Lecture 18 lipid metabolism

needed, catabolism

When energy is _____ lipid ____ occurs.

triacylglycerols, lipases

The _______ from the diet or from lipid stores can be broken down by ____ to fatty acids and glycerol

fatty acid, acetylCoA, TCA

The ___ components of triacylglycerols are converted to ____ by the b-oxidation pathway. The acetylCoA can enter the ___ cycle or can serve as a starting material for a number of biosynthetic pathways.

anabolism, anabolism

_____ side, lipid biosynthesis occurs when there is ____ energy.

fatty acids, ATP

The ____can be synthesized from acetylCoA, and glycerol can be produced from glycolysis intermediates. The two components can be combined in ____-dependent reactions to form triacylglycerols.

triacylglycerol

Most dietary lipids are ingested as ___ compounds.

triacylglycerols

Pancreatic lipases hydrolyze the ____ into free fatty acids and 2-monoglycerides in the lumen of the intestine.

pathway of dietary triacylglycerol digestion from the lumen of the intestine to the lymph system.

-The triacylglycerols are hydrolyzed into free fatty acids and 2- monoglycerides in the lumen of the intestine.
-The 2-monoglycerides and fatty acids are transported into the enterocytes, where they are reassembled into triacylglycerols and packaged into large chylomicron complexes.
-The chylomicrons are exported from the cell and transported in the lymph system to adipocyte cells.
-The adipocytes store the lipid as triacylglycerols until there is a need for energy.

vacuoles

lipids are stored in large ____, which take up the majority of cell volume. They are so large that they sometimes displace the nucleus to the periphery of the cell.

adipose, hormones

in _____ tissue, the hydrolysis of stored triacylglycerol molecules is initiated by ____ such as adrenaline, glucagon, and ACTH.

triacylglycerol lipase

The ______ is activated by an enzymatic cascade that is triggered by a hormone binding to the appropriate receptor.

diacyl, monoacylglycerol

After cleavage of the first fatty acid by the triacylglycerol lipase, the second and third fatty acids are also removed from the ____ and ____ molecules.

glycolysis, gluconeogenesis

glycerol that is released from adipose tissue is taken up in other tissues, where it is integrated into ____ or _____ by a two step pathway.

glycerol is converted to glycolysis or gluconeogenesis

ATP-dependent kinase reaction yields glycerol 3-phosphate. Then, the glycerol 3- phosphate is oxidized to dihydroxyacetone phosphate by an NAD+ dependent dehydrogenase.

acetyl

___ specifically refers to a two carbon group with carbonyl and methyl function. Acetyl groups can be viewed as derivatives of acetic acid.
- encompasses a range of homologous carboxylic acid derivatives.
- includes the acetyl group plus other carboxylic acid derivatives that have one or many methylene groups.

adipose, cytosol

Fatty acids are carried in the blood from ___ tissues in association with serum albumin protein. The fatty acids are taken into the ____ of target cells, where they are activated by being converted to acylCoA derivatives.

acylCoA, high, carboxylic acid

The conversion of a fatty acid into an ____ intermediate is a thermodynamically unfavorable process, because the acylCoA is a thioester derivative. Thioesters have a very ____ energy of hydrolysis, which means it takes a lot of energy to make them starting with a carboxylic acid.

ATP, inorganic

To make the acylCoA derivative, the fatty acid is first activated using ___ The intermediates in the process are ___ pyrophosphate and a fatty acyl adenylate.

2, favorability

The pyrophosphate is cleaved to ___ inorganic phosphates with the release of energy, a pattern that we have previously noted, which contributes to the overall thermodynamic ___ of the reaction.

high, neutral

The acyl adenylate intermediate is a mixed acid anhydride with a ____ energy of hydrolysis. When it is swapped for CoA in the next step, the reaction is thermodynamically ___

oxidation, mitochondria.

Fatty acylCoA derivatives are synthesized in the cytosol of the cell, but the ___ of such derivatives takes place in the matrix of the _____

carnitine, CoA.

