I've now come to associate the word "metabolism" with "shitload of chemical reactions to learn." Apologies if that's how this post is going to turn out...
Firstly, I'm going to provide a quick overview of the anabolism (building up) and catabolism (breaking down) of fatty acids.
Anabolism
Acetyl CoA produced from the oxidation of glucose and some amino acids is the "main ingredient" used in the anabolism of fatty acids. Some acetyl CoA is converted to malonyl CoA with the help of ATP, and then acyl CoA and malonyl CoA together help synthesise fatty acids with the help of NADPH. Fatty acids may then be incorporated into triglycerides etc. I'll cover anabolism in a lot more detail towards the end of this post.
Catabolism
Triglycerides obtained from the diet can be broken down into fatty acids. Fatty acids are then broken down into many units of acetyl CoA via a process known as beta-oxidation. During this process, NAD+ and FAD are reduced to form NADH and FADH2, respectively. NADH and FADH2 are electron carriers that help power the synthesis of ATP. Excess acetyl CoA that is formed can be converted into ketone bodies.
Cofactors Important in Fat Metabolism
As I've mentioned, fatty acids are broken down into acetyl CoA. The "acetyl" part is easy enough to work out- the acetyl group is essentially a carbon atom double-bonded to an O and single bonded to a methyl group. But what's CoA?
CoA, also known as Coenzyme A or CoASH (a reference to the -SH group at the end) is a commonly found molecule that activates acetate and fatty acids by forming thioesters (hence the importance of the -SH group). It is made up of three parts: 3'-phosphoadenosine diphosphate (essentially ADP but with a phosphate group on the 3' carbon as well), pantothenic acid (vitamin B5, which is why B5 is important) and beta-mercaptoethylamine, which has an -SH group at the end which can form thioesters with acetate or fatty acids, as I've already mentioned.
Other important cofactors are NAD+ (nicotinamide adenine dinucleotide) and FAD (flavin adenine dinucleotide). Both consist of adenine bonded to a vitamin. NAD+ contains nicotinamide, which is the amide of niacin (vitamin B3). FAD, on the other hand, contains riboflavin, which is vitamin B2. NAD+ and FAD, as mentioned before, can be reduced when fatty acids are oxidised. They can then carry electrons to the electron transport chain to power the synthesis of ATP.
Moral of the story: eat your B vitamins. Your body needs them to metabolise fat.
Synthesis of Triglycerides
I've given an overview of how fatty acids are formed from the ground up, but for now we're going to start with the formation for triglycerides from already-formed fatty acids.
Firstly, fatty acids are activated with CoA with a bit of help from the enzyme acyl CoA thiokinase. Two of these activated fatty acids can then react with a molecule of glycerol 3-phosphate, which is one of the intermediates in the breakdown of glucose (a process also known as glycolysis). This forms phosphatidic acid- two fatty acids and a phosphate group all esterified to a glycerol backbone. Phosphatidic acid can then lose its phosphate group to form a diacylglycerol. Finally, a third activated fatty acid can come in to form a triacylglycerol (a.k.a. triglyceride).
Digestion of Triglycerides
Bile salts (a topic which I think I'll go into a little more detail in a later post) aid in the digestion of fats. They can emulsify fat (i.e. break it down into small particles) as well as form micelles that contain everything needed for hydrolysing triglycerides into two fatty acids as well as 2-monoglyceride (i.e. glycerol with a fatty acid esterified to the middle carbon). Some of these tools needed for hydrolysing triglycerides include enzymes such as pancreatic lipase.
Transport of Triglycerides
As triglycerides are not water soluble, they have to be carried around the blood in vesicles known as lipoproteins. Lipoproteins have a single layer of phospholipids on the outside, with hydrophilic parts facing outwards towards the blood, and hydrophobic parts facing inwards towards the triglycerides that are being carried. The membranes of lipoproteins may also contain proteins and/or cholesterol, just like many other membranes within the body.
Lipoproteins can originate from several different locations in the body. Chylomicrons are lipoproteins that originate from the mucosa of the small intestine. They carry triglycerides made from dietary fat to the tissues, where they can be used. Very low-density lipoproteins (VLDL) originate from the liver. They carry triglycerides made from newly-synthesised fatty acids to the tissues. As triglycerides are removed, they become low-density lipoproteins (LDL).
Uptake of Fatty Acids from Lipoproteins
There are special enzymes that can release fatty acids from lipoproteins so that they can be taken up by the cells. One of these enzymes is called lipoprotein lipase.
