Fatty Acid Oxidation & Ketogenesis
Terms in this set (53)
What is the major source of ATP synthesis in humans?
Fatty Acid oxidation
Where are fatty acids derived from?
From the diet, stored TG or synthesized mainly by the liver from glucose
The enzymes for FA metabolism will depend on the number of ____
carbon on FA chain
FA are divided into 4 groups. What are those groups?
1. Short chain fatty acid, SCFA (2C or 3C)
2. Medium chain fatty acid, MCFA (4C-12C)
3. Long chain fatty acid, LCFA (12C-20C)
4. Very Long chain fatty acid, VLCFA (>20C)
What is the major pathway for catabolism of saturated fatty acids in mitochondria?
In β-oxidation, 2 carbon fragments are successively removed from the ___ end of the catty acyl coA producing ___, ___ and ___.
carboxyl end, produces acetyl CoA, NADH and FADH₂
What are the 3 steps in β-oxidation?
1. Fatty acid activation
2. Transport of LCFA into mitochondria
3. Carbon backbone reaction sequence
Activation of FA involves 1.___ that utilize ATP to produce high energy 2.____ and 3.____
1. acyl coA synthetase (thiokinase)
2. fatty acyl-AMP
Cleavage of pyrophosphate produces ____ that helps to drive the reaction
Where are SCFA's activated?
Cytosol or mitochondria
Where are MCFA's activated?
They cross the mitochondrial membrane and activated in matrix
Where are LCFA's activated?
Activated by enzymes in ER, outer mitochondrial membrane & peroxisomal membrane
Since β-oxidation occurs in the mitochondria, a specialized carrier is required to transport the acyl group from the cytosol into the mitochondrial matrix. This carrier is 1.____, and the transport process is called the 2.___
2. Carnitine shuttle
Where can be obtained from?
1. Diet (in meat products)
From what amino acids can carnitine be synthesized?
Lysine and methionine
Malonyl CoA inhibits a.___, thus inhibiting the entry of b.___ into the mitochondrial matrix
a. CPT 1
b. Acyl groups
____ and ____ can cross mitochondrial membrane without the aid of carnitine or CPT system
SCFA and MCFA
What is caused by carnitine deficiencies?
Accumulation of LCFA which is toxic
What can cause carnitine deficiencies?
1. Inability to synthesize (eg: in liver disease)
2. Malnutrition or in strict vegetarian
3. Increase requirement (eg: pregnancy, severe infection)
The congenital absence of a CPT-II in cardiac and skeletal muscle results in ???
an inability to use long chain fatty acids as a metabolic fuel, cause myoglobinemia and weakness following exercise
The carbon backbone reactions of β-oxidation consists of a sequence of 4 reactions that result in shortening of the fatty acid chain by two carbons. The steps include:
1. Oxidation that produces FADH₂ (acyl coA dehydrogenase)
2. Hydration (Enoyl coA hydratase)
3. Oxidation that NADH (3-hydroxyacyl coA dehydrogenase)
4. Thiolysis that releases a molecule of acetyl CoA (acyl coA acyltransferase/thiolase)
The 4 steps of β-oxidation are repeated for saturated FA of even numbered carbons. Each cycle produces an ___ group, plus one ____ and one ____
Acetyl, NADH, FADH₂
In β-oxidation, the final thiolytic cleavage produces how many acetyl groups?
Complete beta oxidation of Palmitoyl CoA (16C) produces what final products within how many cycles?
7 cycles produces 8 Acetyl Coa + 7 FADH₂ + 7 NADH + 7 H⁺
After beta oxidation, the acetyl coA produced is then completely oxidised in the ___, which results in the production of ___.
Krebs cycle, resulting in production of ATP, NADH and FADH₂
Where are FADH₂ and NADH oxidized to generate significant amounts of ATP?
In the mitochondrial electron transport chain
From palmitoyl CoA, we get 8 acetyl coA, 7 NADH and 7 FADH₂. The total energy (ATP) will be:
1. Each NADH will produce 3 ATP when oxidized in ETC
2. Each FADH₂ will produce 2 ATP when oxidized in ETC
3. Each acetyl CoA will provide 12 ATP when converted to CO₂ and H₂O by the TCA cycle
Total energy yield = 131
What is the most common IEM of FA oxidation?
Medium-chain fatty acyl coA dehydrogenase (MCAD) deficiency
MCAD deficiency leads to?
Hypoglycaemia (tissue cannot obtain full energy from FA, thus must rely on glucose)
Why are infants particularly affected by MCAD deficiency?
Because their nourishment rely on milk which contains primarily MCAD's.
