Production Of Acetyl Coa From Fatty Acids. Ketone Body Synthesis And Utilization.

Front 1

What are two beneficial features of fatty acids as a stored fuel?

Back 1

a. Highly reduced = more energy.
b. Not hydrated = tightly packed.

Front 2

How are fats stored?

Back 2

triacylglycerols (TAG)

Front 3

What is the first step in the breakdown of TAGs?

Back 3

Bile salts (glycocholate), make fats soluble.

Front 4

a. What do lipases do to fats?
b. Which two lipases act on TAG and in what order?
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Back 4

a. Hydrolyze the TAGs to monoacyglycerol and fatty acids.
b. pancreatic -> intestinal
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Front 5

a. After digestion of TAGs by lipases, what do you have and
b. Where does it go?
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Back 5

a. monoacylglycerols and fatty acids.
b. absorbed through intestinal wall.
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Front 6

What happens after monoacylglycerols and fatty acids are absorbed by the intestines?
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Back 6

They are converted back to TAGs and incorported into small particles known as chylomicrons (apolipoproteins... other lipoproteins include HDLs and LDLs).
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Front 7

Which fatty acids (in terms of length) require special transport (chylomicrons)?
.

Back 7

long chain

Front 8

what causes lipoprotein lipase to breakdown the TAGs in the chylomicrons?

Back 8

Apo C-II, which is in the chylomicron.

Front 9

In tissue, where the TAGs are being broken down to fatty acids by lipoprotein lipase, what happens to the fatty acids?
.

Back 9

They now can enter the cells.
.

Front 10

What is the fate of fats stored adipocytes?

Back 10

re-esterfied to for storage.

Front 11

What are re-esterfied fats?

Back 11

TAGs.

Front 12

Summarize Stage I of the utilization of fatty acid fuels.
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Back 12

1. TAGs are hydrolyzed to fatty acids in the adipocytes
2. released then transported by albumin to tissues requiring energy.
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Front 13

Summarize Stage II of the utilization of fatty acid fuels.
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Back 13

Fatty acids are activated and transported into the mitochondria.
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Front 14

Summarize Stage III of the utilization of fatty acid fuels.
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Back 14

Fatty acids are broken down by ß-oxidation (a step by step process).
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Front 15

what are the hormones that release fatty acids from adipocytes?
.

Back 15

•Glucagon
•ACTH
•epinephrine
.

Front 16

Detail the events leading up to and including Phase I of the utilization of fatty acids: release and transport from adipocytes.
.

Back 16

1. hormone (e.g., glucagon, ACTH, epinephrine) attaches to a receptor.
2. cAMP is generated
3. activation of cAMP dependent protein kinases.
4. phosphorylation (activation) of TAG lipase by kinase.
5. TAG lipase 6. breakdown of TAG to DAG...
6... leading to 3 fatty acids and a glycerol.
6. fatty acids are transported by serum albumin.
.

Front 17

What is the name of the enzyme found on mitochondria that converts fatty acids to fatty-CoA?

BIG PICTURE: why are we doing this?

Back 17

acyl-CoA Synthase

We are going to utilize fatty acids for energy

Front 18

a. What is fatty acid and ATP converted to?
b. What is the enzyme for this rxn.
c. What is unusual about the product of this rxn?
d. What is the goal here?
.

Back 18

a. Acyl adenylate + PPi
b. acyl-CoA synthase.
c. Most of the time the gamma phosphate that is transferred, here it is the AMP.
d. to convert fatty acid to Acyl-CoA so it can be transported into the mitochondria... thus, acyl adenylate + CoA --> Acyl-CoA is formed and then transported into the outer membrand of the mitochondria.
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Front 19

The rxn: R-COO + ATP + CoA --> acyl CoA + AMP + PPi: ∆G° = -.2, but ∆G = -8.4, why?
.

Back 19

the rxn is coupled with the hydrolysis of Pyrophosphate (PPi --> Pi + Pi).

