Fatty acid oxidation Flashcards
hormone mediated TAG degradation in adipocyte
cAMP is produced in the adipocyte when one of several hormones (primarily epinephrine) binds to receptors on the cell membrane, and activates adenylate cyclase.
Hormone-sensitive lipase (HSL) is activated when phosphorylated by a cAMP-dependent protein kinase.
In the presence of high levels of insulin and glucose, HSL is dephosphorylated, and becomes inactive.
Glycerol
glycerol to glycerol phosphate using glycerol kinase (liver)
Fatty acid
uses fatty acyl coa synthetase and fatty acyl CoA enters mitochondrion for Beta oxidation
Carnitine
used to move fatty acids into the mitochondrion
Long chain acyl CoAs are not able to cross the inner membrane.
The transported form is acyl-carnitine, which is synthesized by carnitine acyltransferase I (CAT I) (also called carnitine palmitoyltransferase I, CPT I) using acyl CoA and carnitine as substrates.
Inside the mitochondrial matrix the acyl-carnitine is reconverted to acyl CoA.
CAT I is the rate limiting step in b-oxidation. It is allosterically inhibited by malonyl CoA.
Carnitine deficiency
- result in massive triacylglycerol deposits in the liver
- also result in muscle cramping, hypoglycemia, weakness, or death
acyl coA dehydrogenase
-saturated bond to double bond in beta oxidation
Locate in the mitochondrial matrix.
Oxidize acyl CoAs.
Four forms of the enzyme exist specific for short (4-8), medium (4-14) and long (12-18) and very long carbon chains.
Use FAD and introduce a trans double bond.
Genetic defects in all four enzymes have been described. Results in severe hypoglycemia provoked by fasting. May be a significant cause of “Sudden Infant Death Syndrome”.
Enoyl CoA hydratase
In Beta oxidation
adds water across the trans double bond from earlier step
enoyl CoA–> 3-hydroxyacyl CoA
Beta-hydroxy-CoA dehydrogenase
Oxidizes the hydroxyl generating Beta-keto-acyl-CoA and NADH from NAD
3hydroxyacyl Coa–> 3 ketoacyl Coa
Thiolase
Releases acetyl CoA and transfers the fatty acid shortened b
Energy from fatty acid oxidation
4 step repeated reaction
Each step loses 2C as acetyl coA to
generate NADH and FADH2
Use FADH2 NADH and acetyl CoA to get ATP
Odd number chain fatty acids
need an extra step:
the last round leaves a fatty acyl CoA with three carbons (propionyl CoA).
propionyl CoA carboxylase adds a carboxyl group to the fatty acidcreating D-methylmalonyl Coa, which is converted to L— and then rearranged to succinyl CoA by methylmalonyl Coa mutase in Vit B12 requiring rxn
Succinyl Coa goes to TCA
Vit B12 def
Deficiency of the mutase or in converting Vitamin B12 to the coenzyme form causes methylmalonic acidemia and aciduria because of the accumulation of propionate and methylmalonate in cells.
Peroxisomal Beta oxidation
Peroxisomes are also a major site of b-oxidation.
Very long chain and branched (phytanic acid from plants) fatty acids are preferentially oxidized in peroxisomes.
Although the intermediates are the same the enzymes are unique to peroxisomes.
Some medium chain fatty acids are exported from peroxisomes to the mitochondria for further oxidation.
Zellweger syndrome and X-linked adrenoleukodystrophy are related to defects of peroxisomal b-oxidation.
alpha oxidation of fatty acids
Phytanic acid, a branched-chain fatty acid.
It is not a substrate of acyl CoA dehydrogenase.
It is hydroxylated at the a-carbon by fatty acid
a-hydroxylase, then decarboxylated and
activated to its CoA derivative for b-oxidation.
Deficiency of a-hydroxylase causes Refsum disease.
Acyl CoA dehydrogenase deficiencies
Medium chain dehydrogenase deficiency is most common (1 in 12,000 births in U.S.)
Characterized by:
Hypoglycemia, sleepiness, vomiting, coma
increased urinary excretion of carnitine esters
low tissue carnitine levels
low levels of ketone bodies in fasting state
Can be treated with a low fat, high carbohydrate diet
May be related to SIDS
(medium chain FAs are very high in milk)
Refsum Disease
-lack of alpha-hydroxylase
-Defect in phytanic acid metabolism (peroxisomal)
-Accumulation of large amounts of phytanic acid in liver and kidney
-Pigmented retina and polyneuropathy
-Onset usually before age 20
The symptoms are primarily neurologic.
Persoxisomal biogenesis disorders
Zellweger syndrome
Juvenile onset of a constellation of symptoms.
Usually fatal before age 2
Accompanied by accumulation of phytanic acid due to lack of peroxisomal activities
Ether linked glycerol lipids are also defective (normally synthesized in the peroxisome)
Ketone bodies
-excess acetyl CoA is converted into ketone bodies and exported from the liver
Elevated hepatic acetyl CoA and NADH inhibit pyruvate dehydrogenase, but activate pyruvate carboxylase, the OAA produced thus is used by the liver for gluconeogenesis rather than the TCA cycle.
High levels of NADH and ATP during fatty acid oxidation inhibit the TCA cycle enzymes ( isocitrate dehydrogenase and a-keto-glutarate dehydrogenase complex), which favors ketone bodies synthesis as well.
Water-soluble fuels exported to the brain and other tissues when fuel is not available
Substrates for oxidative metabolism when glucose is low
High levels of NADH during fatty acid oxidation promotes conversion of acetoacetate into 3-hydroxybutyrate
Acetone fate
- small amounts
- eliminated in urine, breath
Acetoacetate and Beta-hydroxybutyrate
produced primarily in the liver
diffuse in blood to other peripheral tissues
reconverted to acetyl CoA (enzyme missing in liver, but containing in brain)
primarily transported to muscles and brain;
other tissues will use if glucose is low
Ketoacidosis
Abnormal rise in the concentration of ketone bodies in blood, lead to ketoacidosis (2 of the ketone bodies are acids which cause the lowering of blood pH) such as under starvation and low carbohydrate diet
T1D
lack of insulin activates hormone-sensitive lipases, thus stimulating FA oxidization
FA oxidation generates excess acetyl CoA, depletes NAD+ pool and increases NADH pool, that slow down the TCA cycle and force excess of acetyl CoA into Ketone body synthesis
