Beta Oxidation & Ketogenesis Flashcards
Fatty Acyl CoA Synthetase
Thiokinase
Presents to outer mitochondrial membrane (cytosolic side)
Activates Fatty acids to fatty acyl CoA
Requires ATP
Stages of Beta Oxidation
- Activation of fatty acid
- transport FA from cytosol to mitochondria
- beta oxidation proper
CPT-I
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.
CPT-II
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.
Basic sequences of beta oxidation
–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)
Acyl CoA dehydrogenase
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
Enoyl CoA Hydratase
Adds H2O to Enoyl CoA in the second step of beta oxidation
Forms 3-hydroxy acyl CoA
3-hydroxy acyl CoA dehydrogenase
Oxidizes the third step (formation of 3-ketoacyl CoA from 3-hydroxy Acyl CoA) of beta oxidation of FAs.
Requires NAD+
Beta ketoacyl CoA thiolase
cleaves Acetyl CoA from Fatty acid CoA in final step of beta oxidation.
Requires CoA
MCAD deficiency
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
Carnitine Deficiency
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)
Jamaican vomiting sickness
Ingestion of unripe Ackee fruit. results in hypoglycemia and vomiting
contains hypoglycin A that inhibits MCAD resulting in inhibition of beta oxidation.
Propionyl CoA
Formed from remaining 3Cs in odd chain faty acid oxidation.
Converted to succinyl CoA to enter TCA cycle in two steps.
- formation of methylmalonyl CoA via Propionyl CoA carboxilase and biotin.
- conversion of methymalonyl CoA to succinyl CoA via its mutase and Vitamin B12
Zellweger syndrome
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.
Refsum disease
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
Ketone Bodies
- 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
Thiolase
Ketogenesis
forms Acetoacetyl CoA from 2 Acetyl CoAs
Reversible
HMG CoA Synthase
Addition of Acetyl CoA to Acetoacetyl CoA to form HMG CoA in ketogenesis
HMG CoA Lyase
Converts HMG CoA to acetoacetate in ketogenesis
Fates of Acetoacetate
- 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)
- 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
Regulation of Ketogenesis
Low insulin to glucagon ratio
Results in increased lipolysis, FA and Beta-oxidation and ultimately Acetyl-CoA for ketogenesis
Hormone Sensitive Lipase
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.
Sites of Beta Oxidation
Mitochondrial matrix of the liver and muscle
Dicarboxylic Acid
Formed when FA undergoes omega oxidation (oxidation at the omega carbon)
