PBIO (Lipid Metabolism)

• Metabolic oxidation of lipids releases large quantities of energy through production of what?

  acetyl-CoA, NADH and FADH2
• What are the chief source of energy in the catabolism of lipids?

  Fatty acids
• What lipids are not catabolized as a source of energy but are excreted? 


  sterols
• These have fatty acids as part of their covalently bonded structures


  Triacylglycerols and phosphoacylglycerols
• the bond between the fatty acid and the rest of the molecule can be hydrolyzed, with the reaction catalyzed by what enzymes?

  lipases and phospholipases
• Release of fatty acids from triacylglycerols in adipocytes is controlled by what?

  hormones
• What is the main hormone that has this kind of effect (release of fatty acids)?

  Epinephrine
• This also mimics epinephrine in this regard

  Caffeine
• Distance runners want to burn fat more efficiently to spare their carbohydrate stores for the later stages of the race
• A hormone binds to a receptor on the plasma membrane of the adipocyte
• This hormone binding activates adenylate cyclase which leads to production of active protein kinase A (cAMP-dependent protein kinase)
• Protein kinase phosphorylates triacylglycerol lipase, which cleaves the fatty acids from the glycerol backbone
• This begins with activation of the molecule

  Fatty-acid oxidation
• In fatty acid oxidation, a thioester bond is formed between what groups? 


  carboxyl group of the fatty acid and thiol group of coenzyme A (CoA-SH)
• What is the activated form of the fatty acid?

  acyl-CoA
• All acyl-CoA molecules are what?

  thioesters
• Why does all acyl-CoA molecules are thioesters?

  since the fatty acid is esterified to the thiol group of CoA 
• What enzyme that catalyzes formation of the ester bond and requires ATP for its action?

  acyl-CoA synthetase
• In the course of the reaction, an acyl adenylate intermediate is formed. The acyl group is then transferred to CoA-SH. ATP is converted to AMP and PPi , rather than to ADP and Pi . The PPi is hydrolyzed to two Pi ; the hydrolysis of two high-energy phosphate bonds provides energy for the activation of the fatty acid and is equivalent to the use of two ATP.
• The formation of the acyl-CoA is endergonic, without the energy provided by the hydrolysis of the two highenergy bonds. Note also that the hydrolysis of ATP to AMP and two Pi represents an increase in entropy.
• The acyl-CoA can cross the outer mitochondrial membrane but not the inner membrane. In the intermembrane space, the acyl group is transferred to carnitine by transesterification.
• Transesterification is catalyzed by which enzyme located in the inner membrane?

  Carnitine acyltransferase
• A compound that can cross the inner mitochondrial membrane is formed?

  Acyl-carnitine
• The enzyme that has a specificity for acyl groups between 14 and 18 carbons long and is often called?


  carnitine palmitoyltransferase (CPT-I)
• The acyl-carnitine passes through the inner membrane via a specific carnitine/acyl-carnitine transporter called?


  carnitine translocase
• Once in the matrix, the acyl group is transferred from carnitine to mitochondrial CoA-SH by another transesterification reaction, involving a second carnitine palmitoyltransferase (CPT-II) located on the inner face of the membrane.
• What is the process in the matrix where a repeated sequence of reactions successively cleaves two-carbon units from the fatty acid, starting from the carboxyl end?

  b-oxidation
• The process is called b-oxidation, since the oxidative cleavage takes place at the b-carbon of the acyl group esterified to CoA.
• The b-carbon of the original fatty acid becomes the carboxyl carbon in the next stage of degradation. The whole cycle requires four reactions
• Fatty Acid Oxidation


  1. Acyl-CoA is oxidized to an a, b unsaturated acyl-CoA (also called a benoyl-CoA)

  2. The product has the trans arrangement at the double bond

  3. Reaction catalyzed by an FAD-dependent acyl-CoA dehydrogenase

  4. Unsaturated acyl-CoA is hydrated to produce a b-hydroxyacyl-CoA

  5. Reaction catalyzed by the enzyme enoyl-CoA hydratase

  6. Second oxidation reaction catalyzed by b-hydroxyacyl-CoA dehydrogenase, an NAD+-dependent enzyme

  7. Product is a b-ketoacyl-CoA

  8. Enzyme thiolase catalyzes the cleavage of the b-ketoacyl-CoA

  9. CoA is required for the reaction

  10. Products are acetyl-CoA and an acyl-CoA that is two carbons shorter than the original molecule

  11. CoA is needed to form the new thioester bond in the smaller acyl-CoA molecule

  12. Smaller molecule then undergoes another round of the b-oxidation cycle
• When a fatty acid with an even number of carbon atoms undergoes successive rounds of the b-oxidation cycle, the product is acetyl-CoA.
• (Fatty acids with even numbers of carbon atoms are the ones normally found in nature, so acetyl-CoA is the usual product of fatty-acid catabolism.) The number of molecules of acetyl-CoA produced is equal to half the number of carbon atoms in the original fatty acid.
• The acetyl-CoA enters the citric acid cycle, with the rest of the oxidation of fatty acids to carbon dioxide and water taking place through the citric acid cycle and electron transport. Recall that most of the enzymes of the citric acid cycle are located in the mitochondrial matrix, and we have just seen that the b-oxidation cycle takes place in the matrix as well.
• In addition to mitochondria, other sites of b-oxidation are

  known. Peroxisomes and glyoxysomes, organelles that carry

  out oxidation reactions, are also sites of b-oxidation, albeit to

  a far lesser extent than the mitochondria. Certain drugs,

  called hypolipidemic drugs, are used in an attempt to control

  obesity. Some of these work by stimulating b-oxidation in

  peroxisomes
• The ultimate precursor of all the carbon atoms in cholesterol and in the other steroids that are derived from cholesterol is the acetyl group of acetyl-CoA.
• Biosynthesis of Mevalonate:

  • The production of mevalonate from hydroxymethylglutaryl-CoA is catalyzed by hydroxymethylglutaryl-CoA reductase
  • The carbonyl group, the one bonded to CoA-SH, is reduced to a hydroxyl group – CoA-SH is released.

  1. This step is inhibited by high levels of cholesterol and is the major control point of cholesterol synthesis.
• HMG-CoA Reductase Inhibitors


  Drugs such as lovastatin are inhibitors of hydroxymethylglutaryl-CoA reductase and are widely prescribed to lower blood cholesterol levels.
• is a condition in which arteries are blocked to a greater or lesser extent by disposition of cholesterol plaques, which can lead to heart attacks

  Atherosclerosis
• A diet high in cholesterol and fats lead to a high level of cholesterol in the bloodstream
• Cholesterol must be packaged for transport in the bloodstream, several lipoproteins are involved in the transport of lipids in blood