In the cytosol, the activated CoA derivative is first transferred to ___, a polar carrier molecule. The fatty acyl carnitine derivative is then transported through the mitochondrial inner membrane into the matrix. In the matrix, the fatty acyl group is transferred from carnitine back to ___

β-Oxidation Cycle, acetylCoA, 2

____begins with a fatty acylCoA derivative with n carbon atoms, and it ends with a fatty acyl derivative with n minus two carbon atoms. the two missing carbon atoms are released as ___. These oxidation cycles are repeated, each cycle shortening the fatty acylCoA by two carbons and releasing an acetylCoA. In the final cycle, a four carbon acylCoA (butyrylCoA) is converted to ___ molecules of acetylCoA.

4, 1.5, 2.5

One cycle of β-oxidation yields ____ ATP’s, ____ ATP’s for the FADH2 and _____ ATP’s for the NADH.

10, 7.5, 3, 1.5, 1

The acetylCoA enters the TCA cycle and yields ____ ATP’s, _____ ATP’s from the ____ NADH’s, ____ ATP’s from the FADH2, and ____ATP equivalent from GTP.

2

It costs ____ ATP equivalents to activate stearic acid to the acylCoA derivative.

9, 10

There are ___ acetylCoA’s fed into the TCA cycle, and each one produces ___ ATP’s for a total of 90 ATP’s.

more, twice, reduced

The answer is that fats are _____ energy rich than carbohydrates. In general, on a per gram basis, fats produce more than ____ the energy as carbohydrates. This reflects the fact that fats are more highly ___ than carbohydrates, and a more reduced compound typically yields more energy in biological oxidation reactions.

even, 2

Most fatty acids contain an ____ number of carbon atoms, and produce the ____ carbon compound acetyl CoA as the only oxidation product.

intermediate, TCA

The propionyl CoA is integrated into mainstream metabolism by conversion to an _____ of the ___ cycle, succinyl CoA.

Propionyl CoA (C3) is Converted to Succinyl CoA (C4),

In the first step, propionyl CoA is carboxylated by a biotin dependent enzyme to yield D-methylmalonyl CoA.
The second reaction converts the carboxylated product from D- to L-methylmalonyl CoA.
In the third reaction, a vitamin B12 dependent enzyme catalyzes the isomerization of L-methylmalonyl CoA to succinyl CoA.

structure of coenzyme B12

cofactor has a polyporphyrin ring system similar to that of the hemes, but the central metal ion is cobalt. the dependent enzymes generally catalyze very exotic isomerization reactions, in which carbon atoms are moved from one place to another.

ketones formation

produced when there is a need for energy in various tissues, or when the rate of the TCA cycle is inadequate to utilize all of the acetylCoA produced by fatty acid oxidation.

glycolysis, carbon dioxide

Under most conditions, acetyl CoA is produced from ___ and fatty acid oxidation at a rate that can be accommodated by the TCA cycle. Under these circumstances, most of the acetyl CoA is converted to ____

ketone, TCA

The acetyl CoA is diverted from the TCA cycle to the formation of ___bodies (short chain fatty acids) as a normal part of metabolism, when there is a specific need for extra energy in various tissues, such as heart muscle. The production of ketone bodies also occurs when the rate of the ___ cycle is inadequate to utilize all of the acetylCoA produced by fatty acid oxidation. Such conditions include starvation, uncontrolled diabetes, or as a result of some low carbohydrate diets in which fatty acids are released very rapidly.

3

There are ______ products of acetyl CoA metabolism that are collectively referred to as ketone bodies. These metabolites are acetoacetate, β-hydroxybutyrate, and acetone.

ketone body synthesis

In the first two steps of _____, two units of acetyl CoA react to form acetoacetylCoA, and a third acetyl CoA unit reacts to produce HMG-CoA. These are also the first two steps in cholesterol biosynthesis.

(ketone body synthesis), removed, acetone

In the third step, an acetyl CoA unit is then ____ from HMG-CoA, releasing acetoacetate. The acetoacetate is converted enzymatically into β-hydroxybutyrate, and is decarboxylated nonenzymatically to give ____

favorable x2

β-oxidation pathway is thermodynamically ____ (as it has to be), and the pathway for fatty acid biosynthesis is also thermodynamically ____

differences between fatty acid biosynthesis and β-oxidation.

