FINAL Fatty acid synthesis and degradation Flashcards
What are the FOUR physiological roles of Fatty acids?
- Fuels molecules- triacylglycerols
- Building blocks of Biomembranes
- covalent modification of certain proteins
- serve as hormone or intracellular receptors
fatty acids can be stored as what molecule that serves as the primary source of our body’s energy?
triacylglycerols
In regards to Fatty acid synthesis and degradation do they mirror each other?
Yes
In fatty acid synthesis, the Activated Acyl group is lengthened by how many carbons ?
Two carbon atoms
In fatty acid degradation, the Activated Acyl group is shortened by how many carbons?
Two carbon atoms
In regards Fatty acids: oxidation, hydration, and cleavage are all a part of what process
Fatty acid degradation
In regards to Fatty acid: condensation, reduction, dehydration, reduction?
Fatty acid Synthesis
When we degrade a 1 Fatty acid, the product, that is a precursor for the TCA cycle is?
Acetyl COA
Where can we get fatty acids?
we get them from degraded triacylglycerol
Triacylglycerols can be found in?
Fat deposits/droplets
Why are Triacylglycerols represented as highly concentrated energy reserves?
Because fatty acids are much more reduced and anhydrous.
What allows Triacylglycerols to be stored in anhydrous form.
b/c Its non-polar nature, energy-rich molecules can be packed in small volumes
what is the lowest fuel reserve in our body?
Glucose 170 kJ
Highest fuel reserve in our body
Triacylglycerols 420,000 kJ
Glucose and glycogen reserves contain enough energy for how long?
used up in approximately 24 hours
how long do triacylglycerols contain sufficient energy for in a scenario of being stuck in a desert with only water?
50 days
In mammals what is the specialized tissue called that is the main site for the synthesis, storage, and mobilization of fat droplets?
Adipose tissue
Adipose tissue can be found almost everywhere, but mainly in what depots?
Subcutaneous and visceral depots
Where can you find commonly an accumulation of adipose tissue?
heart, kidneys, and the adventitia of blood vessels
most dietary lipids are ingested in the form of what?
Triacylglycerols
Dietary lipids are digested by what enzyme and where is it produced?
Pancreatic lipases
What do lipases do to Triacylglycerols?
They hydrolyze Triacylglycerols into free fatty acids and monoacylglycerol.
For Triacylglycerols to be absorbed by intestinal epithelium they require what step?
degradation to fatty acids
Why do Triacylglycerols coalesce into droplets inside in adipose tissue and stored anhydrously?
b/c they are insoluble in water, Hydrophobic
in what are dietary lipids transported in?
Chylomicrons
Chylomicrons are what?
Lipoprotein transport particles
What is the main protein component in Chylomicrons?
apolipoprotein B-48
apolipoprotein B-48 is used for what ?
transport of fat soluble vitamins and cholesterol.
When we eat from our diet we get triacylglycerols what is the process of it going to the lymph system?
- Triacylglycerols are degraded by lipases in the lumen -> Fatty acids + monoacylglycerol
- both are carried into the intestinal cell via FABP ( Fatty acid binding protein)
- fatty acid transport protein ( FATP) transfer them into the SER ( smooth ER)
- In a smooth ER FA’s resynthesize triacylglycerol
- triacylglycerol is enveloped by chylomicrons
- TAG+ Chylomicrons are released to the lymphatic system.
what are the requirements of processing for the utilization of Fatty acids for fuel in peripheral tissue?
- Mobilization
- Activation and localization
- degradation
In peripheral tissue what occurs in the mobilization process?
triacylglycerol is hydrolyzed into constituents molecules and transported to energy required tissues
In peripheral tissue what occurs in the activation and localization process?
The fatty acids are transported to mitochondria for degradation
In peripheral tissue what occurs in the degradation process?
