hormonal state favoring pathway: high insulin/glucagon ratio
- Major tissue site: liver
- Subcellular location: cytosol
- Carriers of acyl/acetyl groups between mitochondria and cytosol: citrate
- Phosphopantetheine-containing active carriers: acyl carrier protein domain, coenzyme A
- Oxidation/reduction coenzymes: NADPH
- Two-carbon donor/product: malonyl CoA
- Activator: citrate
- Inhibitor: long-chain fatty acyl CoA
- Product of pathway: palmitate
Oxidation of Fatty Acids
-
Beta Oxidation:
- Process yields 129 ATP total
- Produces 7 FADH2 molecules, each providing 2 ATP when oxidized by CoQ of the electron transport chain, for a total of 14 ATP
- Produces 7 NADH molecules, each providing 2 ATP when oxidized by NADH dehydrogenase, for a total of 21 ATP
- Remaining 7 acetyl CoA molecules provide 12 ATP each when converted to CO2 and H2O by the TCA cycle, for a total of 96 ATP
- Process requires 2 ATP to activate the palmitate to palmitoyl CoA, subtracted from the total
-
Medium-Chain Fatty Acyl CoA Dehydrogenase (MCAD) Deficiency:
- A metabolic disorder caused by a deficiency in the MCAD enzyme
- Occurs in 1:14,000 births worldwide
- Causes a decrease in the ability to oxidize fatty acids with 6-10 carbons
- Results in hypoglycemia and a build-up of fatty acids in the urine and blood
- Treatment includes avoidance of fasting
Oxidation of Unsaturated Fatty Acids
-
Unsaturated Fatty Acid Oxidation:
- Provides less energy than saturated fatty acid oxidation
- Requires an additional enzyme, 3,2-enoyl CoA isomerase, for monounsaturated fatty acids
- Requires an NADPH-dependent 2,4-dienoyl CoA reductase for polyunsaturated fatty acids
Ketone Bodies: An Alternate Fuel for Cells
-
Ketone Body Synthesis:
- Occurs in the liver
- Ketone bodies are produced from acetyl CoA derived from fatty acid oxidation
- Compounds categorized as ketone bodies: acetoacetate, 3-hydroxybutyrate, and acetone
- Acetoacetate can be reduced to form 3-hydroxybutyrate or decarboxylate to form acetone
-
Ketone Body Use by Peripheral Tissues:
- Ketone bodies are used as an alternate fuel for cells
- Produced in the liver and transported to peripheral tissues
- Can be used by the brain to spare glucose during prolonged fasting
Disorders of Fatty Acid Oxidation
-
Disorders of Fatty Acid Oxidation:
- Present with hypoketosis and hypoglycemia
- Caused by defects in fatty acid oxidation or transport
- Symptoms include muscle weakness, hypoglycemia, and sudden infant death syndrome (SIDS)
Excessive Production of Ketone Bodies in Diabetes Mellitus
-
Diabetic Ketoacidosis:
- Caused by a lack of insulin
- Leads to increased lipolysis and production of ketone bodies
- Symptoms include fruity breath odor, rapid breathing, nausea, vomiting, abdominal pain, confusion, and coma
- A medical emergency that can be life-threatening### Fatty Acid Metabolism
- A fatty acid is a hydrocarbon chain with a terminal carboxyl group and can be saturated or unsaturated.
- Linoleic and linolenic acids are essential for humans.
Fatty Acid Synthesis
- Occurs in the liver following a meal containing excess carbohydrate and protein.
- Carbon required for synthesis is provided by acetyl CoA, energy is provided by ATP, and reducing equivalents by NADPH.
- Citrate carries two-carbon acetyl units from the mitochondrial matrix to the cytosol.
- The regulated step in fatty acid synthesis is catalyzed by Acetyl CoA carboxylase, which requires biotin.
- Citrate is the allosteric activator of Acetyl CoA carboxylase, and long-chain fatty acyl CoA is the inhibitor.
- The enzyme can be activated in the presence of insulin and inactivated by AMPK in response to epinephrine, glucagon, or a rise in AMP.
Fatty Acid Elongation and Desaturation
- Fatty acids can be elongated and desaturated in the ER.
Triacylglycerol Synthesis and Degradation
- Triacylglycerol synthesis occurs in response to ingestion of excess calories as carbohydrate, release of insulin, and protein phosphatase activity.
- Triacylglycerol degradation occurs in response to calorie-deficient diet, release of glucagon, epinephrine, and protein kinase activity.
Fatty Acid Degradation (β-Oxidation)
- Occurs in mitochondria.
- The carnitine shuttle is required to transport LCFA from the cytosol to the mitochondrial matrix.
- A translocase and the enzymes carnitine palmitoyltransferases I and II are required.
- Carnitine palmitoyltransferase I is inhibited by malonyl CoA.
- Once in the mitochondria, fatty acids are oxidized, producing acetyl CoA, NADH, and FADH2.
- The first step in the β-oxidation pathway is catalyzed by one of a family of four acyl CoA dehydrogenases, each of which has a specificity for either short-, medium-, long-, or very-long-chain fatty acids.
Medium-Chain Acyl CoA Dehydrogenase (MCAD) Deficiency
- Causes a decrease in fatty acid oxidation, resulting in hypoketonemia and severe hypoglycemia.
Oxidation of Fatty Acids with an Odd Number of Carbons
- Proceeds two carbons at a time, producing acetyl CoA until three carbons remain (propionyl CoA).
- This compound is converted to methylmalonyl CoA (a reaction requiring biotin), which is then converted to succinyl CoA by methylmalonyl CoA mutase (requiring vitamin B12).
Ketone Bodies
- Liver mitochondria can convert acetyl CoA derived from fatty acid oxidation into the ketone bodies, acetoacetate and 3-hydroxybutyrate.
- Peripheral tissues possessing mitochondria can oxidize 3-hydroxybutyrate to acetoacetate, which can be reconverted to acetyl CoA, thus producing energy for the cell.
Triacylglycerol Synthesis and Degradation
- Triacylglycerol synthesis occurs in the liver cytosol and ER.
- Triacylglycerol degradation occurs in adipose tissue and liver.
Regulation of Fatty Acid and Triacylglycerol Metabolism
- Regulated by hormones and enzymes, such as insulin, glucagon, and epinephrine.
- Insulin stimulates triacylglycerol synthesis, while glucagon and epinephrine stimulate triacylglycerol degradation.
Compare the synthesis and degradation of long-chain, even-numbered saturated fatty acids in this quiz. Test your knowledge of the pathways and processes involved.
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