|Tetradecanoate (14 C)||
|Leucine and Lysine||
Made from spontaneous decarboxylation of acetoacetate, has no metabolic function but an important diagnostic indicator oh high plasma ketone levels since it freely crosses into the alveoli of the lungs and can be detected on breath.
unsaturated (have double bonds)
peroxisomal disorder, clinically recognizable at birth, death usually occurs within 12 months of birth, believe to be caused by defective peroxins (proteins involved in peroxisomal biogenesis)-->leads to relative absense of peroxisome, characterized by accumulation of VLCFAs in plasma and tissues
Central ketone body. Two Acetyl-CoA are made into Acetoacetyl-CoA by Acetoacetyl-CoA Thiolase. Acetoacetyl-CoA and Acetyl-CoA are then made into HMG-CoA by HMG-CoA Synthase which is then acted by HMG-CoA lyase to make this molecule.
Configuration of double bond causes chain to be kinked and shortened
|medium-chain fatty acyl-CoA dehydrogenase deficiency (MCAD)||
autosomal-recessive disorder (1/10000), most common human genetic defect in lipid metabolism, reduces energy production from β-oxidation, causes severe hypoglycemia, medium-chain fatty acid metabolites readily detected in urine, heptatomegaly may occur with notable lipid deposits and altered mitochondrial structure, linked to 10% of cases of sudden infant death syndrome, deficiencies in short-chain and long-chain fatty-acid dehydrogenases have also been decribed, manifest similar clinical features
|Hormone sensitive lipase||
Regulates fatty acid oxidation. Activated by levels of epinephrine and inhibited by high levels of insulin.
|jamaican vomiting sickness||
catabolism of hypoglycin-rare amino acid from unripe fruit of akee tree, produces methylenecyclopropylacetyl-CoA (MCPA-CoA)=irreversible inhibitor of short-chain and medium chain acyl Co-A dehydrogenase-->hypglycemia, vomiting, colvulsions, metabolic coma
production of ketone bodies in liver mitochondrial matrix
normally, acetyl-CoA + oxaloacetate-->citrate via citrate synthase, during periods of high lipid but low CHO intake supply of acetyl-CoA to TCA cycle exceeds amount of OAA that can react with it-->imbalance results in production of ketone bodies in liver mitochondria
2 acetyl-CoA -->acetoacetyl-CoA via ketothiolase + acetyl-CoA-->β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) via HMG CoA synthase -->acetoacetate + acetyl CoA via HMG CoA lyase
spontaneous decarbolyxation of acetoacetate in blood--> CO2 + acetone
acetoacetate + NADH + H+ --> β (3) -hydroxybutyrate via 3-hydroxybutyrate dehydrogenase
|Carnitine Acyltransferase I||
Since the inner mitochondrial membrane is impermeable to acyl-CoA it must be attached to carnitine. This enzyme facilitates this reaction and allows the acyl-carnitine to be transported across the mitochondrial membrane by a translocase.
|Acyl CoA dehydrogenase||
Enzyme for oxidation by FAD (step1)
|fatty acid activation||
takes place before fatty acid oxidation can begin, thiolester bond is formed between the COOH group of the NEFA and the thiol group of coenzyme A (CoA-SH)--> acyl-CoA molecule
endergonic reaction involving acyl-CoA synthetase (thiokinase), two step reaction that occurs in cytoplasm, long-chain acyl-CoAs undergo oxidation in mitochondria
NEFA + CoA + ATP-->Acyl-CoA + AMP + PPi via thiokinase
|Carnitine Acyltransferase II||
This enzyme removed the carnitine from acyl-carnitine when it reaches the mitochondiral matrix and turns it back into acyl-CoA and carnitine.
|Carnitine Acyltransferase Reaction||
Reaction required to get fatty acids across inner mitochondrial membrane
|carnitine palmitoyl transferase II (CPT II) deficiency||
carnitine deficiency, reduced fatty acid oxidation in skeletal and cardiac muscle, cardiomyopathy, muscle pain, cramps following prolonged exercise, muscle necrosis--myoglobinuria (brown urine), diagnosis with cultured fibroblast and enzyme assay, treat with high carbohydrate/low fat diet, avoid fasting
|Enzyme defect in MCAD||
Catabolism of medium chain fatty acids (6-12 C) is deficient due to a defect in the medium chain acyl-CoA dehydrogenase
|Fatty acylation of Coenzyme A||
Required reaction to get fatty acids across outer mitochondrial membrane
|β-oxidation of saturated fatty acids||
1. fatty acyl CoA + FAD-->Δ2-trans-enoyl coA + FADH2 via acyl CoA dehydrogenase
2. Δ2-trans-enoyl coA + H2O --> β-hydroyacyl-CoA via enoyl CoA hydrataes
3. β-hydroyacyl-CoA + NAD+ --> β-ketoacyl CoA + NADH + H+ via β-hydroxyacyl CoA dehydrogenase
4. β-ketoacyl CoA + CoA --> fatty acyl CoA (two carbons shorter) + acetyl-CoA via acyl CoA acyltransferase (thiolase)
|Two steps of fatty acids entering mitochondria||
1) Penetration , 2) Transport across inner mitochondrial membrane
Produced 10 ATPs
|Octadecanoate (18 C)||
when ketogenesis exceeds utilization
Powerful irreversible inhibitor of medium and short chain acyl-CoA dehydrogenases and therefore causes inhibiton of Beta oxidation.
