Beta Oxidation & Ketogenesis

Question 1

Fatty Acyl CoA Synthetase

Answer 1

Thiokinase

Presents to outer mitochondrial membrane (cytosolic side)

Activates Fatty acids to fatty acyl CoA

Requires ATP

Question 2

Stages of Beta Oxidation

Answer 2

1. Activation of fatty acid
2. transport FA from cytosol to mitochondria
3. beta oxidation proper

Question 3

CPT-I

Answer 3

Carnitine palmitoyl transferase

Found in the outer mitochondrial matrix

Binds the acyl group of acyl COA to carnitine to form acyl carnitine that can pass through the inner mitochondrial matrix via translocase

inhibited by Malonyl CoA

CPT-I deficiency is characterized by hypoglycemia. serum carnitine levels are usually elevated. Predominantly affects the liver isoform.

Question 4

CPT-II

Answer 4

Forms Acyl CoA and carnitine from Acyl Carnitine. in the mitochondrial matrix

Enzyme itself is found in the inner mitochondrial membrane.

The Acyl CoA that is formed is then free to undergo beta oxidation

CPT-II deficiency is characterized by carrdioyopathy and muscle weakness. Lipid deposits are found in skeletal muscle. Predominantly affects muscle isoform.

Question 5

Basic sequences of beta oxidation

Answer 5

–Oxidation (removal of H) (requires FAD)
–Hydration
–Oxidation (removal of H) (requires NAD+)
–Cleavage

Enzymes:
Acyl CoA Dehydrogenase
Enol CoA Hydratase
3-hydroxy Acyl CoA dehydrogenase
Thiolase

One sequence of reactions of β-oxidation results in the cleavage of 2 C-atoms (removed as acetyl CoA)

Question 6

Acyl CoA dehydrogenase

Answer 6

Family of chain length specific enzymes that are involved in the first oxidation step of beta oxidation

Forms Enoyl CoA from Fatty Acyl CoA

Requires FAD

Question 7

Enoyl CoA Hydratase

Answer 7

Adds H2O to Enoyl CoA in the second step of beta oxidation

Forms 3-hydroxy acyl CoA

Question 8

3-hydroxy acyl CoA dehydrogenase

Answer 8

Oxidizes the third step (formation of 3-ketoacyl CoA from 3-hydroxy Acyl CoA) of beta oxidation of FAs.

Requires NAD+

Question 9

Beta ketoacyl CoA thiolase

Answer 9

cleaves Acetyl CoA from Fatty acid CoA in final step of beta oxidation.

Requires CoA

Question 10

MCAD deficiency

Answer 10

Medium Chain Acyl CoA Dehydrogenase Deficiency

Decreased ability to oxidize fatty acids with 6 -10 C atoms

Manifested by severe hypoglycemia in response to fasting or illness that reduces appetite

Medium chain acyl carnitines are excreted in urine

Dicarboxylicacids are found in urine (due to increased flux through ω-oxidation)

Presence of CK-MM and myoglobin in the urine indicative of skeletal muscle damage

Question 11

Carnitine Deficiency

Answer 11

Transport of long chain fatty acids into the mitochondria is impaired, and beta-oxidation is decreased

Characterized by hypoglycemia due to impaired gluconeogenesis(remember, acetyl CoA is an activator of pyruvate carboxylase)

Ketogenesis is decreased due to lack of fatty acid as a substrate in systemic carnitine deficiency( presents at early age)

Myopathic carnitine deficiency is characterized by muscle weakness and cardiomyopathy. Normal glucose levels. (presents at a later age)

Question 12

Jamaican vomiting sickness

Answer 12

Ingestion of unripe Ackee fruit. results in hypoglycemia and vomiting

contains hypoglycin A that inhibits MCAD resulting in inhibition of beta oxidation.

Question 13

Propionyl CoA

Answer 13

Formed from remaining 3Cs in odd chain faty acid oxidation.

Converted to succinyl CoA to enter TCA cycle in two steps.

1. formation of methylmalonyl CoA via Propionyl CoA carboxilase and biotin.
2. conversion of methymalonyl CoA to succinyl CoA via its mutase and Vitamin B12

Question 14

Zellweger syndrome

Answer 14

Characterized by defective peroxisomal biogenesis mainly affecting the liver and brain

Increased levels of C-26 fatty acids in circulation as very long chain fatty acids (22 to 26 C atoms) are initially oxidized in the peroxisomes.

Question 15

Refsum disease

Answer 15

Characterized by deficiency of the peroxisomal phytanyl CoA Alpha-hydroxylase(defect in Alpha-oxidation)

In this disorder, phytanateaccumulates in tissues, especially the neurologic tissues

Characterized by visual defects, ataxia and polyneuropathyand skeletal manifestations

Management includes dietary restriction of branched chain fatty acids

Question 16

Ketone Bodies

Answer 16

• Acetyl CoA from fatty acid oxidation are converted to ketone bodies in liver
• The ketonebodies are acetoacetate, 3-hydroxybutyrate (Beta-hydroxybutyrate) and acetone
• Acetoacetate and 3-hydroxybutyrate are transported to peripheral tissues
• In peripheral tissues, they are reconverted to acetyl CoA, that are oxidized by TCA cycle

Question 17

Thiolase

Answer 17

Ketogenesis

forms Acetoacetyl CoA from 2 Acetyl CoAs

Reversible

Question 18

HMG CoA Synthase

Answer 18

Addition of Acetyl CoA to Acetoacetyl CoA to form HMG CoA in ketogenesis

Question 19

HMG CoA Lyase

Answer 19

Converts HMG CoA to acetoacetate in ketogenesis

Question 20

Fates of Acetoacetate

Answer 20

1. can undergo spontaneous carboxylation to form Acetone that is ultimately removed from the body as a waste product.

2, Used to form the ketone body 3-hydroxy butyrate via 3-HB Dehydrogenase (Requires NADH) (Reversible reaction)

3. Activated to a CoA by Thiophorase which is then converted to 2 Acetyl CoAs by Thiolase for use in the Krebs cycle. (requires Succinyl CoA

Question 21

Regulation of Ketogenesis

Answer 21

Low insulin to glucagon ratio

Results in increased lipolysis, FA and Beta-oxidation and ultimately Acetyl-CoA for ketogenesis

Question 22

Hormone Sensitive Lipase

Answer 22

Enzyme involved in the release of FAs from glycerol (TAGs) in the fasting state.

Active in the phosphorylated state.

Stimulated by Epinephrine and the absence of insulin.

Question 23

Sites of Beta Oxidation

Answer 23

Mitochondrial matrix of the liver and muscle

Question 24

Dicarboxylic Acid

Answer 24

Formed when FA undergoes omega oxidation (oxidation at the omega carbon)

Question 25

Thiophorase

Answer 25

Succinyl CoA:acetoacetate CoA transferase

Acetoacetate is activated to acetoacetyl CoA
Coupled with the conversion of Succinyl CoA to succinate.