FATTY ACID METABOLISMBecause the breakdown of fats is a complicated process, this part is divided in a number ofdifferent 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
Triglycerides are hydrolysed by 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 cyclicalAMP. This cyclical AMP activates the enzyme protein kinase A (PKA). Theenzyme PKAphosphorylyse the lipase enzyme and gets activated because of thisphosphorylation. Like in thebreak down of glycogen cyclical AMP is here "the secondmessenger". The hormone insulin inhibits the hydrolysis of triglycerids.Glycerol, that by the break down of triglyceride arise, is phosphorylated by glycerolkinase and isthen oxidised by glycerol phosphate dehydrogenase to dihydroxyacetone phosphate. This is anintermediary of the glycolysis and will be broken down further in this glycolysis.
Fatty acids are bound 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 mitochondrialmatrix inFatty acids are activated at the outer membrane of the mitochondria, but are oxidised inside themitochondria. Because long-chains fatty acids are not easily going through the outer membraneof the mitochondria a special transport mechanism is necessary to transport these fatty acids intothe mitochondria.Activated long-chain fatty acids are combined with carnitine. The acyl group is transferred bythe sulphur atom of coenzyme A on the hydroxyl group of carnitine under formation ofacylcarnitine. This reaction is catalysed by carnitine acyltransferase I, that is bound at the outermembrane of the mitochondria. Activated long-chain fatty acids are combined with carnitine.
Acylcarnitine is then moved through the outer membrane by a translocase enzyme (membraneprotein). The acyl group is transferred back to coenzyme A at the matrix side (in themitochondria) by the membrane. This reaction is catalysed by carnitine acyltransferaseII. Ultimately carnitine is transported back into the cytoplasm by the enzyme translocase inexchange for a coming in of acylcarnitine
Fatty acids are broken by splitting-off of always two carbon atomsFatty acids are broken down by repetitions of separations of parts of two carbon atoms. The reactionsthat 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 toOxalacetate in the citric acid cycle.The break down of fatty acids with a chain of an odd number of carbon atoms leads to the formationof propionyl CoA in the last thiolyse reaction step. In the last reaction step of the fatty acid breakdown 3-ketopentanoyl CoA (5 carbon atoms) is split up in propionyl CoA (3 carbon atoms) andacetyl CoA (2 carbon atoms). Propionyl CoA is converted in methylmalonyl-CoA by the enzymepropionyl-CoA carboxylase. This enzyme needs biotin as an assistant-factor (and bicarbonate andATP) to catalyse the reaction. Methylmalonyl-CoA is converted in succinyl-CoA by the enzyme
methylmalonyl-CoA mutase. This enzyme 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 necessaryThe first reaction in the cycle of the break down ( -Oxidation) of a fatty acid under formation ofan enoyl CoA with a trans double bond between carbon number 2 is the oxidation of an acylCoA and 3.By the break down of an unsaturated fatty acid, the presence of a double bondbetween C-3 and C-4 prevents the formation of a trans double bond between C-2 and C-3. Atrans double bond is necessary for the formation of L-3-hydroxyacyl CoA, because the enzymedehydrogenase is specific for this. An isomerase changes a double bond between C-3 and C-4into a trans double bond between C-2 and C-3. By the break down of a plural unsaturated fattyacid, 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 3as coenzyme reduces the intermediate product to a cis- -Enoyl CoA. The earlier called 3isomerase converts cis- -Enoyl CoA in the trans form, see the figure below.
If the fat breakdown dominates acetyl CoA keton bodies are formedAll by the fatty acid break down formed active acetyl CoA can only be sufficient fast brokendown in the citric acid cycle when sufficient oxalacetate is present. By fasting or by diabetesoxalacetate is used for the gluconeogenesis. Then there is insufficient oxalacetate available toreact with acetyl CoA.Under these circumstances, from two molecules acetyl CoA one molecule acetoacetyl CoA isformed and from that the keton bodies are formed: acetylacetate (diacete), D-3-hydroxybutyrateand acetone.
Acetylacetate is an important fuel in some tissuesThe keton bodies appear to be important energy sources, it is the primary fuels for the heartmuscle and the kidney salt marsh. By fasting or diabetes the brains change from the use ofglucose 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 acidcycle.
The use of acetoacetate as a fuel. Acetoacetate is converted in 2 molecules acetyl CoA what the citric acid cyclecan enter.The liver can supply acetylacetate (not thiolysed) to other organs because the liver itself hasnot the enzyme CoA transferase. Other tissues do have this enzyme.Acetylacetate has a regulating role. High concentrations in the blood are a signal for anexcess of acetyl-units and lead to a delayed lipolyse (fat breakdown) in fat tissue (negativefeedback). Humans and animals cannot convert fatty acids into glucose. Humans and animalscan not convert fatty acids into glucose because they cannot use the acetyl CoA to makepyruvate or oxalacetate. The both carbon atoms are taken up in the citric acid cycle, but isformed by two decarboxylations per balance no extra oxalacetate (no gluconeogenesis).Plants can do that with help of the glyoxylate cycle.
Characteristic differences between the break down and synthesis of fattyacids. 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 +