Explain about oxidation of odd carbon fatty acids
1. Same as beta oxidation of even number carbon saturated FA until the final 3 carbons are reached
2. Propionyl CoA will be produced in addition to a number of acetyl CoA molecules
3. Propionyl coA is metabolized by a three step pathway.
Explain metabolism of propionyl coA
1. Propionyl coA carboxylase will convert it into D-methylmalonyl CoA
2. Converted to L-methylmalonyl coA by epimerase
3. Converted to Succinyl CoA by mutase with the aid of vitamin B12
Explain about oxidation of unsaturated fatty acids
1. β-oxidation occur until the double bond is between C3 and C4
2. The 3,4-cis double bond is isomerized to a 2,3-trans double bond which is a substrate for hydratase
3. β-oxidation resumes at the second step bypassing the first step
What is the effect of bypassing the first step when oxidizing unsaturated fatty acids?
Less energy than that of saturated FA is produced
FA that are not readily oxidized by β-oxidation enters alternate pathway of oxidation. what are those alternate pathways?
1. Peroxisomal β and α-oxidation
2. Microsomal ω-oxidation
What are the functions of these alternate oxidation routes?
1. To convert as much as possible of the unusual FA to compounds that can be used as fuels
2. To convert the remainder to compounds that can be excreted in bile or urine
What are the 2 most common branched chain FA in diet? And why must they go through alternate routes of FA oxidation?
phytanic acid and pristanic acid. They are not substrates of acyl CoA dehydrogenase due to its methyl group on its third β-carbon
Explain oxidation of phytanic acid
1. It is first oxidized to pristanic acid using the α-oxidation pathway
2. Phytanic acid is hydroxylated at the α-carbon by fatty acid a-hydroxylase
3. The product is then oxidized to a carboxyl group with release of original carboxyl group as CO₂
What is the significance of shorthening the FA by one carbon in α-oxidation?
The methyl groups will appear on the α-carbon, thus can no longer interfere with β-oxidation. Peroxisomal β-oxidation can proceed normally releasing propionyl coA and acetyl coA. When the chain is approximately 8C, the FA is transferred to the mitochondria & β-oxidation is resumed
What is Refsum's disease?
A rare inherited disorder due to defect or deficiency of the α-hydroxylase in which phytanic acid accumulates in tissue. It is characterized by nerve and retinal damage, spastic movement, bone and skin changes
What is the treatment for Refsum's disease?
Avoidance of chlorophyll-containing foods, including meat from plant-eating animals.
Explain about ω-oxidation of fatty acid
- FA may be oxidized at the ω-carbon of the chain in the ER
- The dicarboxylic acids produced by ω-oxidation undergo β-oxidation in mitochondria forming compound with 6-10 carbons which are excreted in the urine
Liver mitochondria have the capacity to divert any excess acetyl CoA derived from fatty acid or pyruvate oxidation into ___
The 3 compounds categorized as ketone bodies are:
2. 3-hydroxybutyrate (3HB)
The ketone bodies can be reconverted to acetyl CoA. T//F?
What is the function of Ketone Bodies?
1. KB are important energy source for peripheral tissues.
2. Even the brain can use KB to meet its energy needs if the blood levels rise sufficiently
3. This is important during prolonged fasting
During fasting, liver is flooded with FA mobilized from adipose tissue. The production of hepatic acetyl CoA will:
1. Inhibit pyruvate dehydrogenase (enzyme required to convert pyruvate to acetyl coA to enter TCA cycle)
2. Activate pyruvate carboxylase (enzyme required to convert pyruvate to oxaloacetate)
Oxaloacetate (OAA) is used for ___ rather than for TCA cycle
Ketone bodies are synthesized from acetoacetyl CoA which is produced from:
1. Incomplete breakdown of fatty acids
2. The reversl of the thiolase reaction of fatty acid oxidation
What is the rate-limiting step in the synthesis of ketone bodies?
HMG coA synthase (present in significant quantities only in liver)
Explain a bit on ketolysis
- 3-HB is oxidized to acetoacetate by 3-HB dehydrogenase producing NADH
- Acetoacetate is provided with coA taken from succinyl CoA by thiophorase
What cells/tissues use ketone bodies?
Extrahepatic tissues including brain (but excluding cells that lack mitochondria) efficiently oxidize acetoacetate and 3-HB in this manner.
- Liver CANNOT reconvert acetoacetate to acetoacetyl CoA, and therefore cannot itself use them as fuels (due to lack of thiophorase)
Explain relation of diabetes mellitus with ketones.
1. In type 1 DM, patients may become hyperglycaemic due to lack of insulin
2. Lack of insulin will stimulate lipolysis in adipose tissue and the resultant FFA are substrates for ketogenesis in liver.
3. An elevation of ketone body concentration in the blood will result in acidemia.
4. In uncontrolled DM, the patient may develop severe acidosis (Diabetic Ketoacidosis) and coma