- Fatty acid synthesis involves a biotin dependent carboxylation reaction, but β-oxidation does not.
- A malonic acid derivative is a participant in fatty acid biosynthesis, but not in β-oxidation.
- All of the oxidation-reduction reactions in fatty acid biosynthesis use NADH, but one of the oxidation-reduction steps in β-oxidation uses FAD+.

fatty acid biosynthesis running in the forward direction

-MalonylACP (the replacement for acetylCoA) condenses with an acylACP derivative to form a β-ketone.
-The β-ketone is reduced to a hydroxyl group by a reductase. -The hydroxyl group is dehydrated to form a double bond by a dehydratase.
-The double bond is reduced to a single bond by a reductase

first step of fatty acid biosynthesis,

acetylCoA is carboxylated to form malonylCoA. The reaction is catalyzed by acetylCoA carboxylase. The acetylCoA carboxylase enzyme contains a covalently bound coenzyme, biotin, which serves as a carrier of an activated bicarbonate molecule.

second step of fatty acid biosynthesis

actually consists of two parallel reactions. In one of these reactions, an acetyl group is transferred from acetylCoA to an acyl carrier protein by an acetyl transacylase enzyme. In the other reaction, a malonyl group is transferred from malonylCoA to an acyl carrier protein by a malonyl transacylase enzyme. The products of these reactions, acetylACP and malonylACP, will react with each other in the next step.

final step of fatty acid biosynthesis

enoyl-ACP reductase uses NADPH to reduce the double bond to a single bond. The product is a four carbon butyryl-ACP. That four carbon acyl-ACP can go on to condense with a malonylACP to initiate a second round of biosynthesis—the product of which would be a six carbon acyl ACP.

glyoxylate cycle

_______ is an anabolic metabolic pathway occurring in plants, and several microorganisms, such as E. coli and yeast.

isocitrate, malate

The first reaction that is unique to the glyoxylate cycle is catalyzed by _____ lyase. That reaction cleaves isocitrate into glyoxylate and succinate. The second unique reaction is catalyzed by ____ synthase. In that reaction, glyoxylate condenses with acetylCoA to produce malate.

produce

The genius of the glyoxylate pathway is that it provides a mechanism by which two-carbon acetylCoA units can ____ four-carbon products

acetylCoA, 3, 1

all of the carbons of cholesterol are derived from ______. Cholesterol has ____ six-membered rings and ____ five-membered ring, none of which are aromatic.

Cholesterol Biosynthesis

begins with the two carbon compound, acetylCoA, and ends with a six carbon intermediate, mevalonate. The second stage begins with mevalonate and ends with a five carbon activated isoprene analog, isopentenyl-pyrophosphate. Next, in stage three, six isopentenyl-pyrophosphate units are polymerized to give a 30-carbon intermediate, squalene. And finally in stage four, squalene is converted to cholesterol by a series of rearrangements and ring closure reactions.

Conversion of Mevalonate to Geranyl Pyrophosphate.

the mevalonate is first converted to a pyrophosphate derivative. That takes two ATP’s going to ADP. The next reaction involves an ATP dependent dehydration and decarboxylation. end result is a nice little five-carbon compound isopentenyl pyrophosphate, which has a carbon-carbon double bond at one end. Next, there is an isomerization of that new double bond. At that point, two five-carbon dimethylallyl pyrophosphate molecules condense to form a ten-carbon product, geranyl pyrophosphate, with the release of an inorganic pyrophosphate.

good features of cholesterol

It is a necessary precursor of steroid hormones including progesterone, testosterone, and estradiol.

Conversion of Farnesyl Pyrophosphate to Cholesterol

Then there are a series of reactions that bond various carbon atoms together to form three fused six-membered rings and a fused five membered ring. Somewhere along the line, three carbons are lost as carbon dioxide, a double bond is introduced into one of the six-membered rings, and one of the rings is hydroxylated. We are left with the final 27 carbons of cholesterol—three fused six membered rings, one fused five membered ring, and an eight-carbon hydrocarbon side chain.