Fatty Acid Metabolism Flashcards
What is palmitate?
A physiological saturated fatty acid (C₁₆H₃₂O₂). Alkyl group + carboxyl group.
How are long chain fatty acids removed from glycerol?
Via the activity of lipases.
What happens to palmitate during β oxidation?
First, palmitate is activated by CoA binding to the carboxyl group. Following this the chain is cleaved at every second carbon 7 times (if there is 16 carbons). Each cleavage is a ‘round’ of β oxidation and produces 1 NADH and 1 FADH2 (for ATP synthesis) and an acetyl CoA. A 16 carbon fatty acid will produce 8 acetyl CoA, 8 NADH, 8 FADH.
How are fatty acids activated?
Adenylate synthase catalyses the covalent attachment of phosphoryl group to an O on the carboxyl group forming acyl adenylate (the AMP is formed from ATP hydrolysis releasing 2 x Pi). Then the CoA binds by the catalytic activity acetyl CoA synthetase replacing the AMP and forming acyl CoA. The CoA interacts with the AMP via the sulfhydryl group within the CoA complex displacing the AMP.
What is the first step of β oxidation?
Acyl dehydrogenase removes a hydrogen atom each from carbon 2/α and 3/β allowing a double bond to form between these carbons. (the β carbon is the carbon bound to the acyl CoA group to be cleaved that stays on the chain). The new structure is called trans-Δ2-enoyl CoA and FADH2 is formed from FAD harvesting the electrons from the C-H bonds to bond with hydrogen.
What is the second step of β oxidation?
The double bond is hydrated (3’ CH = CH 2’ +H2O -> 3’ CHOH = CHH 2’) by enoyl CoA hydratase forming 3-L-hydroxyacyl-CoA.
What is the third step of β oxidation?
3-L-hydroxyacyl-CoA dehydrogenase removes the hydrogens from the 3’ carbon forming 3-ketoacyl CoA and generating NADH from NAD+ harvesting the electrons and hydrogens from the bonds.
What is the fourth step of β oxidation?
The terminal acyl-CoA group is cleaved in a thiolysis reaction by the CoA being catalysed by β keto thiolase, forming a new acyl Co-A and giving acetyl CoA from the cleaved group.
(acyl = has an R group on the end acetyl = CH3 on the end)
What is the purpose of β oxidation / fatty acid catabolism?
The produced acetyl CoA can enter the TCA cycle. This response is usually when oxaloacetate is low.
How are ketone bodies made?
Acetyl CoA x 3 condense -> acetoacetate
The product is then either converted to
⇌ D-3-hydroxybutyrate
or
-> acetone
Both of which are ketone bodies that can be used as fuels mostly by muscles and kidneys. The kidneys especially rely on acetone because if they relied on glucose it would be lost in urine.
Explain the metabolic states / conditions when ketone bodies are made?
Under conditions of prolonged fasting or type II diabetes oxaloacetate is consumed to produce glucose. This reduces the availability of oxaloacetate for the TCA cycle which leads to the accumulation of acetyl-CoA (in the liver). When a threshold of accumulation of acetyl CoA is reached ketone bodies are made to be released into the blood to be used as fuel by other cells (especially cardiac muscle and renal cortex cells
What is the atom economy of 1 β oxidation.
1 FADH2 ~ 1.5 ATP (first step)
1 NADH ~ 2.5 ATP (third step)
= 4 ATP -1 ATP invested at the start
= 3 ATP
(btw 1 GTP = 1 ATP)
How does β oxidation in unsaturated fatty acids?
The double bond must be saturated for β oxidation to occur. This is done by transporting the unsaturated fatty acid into the mitochondria (like normal and the saturated parts undergo β oxidation) where it is isomerised and reduced to give a saturated cis enoyl.
If the FA has an odd number of carbons what happens?
β oxidation occurs as normal but the remaining carbon group is converted to succinyl CoA to enter the TCA cycle.
What is the first step of FA synthesis?
An acetyl CoA is carboxylated converting it to malonyl CoA by acetyl-CoA carboxylase (ACC), this requires 1 ATP. The substrates of FA are acetyl-CoA, malonyl-CoA and NAHPH
What enzyme facilitates FA synthesis?
Fatty acid synthase: a homodimer, each protein has 3 domains and 7 catalytic sites. As its a homodimer each FA synthase can produce two FAs simultaneously. The reactions the enzyme catalyses are: condensation -> reduction -> dehydration -> reduction
What does the cysteine part of FA synthase do?
It holds the elongating FA chain in place.
What is required to make palmitate (C₁₆H₃₂O₂)?
1 x acetyl CoA
7 x malonyl-CoA (from 7 acetyl CoA, one ATP per carboxylation)
Each addition of malonyl- CoA requires 2 NADPH -> palmitate requires 14 NADPH
Where does biosynthesis of FA occur?
In the cytosol, on/near the surface of the ER membrane as FAs are hydrophobic.
beta oxidation is in the mitochondria
How are fatty acids further elongated after the activity of FA synthase?
Elongation occurs on/along the ER membrane by elongases attached to the membrane. the reactions are similar to the cytosolic FA synthesis but FA is attached to CoA instead of ACP
Where does FA synthesis take place and what regulates it?
In the brain, liver and kidneys . regulated by hormones produced when mammary glands are activated (during and after pregnancy to make milk).
What conditions cause FA synthesis?
The pathway is used when too much carbohydrate or glucose is ingested and causes an accumulation of citrate as a result of glycolysis -> acetyl CoA -> citrate (citrate can only be metabolised in the TCA cycle. Excess citrate is removed from the mitochondria to the cytoplasm where it will be digested to acetyl CoA (for FA synthesis) and oxaloacetate. Oxaloacetate will then be recycled -> reduced to malate -> oxidised to pyruvate -> mitochondria -> oxaloacetate to achieve equilibrium with acetyl CoA.
Summarise fatty acid anabolism.
Cytosolic pathway: synthesis of saturated fatty acids - predominantly producing palmate.
Additional enzymes and reactions are required to produce the variations of fatty acids found in the body.
Further elongation of FAs occurs via enzyme found on the cytosolic face of the ER membrane.
Unsaturated fatty acids are produced at the ER via reduction reactions.
How are FAs stored?
FAs are covalently bonded to glycerol to be stored as neutral fats. (mono-,di-, or tri- acylglycerol)
