Fatty acid metabolism

Fatty acid metabolism

• 1.
  FATTY ACID METABOLISM Becausethe breakdown of fats is a complicated process, this part is divided in a number of different parts. Below the different parts are indicated. Triglycerides are hydrolysed by cyclical AMP-regulated lipases Fatty acids are bound to coenzyme A before they are oxidised Carnitine transports long-chain activated fatty acids the mitochondrial matrix in Fatty acids are broken by splitting-off of always two carbon atoms oxidation of unsaturated fatty acids yet an isomerase and a reductase are necessary If the fat breakdown dominates acetyl CoA keton bodies are formed Acetylacetate is an important fuel in some tissues
• 2.
  Triglycerides are hydrolysedby cyclical AMP-regulated lipases The first event in the use of fat as energy source is the hydrolysis (= break down by water) of triglycerides by the enzymes that are called lipases. This process is also called lipolyse. Lipases convert triglycerides into glycerol and fatty acids. The hydrolyse by lipases of triglycerol in glycerol and fatty acids. The activity of lipase in fat cells is regulated by hormones like epinephrine and glucagon. These hormones activate the enzyme adenylate cyclase. This enzyme converts ATP in cyclical AMP. This cyclical AMP activates the enzyme protein kinase A (PKA). The enzyme PKAphosphorylyse the lipase enzyme and gets activated because of this phosphorylation. Like in thebreak down of glycogen cyclical AMP is here "the second messenger". The hormone insulin inhibits the hydrolysis of triglycerids. Glycerol, that by the break down of triglyceride arise, is phosphorylated by glycerolkinase and is then oxidised by glycerol phosphate dehydrogenase to dihydroxyacetone phosphate. This is an intermediary of the glycolysis and will be broken down further in this glycolysis .
• 3.
  Fatty acids arebound to coenzyme A before they are oxidised A fatty acid reacts with ATP and coenzyme A to acyl CoA, AMP and pyrophosphate. A fatty acid reacts with ATP and coenzyme A to form acyl CoA, AMP and pyrophosphate. This reaction is catalysed by acyl CoA synthetase. The enzyme acyl CoA synthetase has been bound at the outer membrane of the mitochondria. The balance of the total reaction lies in the direction of acyl CoA because of the fast hydrolysis of pyrophosphate Carnitine transports long-chain activated fatty acids the mitochondrial matrix in Fatty acids are activated at the outer membrane of the mitochondria, but are oxidised inside the mitochondria. Because long-chains fatty acids are not easily going through the outer membrane of the mitochondria a special transport mechanism is necessary to transport these fatty acids into the mitochondria. Activated long-chain fatty acids are combined with carnitine. The acyl group is transferred by the sulphur atom of coenzyme A on the hydroxyl group of carnitine under formation of acylcarnitine. This reaction is catalysed by carnitine acyltransferase I, that is bound at the outer membrane of the mitochondria. Activated long-chain fatty acids are combined with carnitine.
• 4.
  Acylcarnitine is thenmoved through the outer membrane by a translocase enzyme (membrane protein). The acyl group is transferred back to coenzyme A at the matrix side (in the mitochondria) by the membrane. This reaction is catalysed by carnitine acyltransferase II. Ultimately carnitine is transported back into the cytoplasm by the enzyme translocase in exchange for a coming in of acylcarnitine
• 5.
  Fatty acids arebroken by splitting-off of always two carbon atoms Fatty acids are broken down by repetitions of separations of parts of two carbon atoms. The reactions that repeat are oxidation, hydration, oxidation (dehydrogenation) and thiolyse. The three reactions from acyl CoA to 3-ketoacyl CoA are comparable to the reactions of Succinate to Oxalacetate in the citric acid cycle. The break down of fatty acids with a chain of an odd number of carbon atoms leads to the formation of propionyl CoA in the last thiolyse reaction step. In the last reaction step of the fatty acid break down 3-ketopentanoyl CoA (5 carbon atoms) is split up in propionyl CoA (3 carbon atoms) and acetyl CoA (2 carbon atoms). Propionyl CoA is converted in methylmalonyl-CoA by the enzyme propionyl-CoA carboxylase. This enzyme needs biotin as an assistant-factor (and bicarbonate and ATP) to catalyse the reaction. Methylmalonyl-CoA is converted in succinyl-CoA by the enzyme
• 6.