Fatty acids are broken down, step-by-step, into acetyl-CoA. This intermediate is oxidized by the TCA cycle
Triacylglycerols are stored in
lipid droplets in adipocytes
Triacylglycerols are Hydrolyzed by
Hormone-Stimulated Lipases- HS lipase and Perilipin
What stimulates lipolysis?
Epinephrine or glucagon that acts on a 7TM receptor
Protein kinase A phosphorylates what hormone stimulated lipases?
perilipin and HS lipase
Phosphorylation of perilipin results in the activation of?
adipocyte triacylglyceride lipase (ATGL) after binding of its coactivator
HS lipase and ATGL work together to hydrolyze TAG into what constituent molecules that are transported to energy requiring tissues
Fatty acids and glycerol
Fatty acids are not soluble in aqueous solutions. To reach tissues that require fatty acids, the released fatty acids bind to what blood protein?
albumin
What happens to the glycerol that was a resulted of the hydrolysis of triacylglycerol?
- absorbed by the liver and immediately phosphorylated by glycerol kinase.
product: L-glycerol-3-phosphate - L-glycerol-3-phosphate is oxidized by glycerol phosphate dehydrogenase.
product: dihydroxyacetone phosphate - it is isomerized to glyceraldehyde-3-P
- later process by gluconeogenesis or glycolysis
To begin fatty acid degradation Fatty Acids are Linked to what molecule before they are oxidized?
esterified to acyl-CoA
What enzymes esterifies fatty acids to acyl-coA
acyl-CoA synthetase
how many ATP’s are used in equivlance to make acyl-coA?
2
Fatty acids are activated on what part of the mitochondria?
Fatty acids are activated on the outer mitochondrial membrane
Why do fatty acids need to be in the mitochondrial matrix?
for oxidation
integrity of the inner mitochondrial membrane must be maintained, fatty acyl-CoA transport requires a specialized mechanism that entails what?
- the fatty acyl-CoAs are conjugated to carnitine to form an acyl-carnitine intermediate.
catalyzed: carnitine acyl-transferase I. - The acyl-carnitine intermediate is shuttled across the inner mitochondrial membrane through by acylcarnitine translocase
3.when the acyl-carnitine is in the mitochondrial matrix, it can be re-esterified to CoA through the action of carnitine acyl-transferase II.
What happens to the regenerated carnitine molecule after it disassociates with acyl coA?
translocated to the cytoplasm to begin another round of transport.
The simplest case of Fatty acid degradation is represented by a saturated fatty acid chain with an even number of carbon atoms. We will consider this the typical situation, and its degradation follows this sequence:
1.Oxidation by FAD
2. Hydration
3. Oxidation by NAD+
4. Thiolysis by CoA
acyl-CoA dehydrogenase
This enzyme catalyzes the FAD-linked oxidation by a fatty acyl-CoA to?
trans-Δ2-enoyl-CoA.
The first reaction in every round of degradation is catalyzed by?
acyl-CoA dehydrogenase + fad-> FADH
As was seen in the succinate dehydrogenase reaction, FAD is used in the acyl-CoA dehydrogenase reaction as an oxidant instead of NAD+, why is this?
the ΔG for this reaction is not enough to drive the reduction of NAD+ to NADH.
The second reaction in fatty acid degradation in the sequence is catalyzed by ?
enoyl-CoA hydratase.
enoyl-CoA hydratase catalyzes the stereospecific hydration of the double bond C2-C3 to yield what product?
L-3-hydroxyacyl-CoA.
why is enoyl-CoA hydratase extraordinarily stereospecific?
Only one enantiomer of the product is formed.
The third reaction in the sequence of fatty acid degradation is catalyzed by?
L-3-hydroxyacyl-CoA dehydrogenase.
this enzyme L-3-hydroxy acyl-CoA dehydrogenase is specific for what isomer of 3-hydroxy acyl-CoA
L
L-3-hydroxyacyl-CoA dehydrogenase catalyzes a second oxidation reaction, which converts the hydroxyl group at C3 to a ?
keto group
By generating a keto group at position 3 of the fatty acyl-CoA chain, this reaction sets up the….. in FA degradation?
the final step in fatty acid degradation
what is the final reaction in fatty acid degradation catalyzed by?
