Fatty Acid Metabolism Flashcards
A heterogeneous group of water-insoluble (hydrophobic) organic molecules that can be extracted from tissues by nonpolar solvents
Lipids
Serve not only as a major source of energy for the body, but they also provide the means for separating cells and subcellular structures into distinct compartments
Lipids
The digestion of triacylglycerol is initiated in the stomach by an acid-stable lipase called
Lingual Lipase
Also produced that can hydrolyze triacylglycerol molecules containing fatty acids of short or medium chain length
Gastric Lipase
More useful in the neonate, with a less acidified stomach and a diet of breast milk abundant in medium and short chain length TAGs
Gastric Lipase
Activates a pancreatic, phosphatidylinositol triphosphate pathway
CCK
Dietary triacylglycerol is degraded by pancreatic lipase which preferentially removes the fatty acids at carbons #1 and #3, leaving a
2-monoacylglycerol
Binds to both the water-lipid interface and to pancreatic lipase, thereby anchoring and activating the enzyme
-a small pancreatic enzyme
Colipase
This enzyme acts on cholesterol esters, monoacylglycerol, or other lipid esters such as esters of vitamin A
-found in pancreatic juice
Esterase
Phospholipids are degraded by a two-step process. Pancreatic juice is rich in the proenzyme
Phospholipase A2
This enzyme removes the fatty acid at carbon #2 of the phopholipid, leaving a lysophospholipid
Phospholipase A2
The remaining fatty acid at carbon #1 is removed by lysophospholipase, leaving a
Glycerylphosphorycholine
Free fatty acids, free cholesterol, and 2-
monoacylglycerol are the major products of dietary lipid degradation in the
Jejunum
The double bonds in human fatty acids are almost always of the
Cis configuration
Glucose that is not utilized in glycolysis, glycogen synthesis, the HMP pathway, are readily converted to
Fatty acids (stored as TAGs)
Occurs in the cytoplasm of cells of liver, adipose, intestine, lactating mammary glands and to a lesser extent, kidney
Fatty acid synthesis
The process of FA synthesis incorporates carbons from acetyl CoA into the growing fatty acid chain, utilizing
ATP and NADPH as cofactors
Prior to the first catalytic step in fatty acid synthesis, we need to see the transfer of
Acetate units from mitochondrial acetyl CoA to cytoplasm
This transfer is performed via a
Citrate intermediate
This process of translocation across the inner mitochondrial membrane occurs when the matrix-side citrate concentration is
High
The first enzyme of the faty acid synthesis pathyway is
-the site of regulation
Acetyl CoA carboxylase
The remaining several reactions in fatty acid synthesis are catalyzed by a multienzyme complex called
Fatty acid synthase (FAS)
In humans, this enzyme complex consists of a dimer, each monomer of which has
7 enzymatic domains
The FAS also has a domain that covalently binds a molecule of
Phospantetheine
In prokaryotes the phosphopantetheine-
containing domain is a separate peptide, and is referred to as the
Acyl Carrier Protein (ACP)
The product of fatty acid synthase is the 16-carbon saturated fatty acid
Palmitic Acid
Fatty acids can be elongated in the
Mitochondria or ER
Chain desaturation occurs in the
ER
Requires biotin as a cofactor
Acetyl CoA Carboxylase (also PK and propionyl carboxylase)
What is the committed step of FA synthesis?
