Lecture 42

Question 1

What is the difference between synthase and synthetase?

Answer 1

Synthase - No ATP required to produce something

Synthetase - ATP required to produce something

Question 2

Under what physiological conditions does Fatty Acid Oxidation (FAO) become predominant source of energy?

Answer 2

1) By heart muscle which almost exclusively depends on FA oxidation for energy
2) In diabetic patients in whom glucose metabolism is low
3) During periods of starvation
4) During periods of extended exercise (e.g. aerobics, running on a treadmill, running for long distances)

Question 3

The major source of energy for this type of muscle comes from oxidation of fatty acids

Answer 3

Heart muscle

Question 4

By studying disorders of oxidation of fatty acids by mitochondria, scientists are now beginning to understand the following diseases:

Answer 4

1) Symptoms of Reyes-like syndrome
2) Cardiomyopathy
3) Hypotonia
4) Hypoglycemia
5) Developmental delay
6) In some cases sudden infant death syndrome (SIDS)

Question 5

What is a description of the sequential steps in the oxidation of fatty acids?

Answer 5

1) Mobilization of fat from adipose tissue
2) Transport of fatty acids in plasma and their activation in the cells
3) Transport of activated fatty acids to mitochondria and oxidation
4) Formation of and utilization of ketone bodies (excess FA oxidation in starvation and diabetes)
5) Regulation of fatty acid oxidation

Question 6

Which hormones affect lipolysis?

Answer 6

Lipolysis inducing hormones:
1) Epinephrine
2) Glucagon
3) Adrenocorticotropic
Lipolysis inhibiting hormone:
1) Insulin

Question 7

How does albumin work in lipolysis?

Answer 7

Serum albumin acts as a free fatty acid carrier in the blood

Question 8

What are the steps during mobilization of fatty acids in lipolysis?

Answer 8

1) Lipolysis by hormone activation
2) Adenylate cyclase converts ATP to cAMP
3) Protein kinase is then activated to phosphorylate (and activate) triacylglycerol lipase
4) triacylglycerols are then converted to free fatty acids and glycerol
5) fatty acids and glycerol are released from the cell and into the blood stream

Question 9

What occurs to fatty acids when they are transported from the plasma to a cell?

Answer 9

They are bound to Fatty Acid Binding Protein (FABP) in the cytoplasm

Question 10

What happens to fatty acids once they have bound to Fatty Acid Binding Protein (FABP) in the cytoplasm?

Answer 10

1) Fatty acids travel to the outer mitochondrial membrane
2) Acyl CoA synthetase in the outer mitochondrial membrane combines Fatty acids to CoA using ATP to form Acyl CoA
(Fatty Acid + CoA + ATP –> AMP + Pi + Acyl CoA)
3) Acyl CoA then crosses into the mitochondrial intermembrane space (cannot go through inner mitochondrial membrane by itself)

Question 11

What happens to Acyl CoA once it is in the intermembrane space of the mitochondria?

Answer 11

1) Acyl CoA + Carnitine –> Acyl-carnitine with the use of Carnitine acyltransferase 1 in the outer mitochondrial membrane
2) Acyl-carnitine passes through the inner mitochondrial membrane and into the mitochondrial matrix with the help of Carnitine/acylcarnitine translocase
3) Acyl-carnitine + CoA –> Acyl-CoA + carnitine with the help of carnitine acyltransferase 2
4) Acyl-CoA can now be used for fatty acid oxidation (Beta-oxidation) in the mitochondrial matrix

Question 12

What are the steps of the beta-oxidation pathway?

Answer 12

1) Long Chain Acyl-CoA dehydrogenase (LCAD), Medium Chain Acyl-CoA dehydrogenase (MCAD), & Short Chain Acyl-CoA dehydrogenase (SCAD) are used to convert Acyl CoA to 2-trans-enoyl CoA (FAD is reduced in the process to FADH2)
2) 2-trans-enoyl CoA –> L-3-hydroxy acyl CoA; uses H2O & Enoyl CoA hydratase is the enzyme
3) L-3-hydroxy acyl CoA –> 3-ketoacyl CoA; reduces NAD+ to NADH & 3-Hydroxy acyl CoA dehydrogenase is the enzyme
4) 3-ketoacyl CoA + SCoA –> Acetyl CoA; 3-ketoacyl CoA thiolase is the enzyme

Question 13

What is common in SIDS patients (in kids, in particular) who have died from fatty acid oxidation deficiency?