Front 20

What happens immediately after the acyl-CoA enters the intermembrane space?
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Back 20

CPT-I converts the acyl-CoA + carnitine into acyl-carnitine, which can now pass through the inner mitochondrial membrane.
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Front 21

Where is CPT-1 located?
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Back 21

On the outer mitochondrial membrane (facing the intermitochondrial space).
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Front 22

What happens to the acyl-carnitine?

Back 22

after it pass through the inner mitochondrial membrane is converted back into acyl-CoA + carnitine.

Front 23

What drives the carnitine, recently separated from the acyl out of the mitochondrial matrix?
.

Back 23

the ß-oxidation of the acyl, the continued transport of acyl-carnitine and thus the growing concentration of carnitine.
.

Front 24

Where is CPT-II?

Back 24

on the inner mitochondrial membrane, facing the matrix.
.

Front 25

Which fatty acyl need carnitine to enter the matrix?
.

Back 25

long chains (>12-C)
.

Front 26

a. Which organs rely heavily on the ß-oxidation of fatty acyl for energy production.
b. What is generally the cause of clinical deficiency in ß-oxidation?
.

Back 26

a.
• skeletal muscle
• heart
• liver
b. CPT-II is not functional, thus acyl-carnitine gets into the matrix but it's not converted efficiently or at all.
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Front 27

What are the symptoms of adult onset CPT-II deficiency?
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Back 27

• muscle pain
• rhabdomyolysis (muscle breakdown)
• myoglobinuria

Front 28

What trigger the symptoms of adult onset of CPT-II?
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Back 28

pain and some of these other symptoms are triggered by exercise, fasting, infections, exposure to cold.
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Front 29

What are the symptoms of neonate onset of CPT-II?
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Back 29

• heart arrhythmias
• seizure, coma
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Front 30

Which is more severe CPT-II in adult or neonates, why?
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Back 30

a. Neonate
b. extreme and ubiquitous build up of acy-carnitine in the cells and the plasm has a negative effect on heart function.
c. effects uptake of carnitine.
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Front 31

what four enzyme are required for ß-oxidation? and which is most important?

Back 31

• thiolase (most important, it breaks the C-bonds)
• acyl-CoA dehydrogenase
• enoyl-CoA hydrotase
• L-hydroxyacyl-CoA dehydrogenase
.

Front 32

a. What is the role the following enzymes in ß-oxidation?
• acyl-CoA dehydrogenase
• enoyl-CoA hydrotase
• L-hydroxyacyl-CoA

b. What happens next?
.

Back 32

a. To introduce a carbonyl at the ß-carbon... converting all acyl CoA to acetyl CoA.

b. thiolase can then catalyze the breakdown of acetyl-CoA after each cycle.
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Front 33

How many acetyl-CoAs do you get from a 16-carbon molecule?

Back 33

8

Front 34

What is required for the break down of a 16-carbon acyl and what is produced?
.

Back 34

• Required:
7-FAD+
7-NAD
7-CoA
7-H2O

• Produced:
8-acetyl-CoA
7-FADH2
7-NADH
7-H+

If all of the products go through the 130 H2O are produced???
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Front 35

How many ATPs do you get from the breakdown of one 16-carbon acyl?
.

Back 35

108 ATP (6.75/carbon)

(acetyl CoA is going throught TCA cycle with the NADH and FADH2 produced in the cycle... in addition more NADH and FADH2 is being produced through ß-oxidized).
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Front 36

What is the significance of ß-oxidation of fatty acyl as it relates to water?
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Back 36

The process produces 130 water molecules.
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Front 37

Why are saturated fatty acids bad for you?
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Back 37

They precipitate out and clog arteries.
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Front 38

What other uses do acetyl CoAs have besides the TCA cycle?
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Back 38

Some are converted to ketones metabolites.

Front 39

Name three acetyl CoA metabolites (which one is not really a ketone?)
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Back 39

• acetone
• acetoacetate
• D-3-hydrobutyrate (not a ketone)
.

