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Chem251 > Lipid Metabolism > Flashcards

Lipid Metabolism Flashcards

1
Q

Why is the energy content of fats so much greater than that of carbohydrates or proteins?

A
  1. Since the carbon atoms of fatty acids are more reduced, they release more energy when oxidized compared to carbons of carbohydrates and proteins.
  2. Fats can be stored in large amounts in anhydrous form, while proteins cannot be stored in large amounts and carbs require large volume for hydration.
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2
Q

Why are cholesteryl esters located in the interior of a lipoprotein while cholesterol is located on the exterior?

A

Cholesteryl esters are highly hydrophobic and therefore occupy the nonaqueous interior of the lipoprotein. Cholesterol, with a hydroxyl group is weakly polar and therefore can interact with water molecules at the surface of the lipoprotein.

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3
Q

What happens when there is mutation in carnitine palmitoyl transferase I ?

A

Mutation in carnitine palmitoyl transferase I prevents formation of acyl-carnitine, hence no acryl groups enter mitochondria matrix, so none gets B-oxidized.
Consequences:
1. Fatty acids released from adipose tissue stores would accumulate in the liver
2. Glucose levels will fall because glucose will be the primary source of oxidizable energy in the absence of oxidizable fatty acids

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4
Q

What is the role of cobalamin (vitamin B_12) in the methylmalonyl-CoA mutase reaction?

A

B12 is essential for converting (R)-methylmalonyl-CoA to succinyl-CoA. The cobalt alternates between Co (III) and Co(II), thus functions as a free radical generator. The weak C-Co(III) bond undergoes homolytic cleavage such that C and Co each get one electron. This yields a deoxyadenosyl radical that can take a H atom from methylmalonyl-CoA, which then rearranges to form succinyl-CoA.

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5
Q

Infants have high levels of ketone bodies in their blood and 3-ketoacyl-CoA transferase in their tissues prior to weaning. What nutritional advantage does this confer?

A

Prior to weaning, babies only drink milk, which is high fat. The oxidation of fatty acids produces acetyl-CoA which is partly converted to ketone bodies in the liver. Ketone bodies are similar to glucose in that they are water soluble and easily transported. Thus, ketone bodies are readily available as fuels to support the rapid growth of the infant.

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6
Q

What is the equation for ketone body synthesis and degradation? Net result?

A

Synthesis:
2 Acetyl-CoA + H2O –> Acetoacetate + 2CoASH
Degradation:
Acetoacetate + succinyl-CoA + CoASH–> 2 Acetyl-CoA + succinate
Net Result:
Succinyl-CoA + H2O –> succinate + CoASH

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7
Q

What is the advantage of the multi-functional dimeric structure of animal fatty acid synthase?

A

The proximity of multiple enzyme activities involved in fatty acid synthesis on a single polypeptide chain enhances the efficiency of the process.
Moreover, groups that are anchored to the ACP on one subunit are mainly processed by the enzymatic activities on the opposite subunit, allowing two synthesis simultaneously.

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8
Q

Palmitate inhibits what?

A

Inhibits acetyl-CoA carboxylase

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9
Q

Malonyl-CoA inhibits what?

A

Inhibits carnitine palmitoyl transferase phosphorylation

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10
Q

What does citrate activate?

A

Activates acetyl-CoA carboxylase

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11
Q

What are two principal ways in which the cholesterol needs of many tissues are met?

A

Cholesterol can be obtained either by synthesis from acetyl-CoA or from circulating lipoproteins that enter cells by receptor-mediated endocytosis.

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12
Q

How does regulation of HMG-CoA reductase conserve cellular ATP?

A

HMG-CoA reductase catalyzes the conversion of HMG-CoA into mevalonate. This reaction is followed by 3 reactions that consume ATP. Thus, regulating HMG-CoA reducatase conserves cellular ATP.

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13
Q

Inhibition of cholesterol biosynthesis tends to increase the synthesis of what?

A

LDL receptors, so that the circulating lipoprotein LDL will enter the cell when the cell needs cholesterol.

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14
Q

How are triacylglycerols used as energy sources?

A

When energy needs dictate, triacylglycerols stored in adipose(fat) tissue are broken down by hormone-sensitive lipase. Released free fatty acids are transported in complex with albumin to the liver and other tissues.

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15
Q

What is an Acyl-CoA?

A

It is a temporary compound formed when CoA attaches to the end of a long-chain fatty acid. Acyl-CoA undergoes B-oxidation to form Acetyl-CoA.