β-ketothiolase
This enzyme catalyzes the cleavage of the 3-ketoacyl-CoA into two products:
B-ketothiolase
fatty acyl-CoA chain shortened by two carbon atoms, the other is acetyl-CoA.
The two accessory enzymes required to complete unsaturated fatty acid degradation are?
cis-Δ3-enoyl-CoA isomerase and 2,4-dienoyl-CoA reductase
what is the rule in regards to odd and even unsaturated fatty acid chains?
odd-chain unsaturations require only the isomerase, while even numbered ones also require the reductase
what is the resulting product of Palmitoleyl-CoA when it gets to the unsaturated c-c bond
trans-Δ2-enoyl-CoA
Degradation of Odd Chain Fatty Acids Yields what molecule?
Propionyl-CoA + acetyl CoA
Propionyl-CoA goes onto the TCA cycle through a series of reactions to produce what product essential to TCA?
Succinyl CoA
Though most fatty acid oxidation occurs in mitochondria, the oxidation of specialized lipids, including very long chain fatty acids (typically more than 22 carbons), methyl-branched fatty acids, and eicosanoids occurs in?
peroxisomes
For degradation of fatty acids in the peroxisomes it occurs the same but what is different?
the initial dehydrogenation reaction is replaced by an acyl-CoA oxidase that reduces O2 to H2O2.
An aberrant peroxisomal function results in?
a series of inherited genetic diseases of widespread presentation and severity ( Zellweger spectrum disorders
What is produced in the liver from acetyl-CoA when fat breakdown predominates?
ketone bodies
When is it permissible for acetyl-CoA from the degradtion of FA to enter TCA cycle
only when fat and carbohydrate breakdown are balanced
the oxidation of Acetyl-CoA through the TCA cycle is dependent upon the availability
OAA
When carbohydrates are unavailable (or utilized improperly, as in diabetes), mitochondrial levels of OAA drop and acetyl-CoA cannot or can proceed?
cannot proceed
When carbohydrates are unavailable (or utilized improperly, as in diabetes), mitochondrial levels of OAA drop, and acetyl-CoA cannot proceed, these conditions favor gluconeogenesis. Where does the excess acetyl CoA diverted to?
production of ketone bodies in the liver.
As is typically seen in mammals in starved state or uncontrolled diabetics, acetyl-CoA can be converted into acetoacetate in three enzymatic steps. Acetoacetate can then be transformed into either?
D- 3-hydroxybutyrate
and/or
acetone
How does the final product D- 3-hydroxybutyrate form
forms by the NADH-dependent reduction of acetoacetate
acetone results from what
the slow, non-enzymatic decarboxylation of acetoacetate
Utilization of ketone bodies as metabolic fuels essentially involves the reverse chemistry as in their formation. Acetoacetate is converted into acetyl-CoA in two enzymatic steps. list these steps in correct order
- Acetoacetate is activated to acetoacetyl-CoA by transferring the CoA group from succinyl-CoA via a specific CoA transferase enzyme.
- Acetoacetyl-CoA is then cleaved by CoA and thiolase to form two molecules of acetyl-CoA
The major site of ketogenesis
liver
Recall that glucose is the preferred fuel molecule for the brain and red blood cells in healthy, fed people. However, during starvation and diabetic states, the brain can meet up to 75% of its energy requirement through?
ketone bodies
High blood concentrations of ketone bodies are seen in certain pathological conditions, such as diabetic ketosis. This is because ?
acidic nature of ketone bodies can drop blood pH to dangerously low levels.
Type-I diabetics do not produce insulin, which signals to take up additional blood glucose AND to stop lipolysis by adipose tissue what are the effects?
TCA cycle slows and ketones accumulate. Continued triacylglycerol breakdown by adipose tissue results in further ketogenesis by the liver. As blood ketone levels rise, blood pH drops.
