Chemical Reactions of Phosphate Anhydrides - Online Tutor, Practice Problems & Exam Prep

Phosphate anhydrides, like ATP, undergo nucleophilic acyl substitution after forming a magnesium complex, which reduces negative charges, facilitating nucleophilic attack at the gamma phosphate position. Key reactions include hydrolysis with water, alcoholysis with alcohol, and nucleophilic acyl substitution (NAS) with carboxylic acids, producing ADP and various phosphorylated products. Aminolysis can further convert phosphorylated carboxyl groups into amides. Understanding these mechanisms is crucial for grasping biochemical energy transfer and reaction pathways involving nucleophiles.

Chemical Reactions of Phosphate Anhydrides Concept 1

Hey everyone. So let's take a look at the chemical reactions of Phosphate Anhydrides. Now we're going to say here that the multiple negative charges of a Phosphate Anhydride make its phosphorus atoms resistant to nucleophilic attack. Now here we're going to say we have a magnesium ion and a class of enzymes called inorganic pyrophosphatases, it reduces the overall negative charges. Remember, a nucleophile has electrons.

It can be a neutral nucleophile, but usually the best nucleophiles are negatively charged. It's hard for a negative nucleophile to come in and attack a structure that's highly negative. Remember, like charges repel. So here we'd have to use magnesium ions and this class of enzymes to help reduce the negative charge of our phosphate anhydride. Here we'd say they help to create a complex which is our phosphate anhydride magnesium complex, the ionic bonds that form between our phosphoryl oxygen atoms and the magnesium ion.

If we take a look here, we have the magnesium ions forming ionic bonds with two phosphoryl oxygens furthest from the R group. If we take a look here, we have initially our alkylated phosphate anhydride and we can see that we have a bunch of negative charges. A nucleophile will not want to come in and try to target any of these phosphorus atoms like charges repel. So we're using this magnesium coupled with these classes of enzymes. Magnesium typically represents like a silver string.

If you've done the hydrochloric acid magnesium lab experiments, you might have used a little piece of magnesium strip. We see that it's silver in color which matches the silver color that we see here. It's kind of in a mesh with the enzymes themselves. But what effect does this have? Well, here, the magnesium ion comes in and it forms an ionic bond with these oxygens.

These oxygens, we realize that an ionic bond is not a solid bond, we have these dotted lines to represent that, But these two negative oxygens are kind of occupied at the moment with this magnesium. This lowers the amount of free negative charges on the surface of this phosphate anhydride, reducing the overall charge. Because there's less free negative charge, a nucleophile is more likely to come in and want to attack a phosphorus atom. So here, once we've added the magnesium and it forms these ionic connections with these oxygens, that's what we call the complex. So again, anytime we're dealing with a phosphate anhydride, we have to do this first.

We have to introduce the magnesium with this class of enzymes to help lower the overall negative charge before a nucleophile can come in and target any of these phosphorus atoms here. Alright. So just keep that in mind when we're dealing with these different types of chemical reactions.

Chemical Reactions of Phosphate Anhydrides Concept 2

Now that we've talked about the magnesium complex that can form, we now cover the enzyme catalyzed nucleophilic acyl substitution mechanism. Remember, nucleophilic acyl substitution is something you've seen before when it comes to our carboxylic acid derivatives, and the shorthand is NAS. Now here after magnesium complex formation, phosphate anhydrides react with nucleophiles at their gamma phosphate position via this NAS mechanism. So remember, the most important of all the phosphate anhydrides is ATP, which is adenosine triphosphate, and we're going to say here that this is the alpha phosphorus, this is beta, and over here is gamma. So we're talking about targeting this phosphorus here.

If we bring in a nucleophile, we have our magnesium with its enzymes. Basically, what's going to happen is for this nucleophile to attack the gamma, this magnesium has already attached to create our complex. Here we're not showing the complex, but realize it has to form first before the nucleophile comes in and attacks later. Now, we are saying the complex was formed so then the nucleophile can come in. At the end, we would get a phosphorylated nucleophile and then we'd have ADP.

