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I understand that the imidazole ring in histidine is aromatic. I also realize that it retains it's aromaticity when protonated. I am wondering why it is not mentioned at all in basic text books such as Lehninger? Also, across the web there are a number of places claiming that histidine isn't aromatic in all cases. Another reason I am a little confused is, if protonation doesn't harm the aromatic nature, then why is histidine such a weak base? Am I missing something?

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3 Answers 3

This is one of my favorite charts demonstrating the complexity of amino acid properties:

Amino Acid Properties http://www.jalview.org/help/html/misc/aaproperties.html

Histidine is probably the most complicated amino acid in this regard (just compare how many circles it falls into). But don't undersell Cysteine and Methionine; those sulfurs exhibit some surprising behavior, especially when coordinated properly. Cysteine of course forming disulfide bonds, Methionine occasionally functioning as a methyl-transferase.

Biochemistry text books make some over simplifications because presenting the full messiness of these classifications is pretty confusing. Lehninger itself is the worst about this (and especially when presenting math). Voet and Voet is probably the most reliable about presenting this complexity. I still think Lehninger is a better teaching textbook overall (I was first taught Biochemistry from the 3rd edition), but I also recall spending a week being confused about a topic before someone pointed me at V&V and I realized Lehninger was oversimplified to the point of being wrong, in that case.

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I am wondering why it is not mentioned at all in basic text books such as Lehninger?

Books are not flawless.

Another reason I am a little confused is, if protonation doesn't harm the aromatic nature, > then why is histidine such a weak base?

Pyrolles have a weak basicity because of delocalization of the electron lone pair of nitrogen. It is the lone pair of nitrogen, in amines, which gives it basicity (Check Lewis bases and acids) .

In imidazole, the other nitrogen (sp2) has a free lone pair and does contribute to its basicity. As you pointed out before, imidazolium is a stable moiety and imidazole is much stronger base than pyridine.

But compared to lysine (pKb ≃ 10.5) and arginine (pKb ≃ 12.48) it is a weaker base (pKb ≃ 7). Imines are generally weaker bases than amines because the sp2 hybridization of the former gives them a more s-like character; this makes the lone pair to be held more tightly to the nucleus thereby reducing the basicity.

The strong basicity of arginine is because of the guanidium group.

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But the protonation occurs on the pyridine-like nitrogen. It is in sp2 configuration and its lone pair is not involved in the aromatic pi system. –  Alexandra May 6 '13 at 11:43
    
Rather, the protonation of imidazole generates a cation where the positive charge is delocalized, which contributes to its stability. I still do not see why it is a weak base. –  Alexandra May 6 '13 at 11:45
    
Oh my mistake.. the other nitrogen does contribute to its basicity.. i'll edit the answer.. –  WYSIWYG May 6 '13 at 12:44

The imidazole ring in histidine is indeed aromatic. But an aromatic amino-acid is not usually defined as "an amino-acid with an aromatic ring". Rather, they are usually defined by common chemical properties, such as high absorption at 280nm, or better their common metabolic pathway.

Histidine as a stand-alone amino-acid is a weak base, but this is mainly due to the amino and acid groups shared with every amino-acid. The imidazole ring in itself has a neutral pKa.

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I was referring to the basicity of the side chain itself. Why is its pKa neutral? –  Alexandra May 6 '13 at 11:46
    
i dont think there is a term called neutral pKa. pKa of water is ~15.7. pKa of imidazole is ~14 which makes it slightly better acid compared to water but poorer acid compared to carboxylic acids. –  WYSIWYG May 6 '13 at 15:46
    
@WYSIWYG: I was referring to the deprotonation of the acid conjugate, physiologically more relevant. pKa≃7. I agree that 'neutral pKa' is a misnomer. –  biozic May 6 '13 at 17:58

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