Lipid Metabolism
Chapter 21 pages 607-630
Outline
• catabolism of lipids
• energy yields from fatty acid oxidation • ketone bodies
• anabolism (synthesis) of fatty acids
• this is it…. our last lecture…
• it’s fitting, I suppose, that we end with metabolism - this time lipid metabolism; long-term energy storage • glucose is the cell’s source for immediate energy
- and glycogen, being a polymer of glucose, is simply a storage mechanism for glucose • lipids (fats) on the other hand are for long-term storage
- pound for pound, there’s much more energy stored in lipids than in glucose or glycogen • but, like all good things, more energy stored means it’s harder to get that energy out • the oxidation of lipids releases acetyl-CoA, NADH, FADH2
- all of which can be used to generate ATP (energy)
Catabolism of Lipids
• most of the energy gained from lipid metabolism comes from the oxidation of fatty acids - remember: both triacylglycerols (storage form of energy) and phosphoacylglycerols (primary
component of biological membranes) have fatty acids as part of their structures • the bond holding the fatty acid to the rest of the molecule can be hydrolyzed, releasing the
fatty acid
- LIPASES catalyze this release for triacylglycerols - PHOSPHOLIPASES do this for phosphoacylglycerols
• different individual enzymes belonging to these classes hydrolyze different specific bonds and/ or have differing substrate specificity
• interestingly, hormones control the release of fatty acids from triacylglycerols in adipocytes (thru G-protein, cAMP system)
Fatty Acid Transport to the Mitochondria
• to be oxidized (have their high-energy electrons stripped off), fatty acids must first be ACTIVATED
- to make them reactive…
- what have we used to active molecules in the past…? • CoA is linked to a fatty acid through a carboxyl-thiol bond
- this results in an ACYL-CoA (which specific acyl-CoA is formed depends on the fatty acid involved)
• the enzyme that does this is an ACYL-CoA SYNTHETASE
- therefore, we know from the name, this is an ATP dependent process • there are a few different acyl-CoA synthetases
- some specific for longer chain fatty acids, others for shorter - these enzymes activate fatty acids in the cytosol
Oxidation of Fatty Acids
• once in the mitochondrial matrix, a series of reactions repeatedly occurs which successively remove two-carbon units from the fatty acid; starting from the carboxyl end
• this process is called β OXIDATION
- a single removal of a two-carbon unit requires four reactions - it is also important to note that this process is NOT a cycle - we do not return to a starting point
- instead, I think of it as a spiral…
- keep going around and around until there’s nothing left • so let’s do it… let’s oxidize some fats
1) first, the acyl-CoA is oxidized (electrons and protons are stripped off ) - this results in the fatty acid becoming unsaturated…
- who remembers what that means…? - butter… oil….
• the enzyme catalyzing this reaction is an FAD-dependent acyl-CoA dehydrogenase - the product has a trans configuration at the new double bond
2) the unsaturated acyl-CoA is then hydrated (at the double bond) by ENOYL-CoA HYDRATASE resulting in a β-hydroxyacyl-CoA
3) a second oxidation is catalyzed by NAD+ dependent hydroxyacyl-CoA dehydrogenase yielding β-ketoacyl-CoA
4) lastly, THIOLASE catalyzes the cleavage of the β-ketoacyl-CoA
- thiolase joins the two carbon unit that was just cleaved off onto a second CoA molecule - this results in an acyl-CoA that is two carbons shorter than the substrate, and…
… who remembers another two carbon molecule that we joined to CoA a few weeks ago…? - acetyl-CoA (which of course goes to the Citric Acid Cycle)
• for all even numbered fatty acids (and most fatty acids are even) this process continues, again and again, until what’s left are two acetyl-CoAs
- 18 carbon fatty acid → 16 carbon FA + acetyl-CoA → 14 + a-CoA → 12 + a-CoA … 4 carbon FA + acetyl-CoA → two acetyl-CoAs - the number of acetyl-CoAs yielded is always half that of carbons • remember, this is all in the mitochondrial matrix next to the TCA cycle
Energy Yields from β Oxidation
• when metabolizing glucose, the energy released and captured by the oxidation of glucose metabolites is used to eventually make ATP
- through the Citric Acid Cycle, Electron Transport Chain & OxPhos
• of course, the acetyl-CoA released by the β oxidation of fatty acids may also go down this road and be used to make ATP
- but here ATP can come from two sources…
- acetyl-CoA itself and the reduced NADH and FADH2 from β oxidation • let’s consider the 18-carbon fatty acid STERIC ACID
• steric acid is converted into 9 molecules of acetyl-CoA by β oxidation - in the process 8 NADH and 8 FADH2 are reduced
• for each acetyl-CoA that enters the Citric Acid Cycle, one ATP is made (via GTP), one FADH2 and three NADH are reduced
• for steric acid, 17 FADH2 and 35 NADH are reduced total • these electrons will allow 113 ATPs to be made!
- add to that the 9 ATPs made by the Citric Acid Cycle itself and the total yield of ATP from a single molecule of steric acid is 122!!