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16
Q

Fatty Acid Oxidation begins with what step?

A

Fatty acids are first activated by the formation of Acyl-CoA in an ATP=dependent reaction catalyzed by thiokinase.

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17
Q

B oxidation takes place in where?

A

Mitochondrial matrix

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18
Q

How do acyl groups cross the inner mitochondrial membrane to get into the matrix?

A

acyl group is transferred into Carnitine by Carnitine Palmitoyl Transferase I. The resulting acyl-carnitine crosses the membrane via a carrier protein.

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19
Q

What happens to acyl-cartinine in the mitochondrial matrix?

A

Acyl-carnitine is transferred back to acyl-CoA molecule by carnitine palmitoyl transferase II, and the liberated carnitine crosses the membrane back to the cytosol.

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20
Q

What is Beta oxidation?

A

B oxidation degrades fatty acyl groups. In each cycle, C2 fragments are removed as acetyl-CoA units.

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21
Q

What are the 4 steps of standard B oxidation?

A

Start from Fatty acyl-CoA:

  1. Formation of trans-alpha,beta(next to c=o group) double bond.coupled with reduction of FAD to FADH2.
  2. Hydration of double bond to produce 3-L-hydroxyacl-CoA.
  3. Formation of B-ketoacyl-CoA coupled with reduction of NAD to NADH
  4. Thiolysis of C2-C3 bond, resulting in Acetyl-CoA and Fatty acyl-CoA which is 2 carbons shorter.

Repeat above untill everything is converted to Acetyl-CoA

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22
Q

For palmitoyl-CoA, how many cycles of B oxidation is needed and how many acetyl-CoA are made?

A

7 sequences yield 8 Acetyl-CoA.

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23
Q

Is the oxidation of fatty acids exergonic or endergonic?

A

It is highly exergonic.

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24
Q

What are extra step required in oxidation of unsaturated fatty acids, in example Linoleic acid?

A
  1. When a cis-beta,gamma double bond is encountered after several rounds of B oxidation, Enoyl-CoA Isomerase converts it to a trans-alpha,beta double bond.
  2. When a delta4(meaning starting from carbon 4) double bond is encountered in addition the trans-alpha,beta double bond, a NADPH-dependent reduction by 2-4-dienoyl-CoA reductase removes a double bond, resulting in trans-3,4 double bond.
  3. In mammals, 3,2-enoyl-CoA isomerase converts trans-3,4 double bond into trans-alpha,beta double bond.

Then, B oxidation can continue.

In E.coli, 2,4-dienoyl-CoA reductase does step 2 and 3.

25
Q

The final round of B oxidation of odd-chain fatty acids yields what?

A

propinoyl-CoA

26
Q

propinoyl-CoA is converted into what?

A

succinyl-CoA, which is a citric acid cycle intermediate

27
Q

What are the steps of propinoyl-CoA conversion to succinyl-CoA?

A
  1. ATP-dependent carboxylation catalyzed by propinoyl-CoA carboxylase and requires coenzyme biotin to produce (S)-methylmalonyl-CoA
  2. (S)-methylmalonyl-CoA converted to (R)-methylmalonyl-CoA by methylmalonyl-CoA racemase.
  3. (R)-methylmalonyl-CoA transformed into Succinyl-CoA by methylmalonyl-CoA mutase and Coenzyme B12.
28
Q

Explain the steps of reaction from (R)-methylmalonyl-CoA into Succinyl-CoA

A
  1. Homolytic cleavage of the C-Co(III) bond in methylmalonyl-CoA mutase, results in radical C and Co(II)
  2. Adenial radical takes H from beta-carbon of (R)-methylmalonyl-CoA, leaving radical on (R)-methylmalonyl-CoA
  3. Radical (R)-methylmalonyl-CoA undergoes rearrangement involving cyclopropyloxy radical.
  4. Resulting radical after rearrangement takes H back from adenial, resulting in Succinyl-CoA
29
Q

What is the main function of the Cobalt ion in Coenzyme B12?

A

The cobalt functions as a generator of free radicals, which is essential for rearranging the carbon skeleton of (R)-methylmalonyl-CoA into Succinyl-CoA.

30
Q

Why do we care about B-oxidizing fatty acids into acetyl-CoA?

A

Because acetyl-CoA can further undergo oxidation via the citric acid cycle.
Additionally, acetyl-CoA can undergo ketogenesis.