An important biochemical limitation of mammals is ?
they are unable to affect the net synthesis of glucose from fatty acids
Fatty Acid synthesis takes place in three stages.
- The first stage of fatty acid synthesis is transfer of acetyl CoA out of the mitochondria into the cytoplasm. Citrate is transported into the cytoplasm and cleaved into oxaloacetate and acetyl CoA.
- The second stage is the activation of acetyl CoA to form malonyl CoA.
- The third stage is the repetitive addition and reduction of two carbon units to synthesize C16 fatty acid. Synthesis occurs on an acyl carrier protein
What occurs in stage one of fatty acid synthesis?
- Citrate, synthesized in the mitochondria from acetyl-CoA, is transported to the cytoplasm and cleaved by ATP-citrate lyase to generate acetyl CoA for fatty acid synthesis.
- OAA must be returned to the mitochondrion
How does OAA return to the mitochondrion when in fatty acid synthesis?
- OAA is reduced to malate by NADH. This reaction is catalyzed by a cytoplasmic isoform of malate
dehydrogenase - The malate product is oxidatively decarboxylated by NADP+ in a reaction catalyzed by malic enzyme
- The pyruvate formed by malic enzyme can be carboxylated to OAA by pyruvate carboxylase
By completing the citrate/pyruvate shuttle system , how many molecules of NADPH is generated for each acetyl-CoA transferred to the cytoplasm?
one molecule of NADPH is generated
To synthesize palmitate, for example, 8 acetyl-CoA and 14 NAPDH are required. This means that 6 additional NADPH must be generated elsewhere, where?
These additional NADPH are generated by the cytoplasmic pentose phosphate shunt, which yields NADPH by oxidizing glucose in a manner that does not yield pyruvate.
what is the committed step in fatty acid synthesis?
The formation of malonyl -CoA
Once acetyl CoA is synthesized by citrate what enzyme to form what product?
catalyzed acetyl- CoA carboxylase w/ ATP hydrolysis to form Malonyl CoA
Intermediates in Fatty Acid Synthesis are Covalently Coupled to what protein?
coupled with ACP
Where are the growing chains in fatty acid synthesis link to ?
sulfhydryl terminus of phosphopantetheinic acid-derivative of the acyl-carrier protein (ACP).
How does the acyl phase begin and what enzymes catalyze the reactions?
beings with the formation of acetyl-ACP and malonyl-ACP through the functions of acetyl transacylase and malonyl transacylase
Stage 3 of fatty acid synthesis consists of a series of condensation, reduction, dehydration, and reduction rxn’s. What occurs in the first step?
In the first step, acetyl-ACP and malonyl-ACP are condensed to form acetoacetyl-ACP. This reaction is catalyzed by an acyl-malonyl ACP condensing enzyme.
The last three steps of fatty acid synthesis consist of what ?
- convert the keto group at carbon 3 to a methylene group (-CH2-), forming butyryl ACP.
NADPH is the source of reducing power.
The last three reaction in fatty acid synthesis are :
- β-ketoacyl ACP reductase-> D-3-hydroxbutyryl
- 3- hydroxylacyl ACP dehydratase->crontonyl ACP
3.Enoyl ACP reductase ->butyryl ACP
butyryl ACP continues the fatty acid synthesis process up until it reaches 16 carbon acyl-acp, what is significant about this chain?
This C16-acyl-ACP is a good substrate for a thioesterase enzyme, which hydrolyzes the C16-acyl-ACP into palmitate and ACP
How does thioesterase act as a ruler?
acts as a ruler to determine fatty acid chain length.
Because of this thioesterase, fatty acid chains longer than C16 must be synthesized through a different mechanism
The Distinctions Between Bacterial and Mammalian Fatty Acid Synthesis are Mostly Structural, how did we figure this ?