hormone-sensitive lipase (adipose, gonads, adrenal cortex), hepatic intracellular lipase
Made from acetoacetate by reduction with NADH. Since there is usually a lot of NADH due to beta-oxidation and TCA cycle this usually makes up 80% of ketone bodies.
Catalyzes the reaction where Coenzyme A cleaves a acetyl-CoA from Beta-ketoacyl-CoA.
contain both polar and non-polar parts
mechanism to transport long-chain fatty acids across inner mitochondrial membrane, long-chain fatty acids converted to acyl carnitine to cross mitochondrial matrix, operates as antiport where free carnitine and acyl-carnitine derivatives move in opposite directions across inner mitochondrial membrane
one of the regulatory sites in fatty-acid oxidation, shuttle inhibited by ingestion of carbohydrate-rich meal, preventing catabolism of newly synthesized fatty acids
failure in shuttle blocks fatty acid oxidation--> impair ketogenesis, results in lipid accumulation in affected tissues
aka thiokinase, membrane bound enzyme, part of fatty acid activation, condenses fatty acids with Coenzyme A, with simultaneous hydrolysis of ATP to AMP and PPi
formation of a CoA ester is expensive energetically, hydrolysis of PPi drives the reaction strongly forward
|membrane bound translocase||
an integral inner mitochondrial membrane protein that transports palmitoylcarnitine from intermembrane space into matrix in exchange for a molecule of free carnitine that is subsequently moved back out of mitochondria into cytosol
Has a cobalamin cofactor. Converts the intermediate methylmalonly-COA produced from propinoyl-CoA into succinyl-CoA.
Acts as a coenzyme A donor in converting acetoacetate into acetoacetyl-CoA for use in tissue. This reaction is catalyzed by succinyl-CoA:acetoacetyl-CoA transferase. This enzyme is not found in liver. The acetoacetyl-CoA is then cleaved into two molecule of acetyl-CoA by thiolase. Acetyl-CoA can then enter TCA cycle.
reaction product for step 1 - oxidation
|lipoprotein lipase (LPLase)||
hydrolyses TAG in the blood capillaries producing NEFAs and glycerol, glycerol remains in the blood and is transported to the liver
glycerol cannot be utilized by adipocytes as it lacks glycerol kinase
|adrenoluekodystrophy (x-linked Schilder's disease)||
peroxisomal disorder, due to inability to metabolize VLCFAs-->accumulate in body tissues and fluids, esp. in adrenal cortex and white matter of CNS, affected males (X-linked) appear to develop normally until 4-8 years of age when they begin to develop dementia-->vegetative state
Consists of actions by 4 enzymes. FADH is produced during 1st reaction and NADH in the 3rd. After third reaction beta-ketoacyl-CoA is formed, this is then cleaved by Coenzyme A catalyzed by etaB-ketothiolase.
lose weight by eating high protein & low CHO foods, diet works on principle of ketosis, fatty acid oxidation predominates, ketone bodies and high protein diet suppresses appetite
|enzymes of β-oxidation of odd-chain fatty acids||
1. propionyl-CoA carboxylase (biotin dependant)
2. methylmalonyl-CoA epimerase
3. methylmalonyl-CoA mutase (with Vit B12 as cofactor)
elevated levels of methylmalonic acid indicative of vitamin B12 deficiency or methylmalonyl-CoA mutase deficiency
|Enzymes involved in shuttle of fatty acids into mitochondria||
1. Acyl-CoA synthetase (synthasizes Acyl-CoA) 2. Carnitine Acyltransferase I ((CPT1) swaps CoA for carnitine 3. Translocase (transports acyl-carnitine into matrix) 4. Carnitine transferase II (CPTII) (swaps carnitine for CoA)
|L-beta-hydroxy acyl CoA dehydrogenase||
Enzyme for Oxidation by NAD+ (step 3 - beta-oxidation)
|Reactions for fatty acids entering mitochondria||
1) linked to CoA 2) Shuttled into intermembrane space 3) CoA replaced with Carnitine 4) Shuttles in to matrix 5) Carnitine replaced with CoA