- this actually represents a best-case-scenario that few cells ever attain, but it’s still an amazing yield as compared to glucose metabolism
- one glucose = ~33 ATPs three glucoses = ~100 ATPs • water is also made as a result of β oxidation
• this water (along with the water from glucose metabolism) - called METABOLIC WATER – serves as a source for water
- especially for desert animals
• camels do NOT have water in their humps…
- their humps are lipids, allowing water to be produced by β oxidation
• kangaroo rats can live indefinitely with no water at all as long as they have a steady diet of seeds rich in lipids
Ketone Bodies
• KETONE BODIES are substances related to acetone that are sometimes produced as a result of β oxidation
- when more acetyl-CoA is produced than oxaloacetate available to accept them into the Citric Acid Cycle, pyruvate is converted to oxaloacetate to handle the demand
- before that adaptation has a chance to occur, however, ketone bodies can arise • reactions that result in ketone bodies start with two acetyl-CoAs condensing to form
acetoacetyl-CoA
- through another condensation reaction, eventually ACETOACETATE is formed
• acetoacetate may then be reduced to form β-hydroxybutyrate OR it may spontaneously decarboxylate to acetone
- this acetone can actually be smelled on the breath of patients with uncontrolled diabetes or Atkins-fanatics… KETOSIS
• ketosis is a major stress for the body
• ketones are primarily synthesized in the liver and acetoacetate can be used as fuel – in lieu of glucose – by many of the cells in our body
- in fact, the heart and kidneys actually prefer acetoacetate
• the brain possesses enzymes to convert acetoacetate back to two molecules of acetyl-CoA - these can then be used for energy in the standard way…
• these changes – using acetoacetate as a primary fuel source – are long-term adaptations to starvation
- essentially the body is prepared to digest itself…
Fatty Acid Biosynthesis
• the anabolism of fatty acids is not simply fatty acid catabolism in reverse (big surprise…) • fatty acid synthesis is localized in the cytosol
- whereas, fatty acid catabolism was mitochondrial - compartmentalization
• the first step for making fatty acids is transporting acetyl-CoA from the mitochondrial matrix to the cytoplasm
• once in the cytosol, acetyl-CoA is carboxylated to become malonyl-CoA - catalyzed by the acetyl-CoA carboxylase complex (3 subunits)
- the details are in the text… - but all you need to know is this…
• making fatty acids involves the addition – over and over – of two-carbon units to a growing chain of hydrocarbons
- these two carbon units are donated by malonyl-CoA
• in principle, fatty acids are built the same way they were destroyed… … two carbons at a time
• the enzyme complex FATTY ACID SYNTHASE catalyzes these successive reactions (ATP-independent)
• 16-carbon PALMITATE is usually the product of fatty acid synthesis - the carbons come from 8 acetyl-CoA molecules via malonyl-CoA
- however, before the chain can be built in earnest, a priming step is required
• in the priming step, an acetyl from acetyl-CoA is transferred to an ACYL CARRIER PROTEIN (ACP) (part of fatty acid synthase)
• the acetyl group is then transferred from ACP to another protein called β-ketoacyl-S-ACP synthase (you don’t need to know this name)
• now we can start adding two-carbon units from malonyl-CoA
- essentially (simplified), two carbons from malonyl-CoA join with an acetyl-ACP making an acetoacetyl-ACP (four carbons)
• through a series of three reactions, acetoacetyl-ACP is converted into butyryl-ACP - two reductions and a dehydration
• now it’s WASH-RINSE-REPEAT…
• now butyryl-ACP accepts two carbons from malonyl-ACP through two reductions and a dehydration producing a six carbon molecule
• this continues again and again with the fatty acid being assembled on the acyl carrier protein (ACP)
• fatty acid synthase can only add a maximum of 16 Cs
- hence, palmitate being the preferred fatty acid made by mammalian cells
• larger, longer fatty acids are made by modifying different intermediates of this pathway - this occurs in either the endoplasmic reticulum or the mitochondria
- double bonds are also made in the ER
• let’s just take one last brief moment to discuss how we specifically make our two most important lipids:
TRIACYLGLYCEROLS and PHOSPHOACYLGLYCEROLS
• free fatty acids (such as palmitate) are rarely found in the cell - instead, they are usually part of lipids
• triacylglycerols and phosphoacylglycerols are typically made in the ER or liver and/or adipose cells
• glycerol is made from glycerol-3-phosphate; a molecule easily harvested from glycolysis (DHAP) • a fatty acid is then transferred from CoA to the glycerol making a lysophosphatidate
- then another fatty acid is added making a phosphatidate
- then a third fatty acid displaces the phosphate making the triacyl • phosphoacylglycerols are made using phosphatidates
- the phosphate group is linked to an alcohol
- then the second phosphate is removed and the alcohol takes its place
• CTP donates the new phosphate and serine donates the makings for the alcohol group • in the end, we have a phosphoacylglycerol to serve as the primary component of
biological membranes
Summary
• once released from a triacylglycerol or phosphoacylgylcerol, fatty acids (acyls) are linked to CoA for activation
• they are then substrate for β oxidation
- two carbon units are removed and become acetyl-CoA for the Citric Acid Cycle - plenty of electrons are also harvested
- tons of energy stored in fat
• fatty acid anabolism requires a number of preparative steps, however once primed two carbon acetyl groups are added to a growing fatty acid chain linked to acyl carrier protein (ACP)
- the maximum number of carbons added in this way is 16