We've lost this phosphorus to the nucleophile but it's okay. This oxygen here, it's going to gain a hydrogen. The hydrogen that was part of this nucleophile here. So at the end, our ATP with the magnesium and enzymes within a nucleophile helps to create a phosphorylated nucleophile plus our ADP molecule. Notice the arrow is going one way, that's because once you've engaged in this NAS mechanism where you are attacking the phosphorus atom, the reaction overall is no longer reversible.

Right? So we're going to have an arrow going one direction. Right. So again, keep in mind, this is what we're typically going to see when it comes to these NAS reactions and ATP being the most important of all the phosphate anhydrides, we're typically going to see reactions dealing with ATP.

Chemical Reactions of Phosphate Anhydrides Example 1

Hey, everyone. So let's take a look at the following example question. Here it says provide the mechanism for the enzyme catalyzed reaction between ATP and a nucleophile. Now remember, we have our 4 steps. Step 0 is kind of just the prep phase where we have to reduce the overall negative charge of our ATP molecule so that a nucleophile can then go in and attack the phosphorus atom.

So step 0 is our ionic bond formation, which is talking about the magnesium complex that will be formed. Step 1 would then be nucleophilic attack, step 2 would be proton transfer, and then finally step 3 would be our loss of leaving group. So for step 0, we're going to say here that our magnesium ion forms an ionic bond with 2 of the negatively charged oxygens of the phosphate anhydride. So here goes our ATP molecule, we have our magnesium with its class of enzymes, so we're going to form an ionic bond between the magnesium ion and these two oxygens. This lowers the overall free negative charge around so nucleophiles can then come in and attack our phosphorus atom.

We're going to say the nucleophile attacks the phosphorus in the gamma position. So we have alpha, beta, gamma. So, again, remember we have our complex here this whole time. The nucleophile can then come in, attack this phosphorus, kicking the bond up to the oxygen. So here goes our nucleophile that is now attached, and it's positively charged.

Step 2, we're going to say we have a proton transfer from the positively charged nucleophile to the oxygen between the beta and gamma phosphorus atoms. So remember here this is beta, this is gamma, our nucleophile again is attached here. We're going to have a proton transfer. So now the proton is here onto this oxygen. That oxygen is making 3 bonds, so now it's positively charged.

So, again, that oxygen is positively charged because it's making too many bonds. And we're going to say here the oxygen atom pushes its lone pair to kick out ADP as the magnesium ion also is released. Alright. So remember, this whole time the magnesium ions have been attached. Here they go right here. We're going to say our oxygen wants to make a double bond again so it does, helping to kick this whole thing out.

And at the same time, we're disengaging the ionic bonds between oxygen and the magnesium because we no longer need them. So at the end, what do we create? We've created a phosphorylated nucleophile plus we've created ADP. So these would be our products at the end. We have our ADP molecule and we have our phosphorylated nucleophile.

Magnesium, it's been released, disengaged from the molecule, from the structure, so it's still hanging around within this whole reaction. Right? But this is what we care about it. At the end, we have our nucleophile that's been phosphorylated, and we have our ADP molecule.

Chemical Reactions of Phosphate Anhydrides Concept 3

Here, let's take a look at the reactions of ATP. Now, upon magnesium complex formation, ATP can react with a nucleophile at the gamma phosphate position. And we're going to say here that when we talk about these reactions, we're talking about hydrolysis, alcoholysis, and NAS of a carboxylic acid. Now, under hydrolysis, this is the reaction of our ATP with water, alcoholysis is the reaction of ATP with an alcohol, and then finally, NAS of a carboxylic acid is the reaction of ATP with a carboxyl group. If we take a look here at our chart, we have our ATP magnesium complex. Again, remember, we have to form this first before any of these nucleophiles can come and engage with our ATP molecule.