Much of our understanding of fatty acid synthesis comes from the study of bacterial systems, While the structures of bacterial and mammalian synthases are quite different, the series of chemical reactions is very much the same.
When talking about distinctions between bacterial and mammalian fatty acid synthesis we know they have similar chemical reaction but how do they differ sturcturaly?
- fatty acids synthase exists as a dimer of identical 272-kDa subunits that each contain all 7 catalytic sites required to form and release a C16 fatty acid chain.
- it is more stable and catalytically efficient
Are fatty acids synthesized/degraded by the same pathways true or false?
False
where does synthesis take place?
cytoplasm
For the synthetic intermediates they are linked with CoA? t or false
they are link with ACP
The synthetic enzymes are all distinctly by themselves t or f
false- they are apart of alarge, single polypeptide chain called the fatty acid synthase (FAS)
The reductant in fatty acid synthesis is FADH T or F?
false NADPH
The Elongation and Unsaturation of Fatty Acids are Accomplished by?
Accessory Enzyme Systems
In eukaryotes longer chain fatty acids are formed by what process?
elongation reactions that occur on the cytoplasmic face of the endoplasmic reticulum membrane
ER-localized systems are also used to introduce unsaturation into newly formed fatty acid chains through what process?
a series of membrane-bound oxidase enzymes act on saturated fatty acyl-CoAs; they use O2 as an oxidant
Mammals lack the enzymes required to introduce double bonds at positions beyond the C9 carbon of the fatty acid chain. Because of this, mammals cannot synthesize linoleate or linoleate. This gives them the results of?
linoleate and linolenate are denoted “essential fatty acids”. This signifies that they must be supplied in the diet
How does acetyl CoA carboxylase play a key role in controlling fatty acid metabolism?
AMP-activated protein kinase A (AMPK) is activated by high levels of AMP and inhibits carboxylase. Fats are not synthesized when energy is required.
How can hormones control the activity of acetyl-CoA carboxylase?
- catabolic hormones glucagon and epinephrine activate protein kinase A, which phosphorylates and inhibits acetyl-CoA carboxylase
How can the hormone insulin control the activity of acetyl-CoA carboxylase?
insulin activates synthesis by enhancing the phosphorylation of AMPK by protein kinase B, which inhibits AMPK, as well as by stimulating the activity of a protein phosphatase that dephosphorylates and activates acetyl-CoA carboxylase
What is insulins response to glucose levels in regards to fatty acid synthesis?
Insulin will then facilitate synthesis by increasing glucose uptake, thus favoring glucose-6-phosphate synthesis which leads to increased acetyl-CoA (after glycolysis) and NADPH (via the pentose phosphate pathway). Insulin also activates citrate lyase.
Acetyl-CoA can only be controlled by the hormones True or false ?
wrong- can also be controlled by allosteric effectors like citrate and MIG12
citrate mitigates inhibition due to phosphorylation to what enzyme of process?
Acetyl- CoA carboxylase in fatty acid synthesis
What occurs to the activity of acetyl-CoA carboxylase when it dephosphoylated?
Its activity levels are elevated
what end product of fatty acid synthase, inhibits the carboxylase by causing depolymerization
Palmitoyl CoA
How does acetyl-CoA carboxylase regulate fatty acid degradation?
malonyl-CoA, inhibits carnitine acyl-transferase I, and prevents further fatty acid oxidation inside mitochondria when fuel molecules are abundant aka no transport no degradation
How can the excess production of NADH from ethanol processing lead to inhibition of fatty acid degradation in the liver?
Excess NADH also inhibits fatty acid degradation and stimulates fatty acid synthesis, leading to the accumulation of fats in the liver
when there is a build-up of acetyl CoA it can lead to ketone body secretion into liver what occur because of this?
acidosis caused by lactate accumulation.
If acetate cannot be process what is the consequence of this?
acetaldehyde accumulates- Acetaldehyde is very reactive and modifies reactive groups of proteins, causing a loss of protein function. As protein damage accumulates, liver function can fail.
