What Amino Acids can be phosphorylated? (testing in two days)

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Aug 21, 2019
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I am testing in two days. I have done countless questions regarding what amino acids can be phosphorylated through Uworld/ kaplan/ TPR/ AAMC. The consensus is Y, S, and T can be phosphorylated obviously. however I have seen questions contradicting each other regarding D and E taking the place of those AA's. I can see both arguments:

1) the deprotonated carboxylate could act as a potential nucleophile to attack the phosphate resulting in phosphorylation

2) the resonance that coincides with the carboxylate (due to the carbonyl group) makes it a poor nucleophile and thus makes it unable to be phosphorylated

Does anyone have a clear definitive source/ answer to this question? I have done questions that have literally both allowed and not allowed D and E to be phosphorylated, so I was just curious if anyone has a rule of thumb for it?


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Jun 1, 2020
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Ser, Thr, and Tyr are the most commonly phosphorylated amino acids in eukaryotes. Dogmatically speaking, these are the three you should always keep in mind when asked a question related to phosphorylation of a protein/amino acid.

But, there are exceptions (just as there are everywhere in chemistry and biology). Many other amino acids can be phosphorylated, including aspartic acid and glutamic acid, like you mentioned. I think the mechanism by which this happens is how you described in point one. A deprotonated Asp or Glu residue might act as a nucleophile to attack the phosphorous and form a phosphoester.

More recent research indicates that more amino acids can serve as possible candidates for phosphorylation in addition to Ser, Thr, and Tyr. For example, this paper published last year identifies via anion exchange chromatography that His, Arg, Lys, Asp, Glu, and Cys can all be phosphorylated as well.

So the answer to your question is yes, both D and E can be phosphorylated, but I would consider these "edge cases" only, cases that you probably won't be expected to have memorized. If a question has you decide between Ser and Asp for which could be phosphorylated, for example, I would definitely go with Ser. With Y, S, and T, there's a consensus, and there really isn't any room to say "Well, that could be correct, but...," as there might be with D or E.
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