Acetyl CoA Carboxylase
Short-term control by allosteric modifiers includes
Citrate
Allosterically activates the enzyme by promoting formation of large polymers
Citrate
Inhibit acetyl CoA carboxylase by breaking down those polymers
Palmitoyl CoA (and malonyl CoA)
Inhibits acetyl CoA carboxylase through cAMP-mediated phosphorylation
Glucagon
Stimultes acetyl CoA carboxylase by dephosphorylation
Insulin
Long-term control of FA synthesis is exerted via diet, by way of
Insulin and Glucagon
Both a high-carbohydrate diet or a fat-free diet stimulate fatty acid synthesis through increased synthesis of
Acetyl CoA Carboxylase
In contrast, a high-fat diet or fasting (causing increased glucagon levels) results in
Inhibition of FA synthesis
Glucose also contributes to the synthesis of fatty acids and, therefore, to TAG production, by the diversion of
Pyruvate derived acetyl CoA to the enzymes of FA synthesis
Synthesis of glycerol phosphate occurs in both the
Adipose and the liver
Activates fatty acids to their ‘CoA’ form
FA synthetase (thiokinase)
Attaches the fatty acid moieties to the glycerol phosphate “backbone” in a process that also requires a phosphotase
Acyltransferase
Removes the phosphate prior to the addition of the third fatty acid
The Phosphotase
Stored in the cytosol as “depot” fat
Adipose derived TAG
On the other hand, liver-
derived triacylglycerol is packaged in the lipoprotein
VLDL
Fatty acids stored in adipose tissue in the form of neutral triacylglycerol serve as a major
Fuel storage depot
Depot fat mobilization is characterized by the release of free fatty acids from their triacylglycerol parent. The release is initiated by the enzyme
Hormone sensitive lipase
Removes a fatty acid from either C1 or C3 of the triacylglycerol
Hormone sensitive lipase
Next, additional lipases specific for mono- or diacylglycerol degradation remove the remaining
Fatty acids
Following their release, they exit the adipose cell and are transported in the circulation bound to
Albumin
The glycerol molecule may be taken up by liver for
Gluconeogenesis or FA synthesis
The major pathway for catabolism of saturated fatty acids is called
B-oxidation
Two-carbon units are successively removed from the carboxyl end of the fatty acid, in the form of acetyl-CoA
B-oxidation
Subsequently can enter the TCA cycle for additional oxidation and energy generation via the electron transport chain and ATP synthase
Acetyl CoA
The first step of B-oxidation is the conversion of the fatty acid to its activated form called
Fatty Acyl CoA
Because b-oxidation occurs in the mitochondria, the fatty acid must be transported across the mitochondrial membrane. This requires the carrier
Carnitine
Consists of two enzymes, carnitine acyl transferase (CAT) I and II
Carnitine Shuttle
Step one of B-oxidation is the transport of fatty acyl CoA across the outer mitochondrial membrane by
CAT I
Step 2 of B-oxidation takes place on the inner mitochondrial membrane and is catalyzed by
CAT-II
Congenital absence of a member of the carnitine system in skeletal muscle results in diminished ability to use
Long-chain FA’s as fuel
This often takes the form of
Exercise intolerance
Inhibits carnitine palmitoyltransferase I, thus preventing the entry of acyl groups into the mitochondria
Malonyl CoA
Transferred from the Matrix into the intermembrane space to be resused
Carnitine
The steps in B-oxidation are a recurring sequence of four reactions that result in the shortening of the carbon chain by
2 carbons per sequence
These four steps are repeated for fatty acids of even-numbered carbon chains (n/2 - 1) times, each cycle producing
1 acetyl CoA, 1 ADH, and 1 FADH2
The final cleavage in B-oxidation releases
2 acetyl CoAs
The three activities present in the mitochondrial “tri functional protein.” are the
Hydratase, dehydrogenase, and acyltransferase (thiolase)
The B-oxidation of a saturated fatty acid with an uneven number of carbon atoms proceeds by the same reaction steps as that of fatty acids with an even number of carbons until the
Final 3 carbons (propionyl CoA) are reached
The processing of propionyl CoA requires which three things?
Biotin, Vitamin B12, and the enzyme medium-chain acyl-CoA dehydrogenase
The processing of propionyl CoA results in
-can be used in the TCA cycle
Succinyl-CoA
The liver has the enzymatic capacity to divert acetyl CoA derived from fatty acid or pyruvate oxidation into
Ketone Body Synthesis
Exit the liver and are transported via the blood to peripheral tissues where they can be reconverted to acetyl CoA and then oxidized via the TCA cycle
Ketone Bodies
Can the liver utilize ketone bodies for energy?
No
Can occur by:
- ) The incomplete breakdown of fatty acids, or…
- ) The reversal of the thiolase reaction of fatty acid oxidation.
The first step of ketone body synthesis
Next, a third molecule of acetyl CoA condenses with acetoacetyl CoA to produce
HMG CoA
The formation of HMG CoA is catalyzed by
HMG CoA synthase
Finally, HMG CoA is cleaved by
HMG CoA Lyase
This cleavage releases
Acetyl CoA and acetoacetate
Can be reduced to form 3-hydroxybutyrate or can spontaneously decarboxylate to produce acetone
Acetoacetate
In peripheral tissues, 3-
hydroxybutyrate is reoxidized to acetoacetate, which is then converted to
Acetoacetyl CoA
Provided by succinyl CoA via 3-ketoacyl-CoA transferase
The Coenzyme A for this reaction
Missing in the liver, thus preventing it from metabolizing ketones for energy
3-ketoacetyl-CoA Transferase
Then, the acetoacetyl CoA is rapidly removed by
Thiolase
Soluble derivatives
of fatty acids that can be used by peripheral organs to preserve glucose supplies for
glucose-demaning organs
Ketone bodies
Can metabolize ketone bodies in the later stages of a fast
The brain
There’s a sharp edge to this, however, in that as ketone body levels increase, there is also increased strain on the system that regulates
Blood pH
The term applied to this advanced state of starvation, and may be detected by the odor of acetone on the breath
Ketoacidosis
