Fatty Acid Metabolism Flashcards
How are the carbons in a fatty acid labelled?
- carboxylic acid group = group number 1
- first carbon after carboxylic acid carbon = alpha
- last carbon= omega
How is this fatty acid named?
- 9,12-octadecadienoic acid
- 18:2 delta 9,12
- 18:2 (omega - 6) (double bond is 6 carbons from omega carbon)
Describe naturally ocurring double bonds in fatty acids.
They are always cis, causing the fatty acid to kink.
What are the structural consequences of fatty acid unsaturation?
-unsaturated chains bend and pack in less tight with greater potential for motion
How do we come about trans unsaturated bonds in fatty acids?
Hydrogenation
How do trans unsaturated fatty acids lead to cardiovascular disease?
They have higher melting temperature than cis unsaturated FAs, making the membrane more rigid (due to lack of kink, whereas cis unsat FAs have kinks)
How are FAs stored?
On a triglycerol backbone.
What are ketone bodies?
three related compounds (acetone, acetoacetic acid, beta-hydroxybutyric acid) produced during the metabolism of fats.
During the fasted state, what is the energy source for gluconeogenesis once glycogen stores are gone?
beta oxidation of fatty acids
Under what conditions are fatty acids synthesized?
When insulin is expressed (fed state). When energy is high (ATP and NADH) and acetyl coA from glycolysis is high.
What is the overall reaction of palmitate fatty acid synthesis?
- 8 acetyl coA (2 carbons each contribute to overall 16 carbon palmitate)
- 7ATP
- 14 NADPH
Where are FAs synthesized
cytosol of liver, lactating mammary gland, adipose
What is the source of acetyl coA for FA synthesis?
acetyl coA ultimately comes from pyruvate in the mito, but we need acetyl coA to be in the cytosol. The citrate-malate-pyruvate shuttle allows for acetyl coA to be shuttled from mito to cytosol in the form of citrate (after condensing with OAA). In the energy rich state, the TCA cycle will become backed up, so citrate flows readily into the cytosol. Acetyl coA is then liberated by citrate lyase (activated by insulin) and OAA is reduced all the way to pyruvate, resulting in formation of NADPH for FA synthesis.
What are the sources of NADPH for FA synthesis?
- pentose phosphate pathway
- citrate-malate-pyruvate shuttle (malate enzyme reduces malate to pyruvate)
What is the rate-limiting and regulated step of FA synthesis?
acetyl coA carboxylase
Describe the reaction carried out by acetyl coA carboxylase in FA synthesis.
- ATP activates a bicarbonate atom by adding phosphate (biotin carboxylase domain)
- activated carbonyl is added to biotin (biotin carboxylase domain)
- carbonyl is moved from biotin to acetyl coA , forming malonyl coA (transcarboxylase). The biotin domain holds the long biotin arm to a lysine, allowing it to swing from the biotin domain to the transcarboxylase domain.
Describe the regulation of acetyl coA carboxylase.
- ACC is activated when dephosphorylated (dephosphorylation from insulin, must be high energy state for FA synthesis)
- glucagon and epinephrine inhibit ACC (low energy, no FA synthesis)
- build-up of palmitate inhibits ACC (allosteric inhibitor)
Describe the fatty acid synthase dimer protein and its role in FA synthesis.
- multifunctional protein containing acetyl carrier protein (ACP)
- adds two carbonyls from malonyl coA to the carboxylate end of an acyl acceptor
- repetitive condensation and reduction
Describe acetyl carrier protein
- holds acetyl coA
- has long flexible arm so that acetyl coA can move from one FAS domain to another
- contains prosthetic group 4’-phophopant
List the repetitive sequence of reactions carried out by fatty acid synthase.
- condense
- reduce (NADPH)
- dehydrate
- reduce (NADPH)
each round of reactions adds a new malonyl to ACP of FAS, and each round a carbon is lost during condensation as CO2
Describe the condensation reaction carried out by fatty acid synthase.
malonyl coA (3 carbons) and acetyl coA (2 carbons) are condensed together (Acetyl carrier protein esterifies to malonyl coA and brings acetyl coA into proximity). Condensation results in the loss of CO2, which is irreversible and drives the reaction forward. We know have a 4-carbon molecule. One coA group is lost as a leaving group.
Describe long chain FA activation.
This is required to shuttle LCFAs into the mito matrix for beta oxidation.
- free FA is esterified to coA for activation. this molecule cannot pass the inner membrane either,
- to get through the inner membrane, carnitine palmitoyltransferase (CPT) I exchanges carnitine for the coA on the FA-coA. This complex passes through the inner membrane
- CPTII then transfers coA back in the place of carnitine, regenerating fatty acyl-coA
How can ketone bodies be used?
They can be broken down during fasting to avoid breaking down proteins and amino acids. Though the liver cannot use them, they are soluble and can be used by the brian. Beta-hydroxybuterate is the main molecule used by the brain during fasting. Beta-hydroxybuterate is converted to acetoacetate, and coA is transferred from succinyl coA to acetoacetate by beta-ketoacyl coA transferase, creating succinate which can enter the TCA cycle. Acetoacetyl coA is further broken down in acetyl coA to be fed into TCA.
Describe ketoacidosis in type I diabetes.
Insulin is not produced, so glucagon runs free and results in the high, unhindered production of ketones, resulting in ketoacidosis. Therefore, even if the body is fed, it thinks it is in a starved state.
