I know that there are different ways in which an enzyme can be covalently modified (methylation. phosphorylations etc). How do we know which type of modification will target which type of amino acid residue in the active site? For example, my biochem book states the methylation is common at glu.
Covalent enzyme modifications
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I don't know about methylation but phosphorylation you can intuit your way through. Think about how phosphorylation happens. You have a nucleophile that attacks the phosphorus (which acts just like a carbonyl would under nucleophilic attack) on an ATP molecule and cleaves the P-O bond attaching the phosphate group to the ATP. So the question is, what amino acids could serve as the nucleophiles? Well, the most common ones you'll encounter are serine, threonine, and tyrosine. That makes sense, because they have the nucleophilic oxygens that can serve as nucleophiles and attack the phosphate.
There are also less obvious ones - these are all the basic amino acids, which have nucleophilic nitrogen atoms. So lysine, arginine, and histidine. I'm not sure if the MCAT will test you on those because they are generally overlooked and not as prevalent as the amino acids with hydroxyl groups.
There are also less obvious ones - these are all the basic amino acids, which have nucleophilic nitrogen atoms. So lysine, arginine, and histidine. I'm not sure if the MCAT will test you on those because they are generally overlooked and not as prevalent as the amino acids with hydroxyl groups.
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The most common modification is phosphorylation of Ser, Thr, and Tyr.
The carbonyl group is not nucleophilic because although the oxygen in the carboxylate is often anionic, it is also resonance stabilized. In general, carboxylates are not particularly nucleophilic.
The sulfur in methionine is analogous to an ether oxygen. We know from organic chemistry that although oxygen is an electronegative atom, the steric hinderance provided by the two alkyl groups essentially prevents it from being a good nucleophile. This is also the reason why ethers are poor hydrogen bond acceptors.
Similar logic can be employed to describe the nitrogen in tryptophan having low to nonexistent nucleophilicity.
The carbonyl group is not nucleophilic because although the oxygen in the carboxylate is often anionic, it is also resonance stabilized. In general, carboxylates are not particularly nucleophilic.
The sulfur in methionine is analogous to an ether oxygen. We know from organic chemistry that although oxygen is an electronegative atom, the steric hinderance provided by the two alkyl groups essentially prevents it from being a good nucleophile. This is also the reason why ethers are poor hydrogen bond acceptors.
Similar logic can be employed to describe the nitrogen in tryptophan having low to nonexistent nucleophilicity.
You are most certainly right but I just wanted to bring up the interesting example of S-adenosyl methionine (SAM). SAM is made from methionine, which nucleophilically attacks a carbon atom on ATP to make PPi, Pi, and SAM. This is of course rare and this particular case is driven by basically ATP hydrolysis but it does happen - in fact, the production of SAM is crucial to the cell's metabolic pathways. Other than that, methionine isn't really nuclephilic.
The carbonyl group almost always act as an electrophile, at the carbon. That is the basis for all of biochemistry and it is crucial you understand that. You will almost never see a carbonyl group acting as a nucleophile spontaneously. Methionine has been well-explained above but you might raise the example of cysteine, and yes, cysteine phosphorylation exists. But again, the common ones are the hydroxylated amino acids.
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Oh I'm glad you brought up SAM, that's an interesting case, plus the driving force from coupling ATP hydrolysis drives home the point of Met not being a great nucleophile on its own.
Also, while on the topic of rarer phosphorylations, Histidine can definitively be phosphorylated as well. In fact, phosphoglycreate mutase (see glycolysis) uses this mechanism to transfer the phosphate group from C3 to C2 of phosphoglycerate, essentially using histidine as a phosphate-carrier.
Also, while on the topic of rarer phosphorylations, Histidine can definitively be phosphorylated as well. In fact, phosphoglycreate mutase (see glycolysis) uses this mechanism to transfer the phosphate group from C3 to C2 of phosphoglycerate, essentially using histidine as a phosphate-carrier.
