Biochemistry-synthesis and storage of fats as an energy reserve Flashcards
Summarise the overall steps in fatty acid synthesis
Fatty acid synthesis always occurs when glycolysis takes place
at a high rate. When there is excess carbohydrates in ingested
food, it is stored as glycogen and anything in excess is stored as
fat.
Glucose is broken down to 2 pyruvate molecules. Pyruvate can
then form acetyl CoA.
At high rates of glycolysis, acetyl CoA enters the cytosol where
fatty acid synthesis occurs.
Acetyl CoA is not very reactive, so it is converted to malonyl
CoA and combined with acetyl CoA and NADPH to form
palmitic acid (16 carbon molecule). Palmitic acid can then be
modified by elongation and modification.
Fatty acids that cannot be produced by this method are made by modifying fatty acids in the diet.
What is the importance of fatty acid synthesis
In mammals, fatty acid synthesis occurs almost exclusively in the fed state.
Liver: when glycogen stores are filled, glucose is used to make palmitic acid TAG VLDL.
Adipose tissue: glucose can be used to synthesise palmitic acid TAG Stored.
Lactating mammary gland: glucose can be used to make shorter fatty acids than palmitic acid.
Foetus: fatty acid synthesis supplies the fatty acids needed for brain development, subcutaneous fat and lung surfactant.
In Western diets, the high fat content suppresses fatty acid synthesis. It is rare for fatty acid synthesis to contribute a
significant amount to fat stores.
Describe pyruvate dehydrogenase
Pyruvate from glycolysis is the source of acetyl CoA used for fatty acid synthesis.
Pyruvate dehydrogenase converts the 3 carbon pyruvate into 2 carbon acetyl
CoA.
The formation of acetyl CoA is exothermic, so the enzyme is regulated.
Reaction is regulated because it is an irreversible reaction, and acetyl CoA on its
own produces little ATP. In the liver, pyruvate dehydrogenase is only activated
when glucose is plentiful.
Reaction produces NADH which contributes to ATP production.
Pyruvate dehydrogenase is sensitively regulated, as it is inhibited by its
products and stimulated by its substrates. It is also responsive to the energy charge of the cell.
Describe the role of Acetyl CoA in the cytosol
At high rates of glycolysis, lots of pyruvate in the
mitochondria is being converted to acetyl CoA. This
acetyl CoA enters the citric acid cycle to produce
energy. However, when there is an excess of acetyl
CoA, citrate synthase combines acetyl CoA with
oxaloacetate to form citrate. However, the next
enzyme in the process is already saturated, to the
excess citrate is released into the cytosol.
Citrate in the cytosol signals that the rate of glycolysis is
high. In the liver and adipose tissue, extra energy is
stored and muscle cells decrease their use of glucose.
In the cytosol, citrate lyase breaks down the citrate into acetyl CoA and oxaloacetate.
This pathway is important, because it allows oxaloacetate to be returned to the mitochondria, so the citric acid cycle is able
to continue. Also, the process of bringing oxaloacetate back into the mitochondria allows the production of NADPH from
NADH. NADPH is required for fatty acid synthesis.
Pyruvate carboxylase requires acetyl CoA for its activity, and by making oxaloacetate, it allows both the citric acid cycle and
fatty acid synthesis to continue.
Describe the activation of Acetyl Co-A
In order to make the methyl carbon more reactive, acetyl CoA is
converted t malonyl CoA. The free energy of the carboxylic acid
leaving as CO2
later, will provide the energy needed to form a
C− C bond.
Malonyl CoA also inhibits CPT I (allows fatty acids into the
mitochondria for oxidation), preventing a futile cycle.
Acetyl CoA carboxylase controls both fatty acid synthesis and oxidation, and like PDH, is highly regulated.
Describe the role of Malonyl CoA decarboxylase
In muscle, malonyl is used to control fatty acid oxidation, even though the
malonyl CoA cannot be used to synthesise fatty acids.
Both acetyl CoA carboxylase and malonyl CoA decarboxylase are regulated, so
that the availability of fatty acids, and a low energy charge of the cell favours
the entry of fatty acids into the mitochondria. This delays the use of glucose
when fatty acids are available.
What is fatty acid synthase
Fatty acid synthase is a large enzyme with 7 different protein domains (6
of which are enzymes).
The ACP domain is where the nascent fatty acid is attached, until it
reaches a length of 16 carbons, and is hydrolysed by thioesterase II.
Describe fatty acid synthesis
Fatty acid synthesis (reduction, dehydration, reduction) is the opposite of fatty acid oxidation (oxidation, hydration,
oxidation).
Malonyl CoA is decarboxylated and a condensation reaction takes place.
The compound formed is reduced, dehydrated and reduced to form a saturated acyl group.
Another malonyl CoA is used to produce a longer compound and this repeats until the chain is 16 carbons long.
One of the domains in the enzyme releases the free fatty acid.
Describe thioesterase II
Lactating mammary gland produces shorter fatty acid chains than usual, 12 or 14 C long.
The fatty acid synthase is the same, but the tissue contains an extra thioesterase that cleaves the FA chain earlier.
The resultant TAGs are secreted in the milk and are metabolised differently to TAGs with the normal LCFA.