Mobilisation of Triglycerides from Adipose Tissue
When triglycerides are needed, hormones such as glucagon bind to receptors on the outside of the cell. This activates hormone-sensitive lipase, which breaks down triglycerides into fatty acids. These fatty acids can then bind to binding proteins in the plasma, such as albumin. These proteins take fatty acids into tissues where they need to be used.
Transport of Activated Fatty Acids into the Mitochondria
As I've mentioned before, fatty acids can be broken down to provide energy for the production of ATP. This occurs in the mitochondria. For this to occur, however, fatty acids must first get into the mitochondria.
Firstly, the fatty acid is activated with CoA. Coenzyme A is then swapped with carnitine, as while acyl CoA cannot cross the mitochondrial membrane, acyl carnitine can. Acyl carnitine moves across the mitochondrial membrane via an enzyme called translocase. Once within the mitochondrion, acyl carnitine can convert back to acyl CoA before undergoing the process of beta-oxidation, which I'm about to cover in more detail...
Beta-Oxidation of Fatty Acids
Beta-oxidation of fatty acids removes two carbon atoms at a time as acetyl CoA, as I mentioned in my initial post about fatty acids. As acetyl CoA is released, NAD+ and FAD are reduced to NADH and FADH2, respectively. They are then able to power the synthesis of ATP.
Now to go into a bit more detail...
Each step of beta-oxidation involves breaking the bond between the alpha and beta carbons. The alpha carbon is the carbon NEXT to the carbonyl carbon (not the carbonyl carbon itself), and the beta carbon is the one after that (again, not the carbonyl carbon).
The first enzyme to do its job is acyl CoA dehydrogenase. Acyl CoA dehydrogenase removes hydrogen (hence "dehydrogenase") from the alpha and beta carbons, forming a double bond between them.
Next up is enoyl CoA hydratase. As the name of the enzyme suggests, it hydrates the bond by adding water to it. This replaces the -H on the alpha carbon and adds an -OH group to the beta carbon.
The third enzyme required is beta-hydroxyl acyl CoA dehydrogenase. This enzyme removes the hydrogen from the -OH group on the beta carbon, leaving it with an =O group instead.
The final enzyme to act is thiolase, which forms a thioester bond between the beta carbon and CoASH. This also breaks the bond between the alpha and beta carbons, leaving us with acetyl CoA and a slightly shorter acyl CoA.
Oh and just so you know- only the two steps catalysed by dehydrogenase enzymes are oxidation reactions, and thus they are the only reactions that reduce NAD+ and FAD.
More Stuff on ATP Production
(Okay, that wasn't the title of the slide, but it was a lot more snappy than what's actually on the slide, which is "Oxidative Phosphorylation using Energy from NADH and FADH2 Produces ATP.")
After breaking down the fatty acids into acetyl CoA, even more energy can be provided through the further breakdown of acetyl CoA in the citric acid cycle. (Acetyl CoA is also produced through glycolysis of sugars, thus making the citric acid cycle doubly useful.) In the citric acid cycle, CoA is oxidised further into CO2, providing even more electrons to reduce NADH and FADH2.
What happens to these electrons? Well, they then go to the electron transport chain in the inner mitochondrial membrane, where they create a proton gradient which powers ATP synthase, the enzyme that produces ATP. ATP is essentially a form of energy that is usable by the cell- something that you should probably know by now.
Introduction to Fatty Acid Synthesis
Fatty acid synthesis occurs in the cytoplasm. As I've mentioned before, it starts with acetyl CoA. Some acetyl CoA is converted to 3-carbon malonyl CoA with the addition of CO2 and ATP (as mentioned in my post about glycogen metabolism, anabolism tends to require energy). Acetyl CoA and malonyl CoA are then activated by a protein called acyl carrier protein, or ACP. Acetyl-ACP and malonyl-ACP then react together to release CO2 and ACP to form 4-carbon acetoacetyl-ACP, which has a ketone group. Acetoacetyl-ACP can then be reduced by NADPH (an electron carrier similar to NADH) to form butyryl-ACP. Butyryl-ACP can then react with malonyl-ACP to form a 6-carbon chain, and then that 8-carbon chain can react with malonyl-ACP to form an 8-carbon chain, and so on until the desired length is formed. Eventually, the ACP group is released.
And that's it for this post! Next up I'll talk more about cell membranes.
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