31
Q

What is the reactant and the products of ketogenesis?

A

Reactant: acetyl-CoA
Products: acetoacetate, B-hydroxybutyrate, acetone
which are collectively known as ketone bodies

32
Q

What is a characteristic of ketone bodies?

A

They are water soluble.

33
Q

What is the purpose of ketone bodies?

A

They are important sources of metabolic energy under certain circumstances like starvation.
They are sent to brain, heart, skeletal muscle via bloodstream.

34
Q

What are the steps of ketogenesis?

A
  1. Claisen condensation of two acetyl-CoA into acetoacetyl-CoA, catalyzed by thiolase
  2. Condensation of acetoacetyl-CoA with another acetyl-CoA to produce HMG-CoA, catalyzed by HMG-CoA synthase.
  3. HMG-CoA cleaved into acetyl-CoA and acetoacetate by HMG-CoA lyase
  4. Acetoacetate can be reduced to B-hydroxybutyrate in a NADH-dependent reaction
  5. Acetoacetate can undergo spontaneous decarboxylation to form acetone
35
Q

What is the definition of ketogenesis?

A

Formation of ketone bodies from acetyl-CoA

36
Q

What happens to ketone bodies after they are made?

A

They are sent to tissues and converted into two acetyl-CoA units. Succinyl-CoA supplies the CoA for this process, thus when this happens it won’t be used in the citric acid cycle to generate GTP and succinate.

37
Q

List the differences of fatty acid synthesis compared to fatty acid B-oxidation

A
  1. It is reductive
  2. It occurs in cytosol
  3. It uses NADPH as hydrogen donor
  4. Uses malonyl-CoA as its C2 donor
  5. Growing acyl chain is attached to ACP rather than CoA
  6. Uses different set of enzymes and is independently regulated
38
Q

For fatty acid biosynthesis to occur, what are needed in sufficient amounts? at where?

A

Acetyl-CoA and NADPH, at cytosol

39
Q

How does acetyl-CoA formed in mitochondrial matrix get to the cytosol?

A
  1. Acetyl-CoA reacts with oxaloacetate to form Citrate, which readily crosses the membrane via a transporter.
  2. In the cytosol, Citrate is converted to pyruvate in a series of reactions that liberates Acetyl-CoA and also generates NADPH in 1:1 ratio.
    Pyruvate tehn enters mitochondrion and gets converted to oxaloacetate
40
Q

What is the first committed step in fatty acid synthesis? Explain how.

A

The conversion of acetyl-CoA into malonyl-CoA, catalyzed by acetyl-CoA carboxylase which is a biotin-dependent enzyme.

  1. biotin + bicarbonate –> carboxybiotinyl enzyme, which is basically an activated CO2
  2. Activated CO2 gets transferred from biotin to acetyl-CoA, forming malonyl-CoA.
41
Q

How is the first committed step in fatty acid synthesis highly regulated?

A

The enzyme Acetyl CoA carboxylase is regulated both allosterically and by covalent modification.
Many ways:
1. Citrate allosterically increases the Vmax of the enzyme.
2. Long-chain acyl-CoAs inhibit the reaction
3. Phosphrylation inactivates enzyme

42
Q

What are the steps of Fatty Acid Synthesis from acetyl CoA and malonyl CoA? Occurs at where?

A

Occurs within Fatty Acid Synthase:
1-2. Synthase is primed by transferring acetyl and malonyl groups from acetyl CoA and malonyl CoA to terminal sh of the phosphopanthetheine group of ACP(acryl carrier protein), to form Acetyl-ACP and Malonyl-ACP.
3. Acetyl group transferred to a Cys-SH group of enzyme, malonyl-ACP is decarboxylated and condenses with the acetyl group to form Acetoacetyl-ACP.
4-6. Acetoacetyl-ACP is reduced by NADPH to form a hydroxyl group, then the hydroxyl group is eliminated in a dehydration reaction to form a double bond, then the double bond is reduced by NADPH to produce Butyryl-ACP.
7. Butyryl-ACP is transferred from the ACP to the enzyme Cys SH. Then, the cycle starts anew by the transfer of another malonyl group to the now vacant ACP site in the fatty acid synthase.
8. Repeat the entire cycle 7 times to yield Palmitoyl-ACP which is a C16 acyl chain. Overall, used 8 acetyl-CoA and 14 NADPH.
The completed saturated chain is released by thioester cleavage catalyzed by palmitoyl thioesterase to form Palmitate and H-SACP.

