Lecture 42 Flashcards
Energy Metabolism III: Degradation of Fatty Acids
1
Q
energy production
A
- fatty acids activated and carried into the mitochondria (long chain FAs)
- once in mitochondria, enzymes perform β-oxidation to breakdown FAs into acetyl CoA
- medium chain fatty acids can be carried in the bloodstream by albumin
pg 1119
2
Q
fatty acid chain length and saturation (review)
A
- short chain: 1-4 carbons
- medium chain: 6-12 carbons
- long chain: 14-20 carbons
- very long chain: 22+ carbons
- saturated have 0 double bonds, unsaturated have 1+ double bonds
pg 1120
3
Q
fatty acids degradation: overview
A
- long chain fatty acids are activated in the cytosol to fatty acyl CoA
- fatty acyl CoA is then transported into the mitochondria to be converted to fatty acyl carnitine and then undergo β-oxidation
- acetyl CoA end product goes to the TCA cycle
pg 1121
4
Q
fatty acid activation
A
- ATP + fatty acid uses fatty acyl CoA synthetase to become fatty acyl AMP (enzyme bound) and pyrophosphate
- fatty acyl AMP uses fatty acyl CoA synthetase again to become fatty acyl CoA
- pyrophosphate uses inorganic pyrophosphatase to release energy and 2 inorganic phosphate
- part of CoA is derived from pantothenic acid (vitamin B5)
pg 1122
5
Q
fatty acid transport into mitochondria
A
- fatty acid bound to albumin enters the cytosol where the FA is converted to fatty acyl CoA by acyl CoA synthetase (needs ATP)
- fatty acyl CoA transported into the mitochondria by carnitine: palmitoyl-transferase I (CPT I) which breaks it into CoA and fatty acylcarnitine (carnitine is a carrier used in reaction)
- CPT II converts CoA and fatty acylcarnitine back to fatty acyl CoA and carnitine inside the inner mitochondrial membrane
pg 1123
6
Q
L-carnitine
A
- amino acid derivative
- obtained from the diet (meat)
- can be synthesized endogenously from L-lysine and methionine in liver and kidney but NOT from skeletal and cardiac muscle cells
- highly efficient renal reabsorption (deficiencies in L-carnitine are very rare)
- body carnitine stored in skeletal and heart muscle due to high-affinity uptake systems
- carnitine enters cells via carnitine transporters: OCTN2 (organic cation transporter novel 2) is expressed in heart, muscle and kidney; liver has a different, low-affinity, high-capacity carnitine transporter
pg 1124
7
Q
carnitine transporter deficiency
A
- mutations in the OCTN2 gene
- lead to primary carnitine deficiency
- result in decreased ability of muscle tissues to use LCFA as a fuel, lipid accumulation with muscle weakness
- extremely low plasma carnitine levels
- carnitine is excreted in the urine
- individuals are at risk for heart failure, liver problems, coma, and sudden death
- triggered by fasting, illness and stress
- treatment is by supplementation with carnitine at very high doses
pg 1125
8
Q
CPT-II deficiency
A
- affects cardiac and skeletal muscle
- autosomal recessive (rare)
- elevated C16- and C18:1-acylcarnitines and low carnitine
- 3 forms: lethal neonatal, severe infantile, and mild myopathic (majority of cases in adulthood presents with exercise intolerance and attacks of rhabdomyolsis -> breaking down of SKM cells - dark urine due to myoglobin)
pg 1126
9
Q
long-chain fatty acids degradation
A
fatty acyl CoA goes through the β-oxidation spiral until only molecules of acetyl CoA remain
10
Q
β-oxidation
A
spiral pathway, repeats several times depending on FA length; continues until chain broken into 2 acetyl-CoA; attacks the β-carbon on fatty acyl CoA
- dehydrogenation #1: acyl-CoA dehydrogenase (chain length specific), e- transfer to FAD, production of double bond at β-carbon; produces 1.5 ATP
- hydration: break double bond and add -OH group
- dehydrogenation #2: NAD+ electron acceptance; produces 2.5 ATP
- formation of acetyl CoA: β-keto thiolase cleaves bond and releases acetyl CoA
pg 1128
11
Q
β-oxidation energy yield
A
large amount of energy from long chain fatty acids as compared to glucose (roughly 129 ATP from a 16 C FA)
pg 1129
12
Q
energy yield comparison
A
- reducing potential of a FA much higher than a carb bc carbs already have a lot of oxygen
- oxidation of 1 glucose: 36-38 ATP; oxidation of 1 16C FA: 129 ATP
pg 1130
13
Q
regulation of LCFA degradation
A
- done by acetyl CoA carboxylase-2 (ACC-2) which converts acetyl CoA to malonyl CoA
- malonyl CoA prevents fatty acids from entering mitchondria by inhibiting CPT I