MCFA are slightly more water soluble, and are absorbed directly into the portal blood and are therefore available as a fuel
sooner than LCFA.
MCFA acetyl CoA may also be used to elongate fatty acids, LCFA are essential for the health development of the brain.
Explain the methods of modification of fatty acids
There are a variety of fatty acids with different physical properties.
Human FAS (fatty acid synthase) only makes saturated 16 carbon fatty acids, not sufficient for the range of purposes that
fatty acids are needed for.
Ingested fatty acids may also not meet the exact requirements of the body, for this reason, synthesised and ingested fatty
acids may be modified.
The modifications are of two types: modifying the saturation and altering the
length. These modifications occur in the smooth endoplasmic reticulum of the
cell.
1. Elongation of fatty acids
Elongation of fatty acids on the smooth endoplasmic reticulum uses a similar
mechanism to fatty acid synthase. It is catalysed by elongases (ELOVL1-5).
2. Desaturation of fatty acids
Human cells contain three different desaturases: ∆9, ∆6, ∆5
desaturase, which desaturate at carbons 9 and 10, 6 and 7,
and 5 and 6 respectively.
No enzyme affects the hydrocarbon chain on a fatty acid
molecule, so we are unable to produce omega 3 and 6 fatty
acids.
∆𝟗 desaturase: only works on fully saturated fatty acids.
∆𝟔 desaturase: only works on fatty acids with a C=C double
bond in the ∆6 position leading to a methylene interruption
between the double bonds.
∆𝟓 desaturase: only works on fatty acids with a C=C bond in
the ∆5 position leading to a methylene interruption between
the double bonds.
3. Retroconversion of fatty acids
Making fatty acids shorter. It is similar to fatty acid oxidation,
but does not occur in the mitochondria (in peroxisomes).
Carbons are removed from the acetyl CoA side of the molecule.
Produces H2O2
in peroxisomes. This is why they have so much
catalase to break the H2O2 down.
What is the need for modification of fatty acids?
The enzymes that carry out the modifications of fatty acids are not very
specific with regards to substrate, so availability determines the products
made.
Mostly n-3 (omega 3) and n-6 (omega 6) fatty acids are preferred, but when
their presence in the diet is low, newly synthesised fatty acids become
substrates for modification.
For this reason, levels of Mead acid (20:3n-9) in the blood are used as a
measure of essential fatty acid deficiency.
Humans cannot make n-3 or n-6 fatty acids, so they must be obtained in the
diet.
Elongation, desaturation and Retroconversion allow humans to convert
within n-series, but not between them.
Describe the process of TAG synthesis
Both the liver and adipose tissue can incorporate fatty acids into TAG, the liver at any time, adipose tissue during the fed
state.
Glycerate-3-phosphate is produced:
o By the liver: at any time. Particularly during the fasting state. Free glycerol is phosphorylated by glycerol kinase,
using ATP. The liver produces VLDL.
o By adipose tissue: during the fed state, when there is a lot of glycolysis. Glycerol-3-P dehydrogenase converts
dihydroxyacetone-P into G3P, using NADH to form NAD. Adipose tissue uses TAG for intracellular storage.
The liver expresses both enzymes, so can make TAG during the fed state when there is lots of glycolysis and during the
fasting state when there is a lot of glycerol in the blood but glycolysis is low.
Adipose tissue only has glycerol-3-P dehydrogenase so only makes TAG during the fed state, and during fasting, it can break
TAG down.
Describe adipose tissue regulation
Perilipin prevents hormone sensitive lipase from accessing
TAG in the adipose cell (fed state).
If during exercise or fasting (insulin levels low or adrenaline
present), perilipin and hormone sensitive lipase are
phosphorylated. Hormone sensitive lipase can then remove 2
fatty acids from the lipid droplet in the cell. The TAG is not
released.
Monoacylglycerol lipase (MAG lipase) then breaks down the
fatty acids and the products transported to the blood.
The released acids can be free in the plasma or bind to
albumin.
What is fructose
When fructose is metabolised by the liver, it is converted to
fructose 1-P (by fructokinase), then to dihydroxyacetone
phosphate and glyceraldehyde (and then to glyceraldehyde
3-P).
Both are intermediates of glycolysis.
These then enter the pathway after a key regulated enzyme
(phosphofructose kinase), forcing the liver to make more fat
than it normally would.
This means that fructose metabolism is less regulated than glucose metabolism.
High fructose corn syrup is made by converting corn starch to glucose, and then fructose. It often replaces sucrose in many
foods, especially sweetened beverages, as it is significantly sweeter.
As well as unregulated entry into metabolism potentially increasing rates of de novo fatty acid synthesis, the pancreas does
not have a GLUT5 transporter, so fructose does not increase insulin release (nor leptin release).
It is suggested that fructose interacts with weight homeostasis mechanisms differently, allowing a higher caloric intake
before appetite is suppressed.
High fructose meals have been shown to increase circulating TAG, decrease plasma leptin] and [insulin], without
suppressing plasma [ghrelin].
Insulin is not released in response to fructose. It therefore does not make an individual feel full when compared to
consuming glucose.