  methylmalonyl-CoA mutase. Thisenzyme needs coenzyme B12 (a product ofvitamin B12) to catalyse this reaction. Succinyl CoA can be further broken down in the citric acid cycle. oxidation of unsaturated fatty acids yet an isomerase and a reductase are necessary The first reaction in the cycle of the break down ( -Oxidation) of a fatty acid under formation of an enoyl CoA with a trans double bond between carbon number 2 is the oxidation of an acyl CoA and 3.By the break down of an unsaturated fatty acid, the presence of a double bond between C-3 and C-4 prevents the formation of a trans double bond between C-2 and C-3. A trans double bond is necessary for the formation of L-3-hydroxyacyl CoA, because the enzyme dehydrogenase is specific for this. An isomerase changes a double bond between C-3 and C-4 into a trans double bond between C-2 and C-3. By the break down of a plural unsaturated fatty acid, a cis- 4 double bond forms another problem. Through dehydrogenation of this part, a 2,4- dienoyl intermediate product is raised, that is no substratum for the following enzyme in the - Oxidation. This problem is solved by the enzyme 2,4-dienoyl CoA reductase that with NADPH 3 as coenzyme reduces the intermediate product to a cis- -Enoyl CoA. The earlier called 3 isomerase converts cis- -Enoyl CoA in the trans form, see the figure below.
• 7.
  If the fatbreakdown dominates acetyl CoA keton bodies are formed All by the fatty acid break down formed active acetyl CoA can only be sufficient fast broken down in the citric acid cycle when sufficient oxalacetate is present. By fasting or by diabetes oxalacetate is used for the gluconeogenesis. Then there is insufficient oxalacetate available to react with acetyl CoA. Under these circumstances, from two molecules acetyl CoA one molecule acetoacetyl CoA is formed and from that the keton bodies are formed: acetylacetate (diacete), D-3-hydroxybutyrate and acetone.
• 8.
  Acetylacetate is animportant fuel in some tissues The keton bodies appear to be important energy sources, it is the primary fuels for the heart muscle and the kidney salt marsh. By fasting or diabetes the brains change from the use of glucose to the use of acetylacetate as fuel. Acetylacetate is activated by the transfer of the CoA of succinyl CoA to acetylacetate. Acetoacetyl CoA is then thiolysed to two molecules acetyl CoA that go into the citric acid cycle.
• 9.
  The use ofacetoacetate as a fuel. Acetoacetate is converted in 2 molecules acetyl CoA what the citric acid cycle can enter. The liver can supply acetylacetate (not thiolysed) to other organs because the liver itself has not the enzyme CoA transferase. Other tissues do have this enzyme. Acetylacetate has a regulating role. High concentrations in the blood are a signal for an excess of acetyl-units and lead to a delayed lipolyse (fat breakdown) in fat tissue (negative feedback). Humans and animals cannot convert fatty acids into glucose. Humans and animals can not convert fatty acids into glucose because they cannot use the acetyl CoA to make pyruvate or oxalacetate. The both carbon atoms are taken up in the citric acid cycle, but is formed by two decarboxylations per balance no extra oxalacetate (no gluconeogenesis). Plants can do that with help of the glyoxylate cycle.
• 10.
  Characteristic differences betweenthe break down and synthesis of fatty acids. Break down of fatty Structure of fatty acids acids In which part of the cell mitochondria Cytoplasm Bond of intermediate acyl transport protein coenzyme A products on ACP enzymes in one protein Enzyme system separate enzymes chain separation of C2 (acetyl addition of C2 Change of the chain length CoA) donor: malonyl ACP Oxidizers: FAD and Redox Reducers: NADPH NAD +