- malonyl-CoA decarboxylase (MCoADC) converts malonyl CoA back to acetyl CoA
- AMPK (AMP kinase) inhibits ACC-2 and activates MCoADC; is activated by AMP which comes from reverse reaction of 2 ADP back to AMP+ATP (from adenylate kinase/myokinase)
- accumulation of citrate in the mitochondria signals high energy -> it goes to the cytosol and is converted to acetyl CoA
pg 1131
14
Q
summary of LCFA degradation
A
- major dietary fat: palmitate (C16), stearate (C18), oleate (C18:1) and linoleate (C18:2)
- plasma transport: as part of ChyM of bond to albumin
- cellular metabolism: activated in the cytosol, enter the mitochondria via CPTI/CPTII transport (site for regulation!), undergo β-oxidation in the mitochondria producing acetyl CoA, energy yield for 1 molecule palmitoyl-CoA generates 130 ATP
pg 1132
15
Q
CPT-I deficiency
A
- affects the liver (extremely rare)
- leads to inability to use LCFA for fuel and greatly impairs that tissue’s ability to synthesize glucose during a fast
- symptoms: appear during early childhood -> hypoketotic hypoglycemia; hepatomegaly, liver malfunction, elevated blood carnitine; risk for NS damage, liver failure, seizures, coma, sudden death; can be triggered by periods of fasting or by viral infections
pg 1132
16
Q
degradation of MCFA
A
- dietary sources of (C6-12): dairy, coconut oil and palm kernel oil, human milk
- plasma transport: albumin (enter circulation from gut to portal vein), not incorporated in chylomicrons
- liver is the primary site of metabolism (for MCFA): enter the mitochondria without the need of transporters (metabolized more quickly), activated inside the mitochondria, undergo β-oxidation to form acetyl CoA
- clinical correlations: MCFA feeding, MCAD deficiency
pg 1133
17
Q
MCFA feeding
A
suitable for patients with fat malabsorption
pg 1133
18
Q
energy production from MCFA - liver
A
- MCFA bound to albumin in blood
- MCFA enter hepatocytes still carried by proteins (FABP) because they are hydrophobic
- converted to MC fatty acyl-CoA in the mitochondria where they undergo β-oxidation to acetyl CoA
pg 1134
19
Q
medium-chain fatty acyl CoA dehydrogenase (MCAD) deficiency
A
- most common inborn error of β-oxidation (1:14000 births)
- autosomal-recessive disorder
- results in decreased ability to oxidize FAs with 6-10 carbons (which accumulate and can be measured in urine)
- symptoms: severe hypoglycemia (tissues increase reliance on glucose) and hypoketonemia (decrease acetyl CoA production)
- treatment includes avoidance of fasting
pg 1135
20
Q
energy production from LCFA
A
chylomicron remnants in the blood carry LCFAs into the hepatocytes where they undergo lysosomal degradation and are converted to fatty-acyl-CoA to undergo β-oxidation
pg 1136
21
Q
very long chain FAs (VLCFA)
A
- food sources of (C>21): minimal, most produced endogenously
- plasma transport: as part of lipoproteins
- liver metabolism: exclusively in peroxisomes via β-oxidation
- component of membrane lipids
pg 1137
22
Q
Zellweger Spectrum Disorders (ZSD)
A
- mutations in at least 12 genes encoding peroxins, which are essential for the formation and normal functioning of peroxisomes
- leads to inability to metabolize VLCFA which accumulate in the blood and tissues
pg 1137
23
Q
degradation of odd number FA
A
- 3 reactions take place to convert propionyl CoA (3 carbon) to succinyl CoA (4 carbon)
- propionyl CoA to D-methylmalonyl CoA via propionyl CoA carboxylase (requires biotin)
- D-methylmalonyl CoA to L-methylmalonyl CoA via methylmalonyl CoA epimerase
- L-methylmalonyl CoA to succinyl CoA via methylmalonyl CoA mutase (requires coenzyme B12)
pg 1138
24
Q
vitamin B12 deficiency and heritable methylmalonic acidemia/aciduria
A
vitamin B12 deficiency:
- patients present with elevated levels of propionate and methylmalonate in the urine
heritable methylmalonic acidemia/aciduria:
- mutase is missing or deficient (or affinity for coenzyme is reduced)
- inability to convert vitamin B12 to its coenzyme form
- both present with metabolic acidosis and neurological manifestations
pg 1140
25
Q
degradation of branched-chain FA (Refsum disease)
A
- deficiency in a single peroxisomal enzyme, the phytanoyl coenzyme A hydroxylase that carries out α-oxidation of phytanic acid
- symptoms: retinitis pigmentosa, cerebellar ataxia, and chronic polyneuropathy
- treatment: dietary restriction (low-phytanic acid diet)
pg 1141