In hydrolysis, we have our water coming in. At the end, we create our hydrogen phosphate, so OH, and we have ADP. In alcoholysis, we create our phosphorylated alkoxyl group, so OR, and again we create ADP. Here, it looks exactly like this. There's no point in showing it over and over.

Just realize that this ADP is the same as this ADP. And then when we're dealing with NAS, we have our carboxyl group, our carboxylic acid. So we're going to make a phosphorylated carboxyl group which would be this and plus ADP. Now, this last one, we can go a step further and do one more thing. We could do a reaction of this phosphorylated carboxyl group with an amine.

And if we do it with an amine, then it becomes aminolysis. Aminolysis follows the same steps 1, 2, 3 that we learned previously when it comes to our phosphate anhydrides. Look and see that step 0 is no longer there. That's because we don't need to incorporate magnesium with the enzymes because there's not an excess of negative charges. We only have to contend with these two negative charges, which is not that much.

So this amine is free to come and attack or interact with this phosphorylated carboxyl group. Now, doing that will give us at the end, it's going to give us an amide. So R₂N, so we create an amide, and then again, we create a hydrogen phosphate. So here, we're going to create our hydrogen phosphate, so OH. Again, when it comes to these reactions of ATP, these are the 3 reactions we need to keep in mind.

We have hydrolysis, we have alcoholysis, and we have NAS with a carboxylic acid. That one can go further through aminolysis to give us at the end an amide plus a hydrogen phosphate. But remember, all these reactions cannot work until we first create our magnesium complex.

Once we do that, then these nucleophiles can then engage with the gamma position of the gamma phosphate position of our ATP molecule.

Chemical Reactions of Phosphate Anhydrides Example 2

Hey everyone. So here it says, what products are formed when ethanol reacts with ATP in the presence of magnesium and its necessary pyrophosphatases? Alright. So, remember, we have ATP and we're reacting with an alcohol, so that means we're dealing with alcoholysis. In alcoholysis, what do we create?

That's right, we create a phosphorylated alkoxyl group. So ethanol is going to be this structure here and we're going to phosphorylate it. So remember all that means is we're going to have our phosphate group here and then we're going to phosphorylate it. So this oxygen of the alcohol so here goes our phosphorylated alkoxyl group plus, remember we're going to make ADP. So here we have to just show our ADP.

We have this H here connected to the oxygen. Okay. And then we have CH₂ connected to our 5 structured ring. We have our OHs here, and then we have our adenine or adenine nitrogenous base. So these would be our 2 products that we make.

When we react, once we make our magnesium complex, which is why the magnesium ion and the enzymes are there, our alcohol is free to engage with our ATP. At the end what we would get is our phosphorylated alkoxyl group which would be this, plus ADP. Right. So these would be our two answers.

Write a mechanism for enzyme-catalyzed hydrolysis of the ATP molecule. 

Hey everyone. So here it says, write a mechanism for the enzyme catalyzed hydrolysis of the ATP molecule. Now, we know that the first step is the creation of our magnesium complex. We would use our magnesium with its class of enzymes necessary to do this. Here, when we do this we would create ionic bonds between these two negatively charged oxygens and magnesium ion. Once it's been created, then our water which acts as our nucleophile can come in and attack. It'll attack the gamma phosphorus atom. So it comes in here, hits here kicking this bond up to the oxygen. So then we're going to have here initially, a negative oxygen. Here's the phosphorus that's been attacked, which is still connected to the magnesium ion. Okay. We have this. And because the rest of this ATP molecule here is unaffected by any of this, we're just going to substitute an R group for it. Because none of it's changing. We're only focusing on the parts that are being affected. Again, the water molecule here has been attached. Oxygen's making 3 bonds so it's positively charged. What we get now is we're going to get a proton transfer and remember, the hydrogen on the positively charged nucleophile is going to go from it to the oxygen that's in between our beta phosphorus and our gamma phosphorus. So over here we're going to show that. So here it goes getting added there. This is positive now. Connected to R. We're still connected to magnesium. And then here goes the it's no longer water. It's an OH group. What happens next is that oxygen decides it wants to remake a double bond. And when it does that, this acts as a leaving group and gets kicked out. And at the end, because it got kicked out, we create a for our final products, we're going to have our hydrogen phosphate, which is this, OH down here. So we have our hydrogen phosphate plus we create ADP. So here goes our ADP. And remember, when this is getting kicked out, the ADP is getting kicked out at the same time. Oxygen and magnesium, their ionic bonds are dissolving. There's no connection between them anymore because we don't need it. So that's how we get to the end having hydrogen phosphate and ADP as our final products. Alright. And again, because the rest of the ATP molecule has been unaffected we're really focusing on the phosphate and hydride portion of it. We can just show the rest of it as an R group for now.