43
Q

What is a characteristic of animal Fatty Acid Synthase?

A

It is a dimer, each polypeptide has multiple enzyme activities and 2 fatty acids are synthesized simultaneously. ACP moves the growing acyl chain between active sites of enzymatic activities.

44
Q

How are triacylglycerols synthesized?

A

Precursor DHAP formed in glycolysis.
1. DHAP acyltransferase acylates DHAP into acyl-DHAP.
2. acyl-DHAP reduced by NADPH to Lysophosphatidic acid
Alternatively,
1. DHAP reduced by NADPH to Glycerol-3-Phosphate
2. Glycerol-3-Phosphate acylated by G3P-acyltransferase to Lysophosphatidic acid
Then,
3. Lysophosphatidic acid acylated tp Phosphatidic acid
4. Phosphatidic acid de-phosphorylated into diacylglycerol
5. Diacyl-glycerol acylated to Triacylglycerol

45
Q

Increase in Malonyl-CoA inhibits results in what?

A

Increase in fatty acid synthesis and decrease in fatty acid oxidation.
Malonyl-CoA inhibits carnitine palmitoyl transferase I, thus prevents acyl-CoA from entering mitochondrion.

46
Q

Short term regulation are complemented by what?

A

long term hormonal regulation, which alters the levels of key enzymes

47
Q

All 27 carbon atoms of cholesterol are derived from what?

A

Acetate

48
Q

What are the major steps of cholesterol synthesis?

A

Precursor: Acetate is converted to HMG-CoA (from ketone body biosynthesis)

  1. NADPH dependent reduction of HMG-CoA into Mevalonate
  2. ATP-dependent phosphorylation of Mevalonate into Phosphomevalonate.
  3. ATP-dependent phosphorylation of phosphomevalonate into pyrophophomevalonate
  4. ATP-dependent carboxylation of pyrophosphomevalonate into Isopentenyl Pyrophoshphate. ATP is used to make hydroxyl a good leaving group
  5. Dimethylallyl pp + Isopentenyl pp = Geranyl pp (5+5 = 10)
  6. Geranyl pp + Isopentenyl pp = Farnesyl pp (10+5 = 15)
  7. Farnesyl pp + Farnesyl pp = Squalene (15+15 = 30)
  8. Squalene oxidized into epoxide and cyclized into Lanosterol
  9. Lanosterol undergoes many steps to remove 3 carbons and results in C27 Cholesterol.
49
Q

How is cholesterol amount regulated?

A

Cholesterol biosynthesis is controlled by HMG-CoA reductase, which catalyzes the rate-limiting conversion of HMG-CoA to mevalonate. The enzyme is inactivated by phosphorylation in short term. In long term, the enzyme level is inversely proportional to cholesterol level.

50
Q

What are statins?

A

Statins are group of drugs that inhibit HMG-CoA reductase via complementary interactions at the active site of the enzyme. By inhibiting HMG-CoA, less cholesterol is made.

51
Q

What is the point of cholesterol? What does it do?

A

Cholesterol is essential for cell membrane integrity.
Also, cholesterol can be transformed into bile acids or cholesteryl esters.
Cholesterol is also the precursor of steroid hormones.

52
Q

Elevated levels of blood cholesterol is strongly correlated with what?

A

Atherosclerosis, which is a risk factor for cardiovascular disease.

53
Q

The mitochondrion outer membrane is ___________ while the inner membrane is ___________

A

semipermeable, highly impermeable

54
Q

Ions and metabolites can generate _____________ across mitochondrion inner membrane

A

ion gradients

55
Q

What is a type of lipid that is a major membrane component?

A

Glycerophospholipids. Phosphodiester forms polar head group

56
Q

What is the difference between triacylglycerols and glycerophospholipids?

A

Triacylglycerols are 3 fatty acids esterified to glycerol, thus nonpolar and can be stored in cellular compartments as fuel as adipocytes(fat cells). Glycerophospholipids have phosphate, thus they have hydrophilic and hydrophobic regions, thus structural component of membranes.

57
Q

What is the storage form of triacylglycerols? How are they used?

A

Adipocytes (fat cells).

Triacylglycerols must be hydrolyzed to release the fatty acids.

58
Q

Name 2 examples of fatty acids

A

Stearic acid, Linoleic acid

Chem251 (4 decks)

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