Answer 13

Major causes are due to a deficiency in Medium Chain Acyl CoA Dehydrogenase (MCAD)

Question 14

How do you know how many cycles it will take to oxidize a fatty acid?

Answer 14

(The # of Carbons - 2) / 2

e.g. Palmitoleic Acid = 16C, 7 cycles

Question 15

The oxidation of a ______ fatty acid produces more energy than the oxidation of a _____ fatty acid

Answer 15

saturated; unsaturated (for every double bond, you will not reduce FAD to FADH2 because you bypass the double bond)

Question 16

What is different about plant and animal fatty acids?

Answer 16

1) Plants have an odd number of carbons in their fatty acid chains, resulting in a slightly different beta oxidation process
2) Instead of just producing Acetyl CoA from oxidation, plant fatty acid oxidation also results in the production of a Propionyl CoA
3) Propionyl CoA can be converted to Succinyl CoA to be used in the citric acid cycle

Question 17

How does the body produce energy in times of starvation or diabetes?

Answer 17

1) Excessive Fatty Acid oxidation in mitochondria

2) Ketone body formation through the use of Acetyl CoA produced from fatty acid oxidation

Question 18

Describe the steps of ketone body formation

Answer 18

1) 2 Acetyl CoA –> Acetoacetyl-CoA with the use of Beta-ketothiolase
2) Acetoacetyl-CoA –> 3-hydroxy-3-methyl Glutaryl-CoA (HMG CoA) with the use of Acetyl CoA
3) HMG CoA –> Acetoacetate with the use of HMG CoA lyase
4) a) Acetoacetate –> Acetone + CO2
b) Acetoacetate –> D-3-hydroxybutyrate witth the use of D-3-OH butyrate dehydrogenase and the reudction of NAD+ to NADH

Question 19

What happens to the plasma concentration of ketone bodies, glucose, free fatty acids, & acetoacetate during starvation?

Answer 19

As blood glucose levels decrease, the levels of ketone bodies, free fatty acids, & acetoacetate all increase in the blood

Question 20

How are ketone bodies utilized?

Answer 20

They can be used by the heart, brain and muscle for energy

Question 21

Describe the process of ketone body breakdown

Answer 21

1) D-3-hydroxybutyrate is broken down into acetoacetate by 3-hydroxybutyrate dehydrogenase
2) Acetoacetate is broken down into acetacetyl CoA by Succinyl CoA:Acetoacetate CoA Transferase and produces Succinate from Succinyl CoA in the process
3) Acetoacetyl CoA is broken down into 2 Acetyl CoA by thiolase

Question 22

Is the concentration of ketone bodies in the blood ever zero, even if one is full from eating?

Answer 22

Absolutely not. There are always ketone bodies in the blood

Question 23

How is fatty acid oxidation (FAO) regulated?

Answer 23

1) Enzyme CPTI (carnitine-palmitoyl transferase 1) is the rate limiting enzyme. It is inhibited by Malonyl CoA, a product formed during fatty acid synthesis
2) Hormonal regulation of FA oxidation:
a) Glucagon increases triacyl glycerol or hormone sensitive lipase (more breakdown)
b) Epinephrine increases triacyl glycerol or hormone sensitive lipase (more breakdown)
c) Insulin decreases triacyl glycerol or hormone sensitive lipase (less breakdown)

Question 24

What are four types of FAO deficiencies?

Answer 24

1) Carnitine deficiency - corrected by adding cartinitine to diet
2) Fattyacyl CoA synthetase deficiency - give patient C8-C10 fatty acids because they get into the mitochondrial matrix just as easily as free fatty acids
3) Short chain (SCAD - C4, C6, C8), medium chain (MCAD - C8, C10, C12), long chain (LCAD) & multi-chain (MCAD) dehydrogenase mutations - required test for neonates (cannot transport carnitine into mitochondrial matrix)
4) Acyl Carnitine-Carnitine translocase mutations

Question 25

What is the MCAD deficiency test in Neonates?

Answer 25

1) MCAD has broad specificity - it will oxidize C6, C8, C10 chain length FA
2) In MCAD deficiency, plasma will primarily contain ester of carnitine with dicarboxylic acids from C8 and C10 fatty acids (HOOC-(CH2)6-CO-carnitine), (HCOO-(CH2)8-CO-carnitine)
3) It is these carnitine esters that are quantified by mass spectrometry