Synthesis

In my previous posts, I've spoken a lot about how things are broken down. This will be my first post about synthesis, specifically the synthesis of glucose, glycogen and fatty acids.

Describe the reactions and regulation of anabolism of glucose (gluconeogenesis from various substrates) and fatty acids

Anabolism of Glucose - Reactions

In this post, I'm only going to cover gluconeogenesis, or formation of glucose from a source other than glycogen. Glycogen is just a chain of glucose, so getting glucose from glycogen is too easy- all you need to do is break down the glycogen chain. I've detailed both the breakdown of glycogen to glucose, as well as the synthesis of glycogen from glucose, in an earlier post.

Anyway, back to gluconeogenesis. Substrates for gluconeogenesis include pyruvate, lactate, other sugars (such as galactose and fructose), glycerol and amino acids. Note that Acetyl CoA cannot undergo this process.

For the purposes of this post, we're going to focus on pyruvate. Conversion of pyruvate to glucose is essentially the opposite of the glucose -> pyruvate pathway (a.k.a. glycolysis), which I've explained here. However, as I mentioned in that earlier post, some of the steps in the glycolysis pathway are irreversible, so we need other enzymes to bypass them. The steps that require bypassing are the following:

1. Pyruvate --> Phosphoenolpyruvate (PEP)
2. Fructose 1,6-bisphosphate --> Fructose 6-phosphate
3. Glucose 6-phosphate --> Glucose

The first of these reactions, the conversion of pyruvate to PEP, actually requires two enzymes. Firstly, pyruvate carboxylase converts pyruvate, bicarbonate and ATP to oxaloacetate, ADP and phosphate. In the second step, PEP carboxykinase converts oxaloacetate and GTP to PEP, GDP and CO₂.

The second reaction is a lot simpler: fructose 1,6-bisphosphatase converts fructose 1,6-bisphosphate into fructose 6-phosphate. Energy is released in this step (though this doesn't make up for all of the energy required in anabolism, as I'll get to in a bit).

The third reaction is also relatively simple: glucose 6-phosphatase converts glucose 6-phosphate into glucose.

Overall, this is a somewhat energy-hungry process. Two pyruvate molecules are required for every glucose molecule, as pyruvate has 3 carbons and glucose has 6 carbons. Two ATP molecules and one GTP molecule are required for each pyruvate molecule (conversion of pyruvate into PEP requires ATP and GTP, as mentioned above, plus conversion of 3-phosphoglycerate into 1,3-bisphosphoglycerate requires ATP). Hence, the overall energy requirement per molecule of glucose is 4ATP and 2GTP, and since 1 GTP ~ 1 ATP, this can be simplified to 6ATP. Here's the overall equation:

2 Pyruvate + 6 ATP --> Glucose + 6 ADP + 6 P_i + 4H⁺

Anabolism of Glucose - Regulation

Of course, some regulation needs to occur, otherwise you'd be breaking down glucose at the same time that you're producing it, which would be really counter-intuitive. For the most part, regulation is handled by the presence or absence of "ingredients" that are required for the process to occur.

Another thing that's worth mentioning is that most amino acids (basically all of them except for leucine and lysine) can upregulate gluconeogenesis. Glucogenic amino acids can enter the citric acid cycle at various points, causing an increase in oxaloacetate production. An increase in oxaloacetate production then causes an increase in gluconeogenesis.

Anabolism of Fatty Acids - Reactions

Acetyl CoA serves as the main "building block" for fatty acids. Excess acetyl CoA can be diverted from the citric acid cycle in order to store energy. The first step of this process is the transport of acetyl CoA from the mitochondria into the cytosol, where fatty acid synthesis occurs.

Acetyl CoA can't exit the mitochondrial matrix as it is. Instead, it has to combine with oxaloacetate to form citrate (which you might remember as being one of the steps of the citric acid cycle), which can then exit the mitochondria through the citrate/pyruvate shuttle. Once in the cytosol, ATP-citrate lyase can break citrate back down into oxaloacetate and acetyl CoA.

The next step now is to convert acetyl CoA into malonyl CoA. This is a carboxylation reaction (i.e. a reaction in which a carboxyl group is added). This requires acetyl CoA carboxylase and some ATP. After this happens, the building happens, catalysed by fatty acid synthase. Fatty acid synthase is a multi-enzyme polypeptide, which basically means that it's a one-stop shop of all of the enzymes that you need for making a new fatty acid. The growing fatty acid chain is continually bound to the enzyme, so side reactions are reduced.

There are many steps involved, but given that we didn't go into a massive amount of depth, I don't think we need to know what attacks what and all those nitty-gritty details. We might need to know the overall reaction though:

Acetyl CoA + Malonyl CoA + 14NADPH + 14H⁺ --> Palmitate + 7CO2 + 14NADP⁺ + 8CoASH + 6H₂O

Note that NADPH is required in this process. ATP is also required to synthesise malonyl CoA in the first place, according to the following reaction:

Acetyl CoA + ATP + HCO₃^- --> Malonyl CoA + ADP + H₂O

Anabolism of Fatty Acids - Regulation

There are two main sites of fatty acid synthesis: conversion of acetyl CoA to malonyl CoA, and transport of already-formed fatty acids into the mitochondria.

Let's start with the first site: formation of malonyl CoA. Regulation of this step is quite simple: having an excess of citrate, which leads to an excess of acetyl CoA, will upregulate formation of malonyl CoA (I guess the cell wants to get rid of its excess acetyl CoA?). Conversely, an excess of palmitic acid, or fatty acids in general, can provide negative feedback, preventing further formation of malonyl CoA.

Now for the second site of regulation: transport of fatty acids into the mitochondria. If transport into the mitochondria decreases, fatty acids can build up in the cytosol, negatively regulating formation of malonyl CoA, as I just described.

Explain the difference between glycolysis, glycogenolysis, gluconeogenesis and glycogenesis

• Glycolysis: Breakdown of glucose to release energy.
• Glycogenolysis: Breakdown of glycogen to form glucose.
• Gluconeogenesis: Formation of glucose from a source other than glycogen.
• Glycogenesis: Formation of glycogen from glucose.

Remember: -lysis = breakdown, -genesis = formation.

Have an understanding of the energy demands of anabolic processes.

I'm not really sure what to put here other than that anabolic processes tend to require energy, which is usually generated by catabolic processes.