Provide final product from the reaction of aspartic acid, ATP and ethylamine. 

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• D.

Here’s what students ask on this topic:

What is the role of magnesium ions in the reactions of phosphate anhydrides?

Magnesium ions play a crucial role in the reactions of phosphate anhydrides by reducing the overall negative charge on the phosphate anhydride molecule. This is achieved through the formation of a magnesium-phosphate complex, where magnesium ions form ionic bonds with the negatively charged oxygen atoms of the phosphate group. This reduction in negative charge makes the phosphorus atoms more susceptible to nucleophilic attack, facilitating reactions such as nucleophilic acyl substitution (NAS). Without the presence of magnesium ions, the high negative charge density would repel nucleophiles, making the reaction less likely to occur.

How does nucleophilic acyl substitution (NAS) occur in phosphate anhydrides?

Nucleophilic acyl substitution (NAS) in phosphate anhydrides occurs after the formation of a magnesium-phosphate complex. The magnesium ions reduce the negative charge on the phosphate anhydride, allowing a nucleophile to attack the gamma phosphate position. For example, in ATP, the nucleophile targets the gamma phosphorus atom, leading to the formation of a phosphorylated nucleophile and ADP. This reaction is typically irreversible, as indicated by a one-way reaction arrow. The NAS mechanism is essential for various biochemical processes, including energy transfer and metabolic pathways.

What are the key reactions involving ATP and nucleophiles?

The key reactions involving ATP and nucleophiles include hydrolysis, alcoholysis, and nucleophilic acyl substitution (NAS) with carboxylic acids. In hydrolysis, ATP reacts with water to produce ADP and hydrogen phosphate. In alcoholysis, ATP reacts with an alcohol to form a phosphorylated alkoxyl group and ADP. In NAS with carboxylic acids, ATP reacts with a carboxyl group to produce a phosphorylated carboxyl group and ADP. Additionally, the phosphorylated carboxyl group can undergo aminolysis with an amine to form an amide and hydrogen phosphate. These reactions are crucial for understanding biochemical energy transfer and metabolic pathways.

Why is ATP considered the most important phosphate anhydride?

ATP (adenosine triphosphate) is considered the most important phosphate anhydride because it serves as the primary energy currency in biological systems. ATP undergoes various reactions, such as hydrolysis, alcoholysis, and nucleophilic acyl substitution (NAS), to transfer energy and facilitate biochemical processes. The gamma phosphate position of ATP is particularly reactive, allowing it to participate in these energy-transfer reactions. The ability of ATP to form a magnesium complex, reducing its negative charge and making it more susceptible to nucleophilic attack, further underscores its central role in cellular metabolism and energy transfer.

What is the significance of the gamma phosphate position in ATP reactions?

The gamma phosphate position in ATP is significant because it is the primary site for nucleophilic attack in various biochemical reactions. After forming a magnesium complex, which reduces the negative charge on ATP, nucleophiles can target the gamma phosphate position. This leads to the formation of phosphorylated products and ADP. The gamma phosphate position's reactivity is crucial for processes such as hydrolysis, alcoholysis, and nucleophilic acyl substitution (NAS) with carboxylic acids. These reactions are essential for energy transfer and metabolic pathways in cells, highlighting the importance of the gamma phosphate position in ATP.