Front 40

Where are ketones made from acetyl CoA?

Back 40

ONLY in the Mitochondrial Matrix of the Liver.
.

Front 41

What is the rxn dynamic of the following ketones?
• acetoacetate
• acetone
• D-3-hydrobutyrate
.

Back 41

• acetoacetate in equilibrium with D-3-hydrobutyrate (production of acetoacetate from D-3-HB is NAD dep.)
• acetoacetate is converted to acetone
.

Front 42

Besides clipping of the final acetyl CoA in ß-oxidation, what does thiolase do in ketone synthesis?
.

Back 42

Thiolase catalyzes the conversion of 2 acetyl-CoA into on acetoacetyl-CoA... and vice versa... so thiolase is important in the conversion and utilization of ketones to and from acetyl CoA

Front 43

a. What is the fate of acetoacetyl-CoA?
b. What catalyzes this process?

Back 43

a. it is converted to HMG CoA.
b. HMG CoA synthase

Front 44

a. What is the fate of HMG CoA?
b. What catalyzes this process?

Back 44

a. it is converted to acetoacetate.
b. HMG CoA lysase

Front 45

a. In the equlibrium of acetoacetate to hydroxybutyrate, what drives the rxn to hydroxybutyrate.

.

Back 45

a. High [NADH]= hydroxybutyrate... low [NADH] = acetoacetate

Front 46

What is the fate of acetone?
.

Back 46

Of no energy use, thus it is excreted.
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Front 47

What tissues/organs prefer ketones as an energy source?
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Back 47

• Kidney cortex
• heart muscle.
• peripheral tissues during periods of fasting or starvation.
.

Front 48

Ketones are small, do they need help in blood transport?
.

Back 48

no.
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Front 49

What is the range of ratio between... hydroxybutyrate: acetoacetate?
.

Back 49

1:1 to 10:1 in favor of hydroxybutyrate.
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Front 50

Why would find hydroxybutyrate and acetoacetate circulating through the blood?
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Back 50

They can be converted to acetyl-CoA and thus they are a fuel source.
.

Front 51

Can acetoacetate be directly reactivated?
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Back 51

no only as part of cholesterol synthesis.
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Front 52

A. Describe the 2 steps in ketone utilization, which converts acetoacetate into 2 acetyl CoA in the mitochondrial martrix... include enzymes and other requirements?

B. Which is the rate limiting step?
.

Back 52

STEP I:
a. acetoacetate --> acetoacetyl CoA
b. requires
• CoA transferase
• Succinyl CoA
A:
STEP II:
a. acetoacetyl CoA --> 2 each of acetyl CoA
b. requirements:
• thiolase
• CoA (for the second acetyl CoA.)

B. STEP I

Front 53

a. Where did the succinyl come from in the reactivation of acetoacetate CoA?
b. is GTP produced in this use of succinyl CoA?

.

Back 53

a. It is siphoned off of the TCA cycle.
b. no

Front 54

a. At what level does the blood become saturated with ketones? (ketonemia, ketonuria)
b. in which people is this common?
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Back 54

a. 12mM
b. dieters
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Front 55

What danger is involved in increased blood ketone concentration?
.

Back 55

blood loses its buffering capability resulting in the lowering of pH.
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Front 56

a. Which hormones regulate ketogenesis?
b. Which hormone is the hormone of fasting?
.

Back 56

a. glucogon, ACTH, and epinephrine releases fatty acids from adipocytes.

b. Glucagon (targets the liver... opposed by insulin.)
.

Front 57

Name the 3 points of regulation for ketones.

Back 57

1. Hormones

2. Uptake of fatty acids: Malonyl-CoA (inhibits CPT-I)

3. the acetyl-CoA is used in the TCA cycle instead of ketogenesis, where as the level of serum ketones increase more free fatty acids are converted to ketones. And as NADH increase the TCA cycle slows down and ketones are preferentially made in its place.
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