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Background

I'm interested in the acid-base properties of a metabolite, biotinyl 5' AMP in the cell. Biotinyl-5'-AMP can react with protein lysine side chains at the anhydride linkage to form biotinyl-lysine. This immediate reaction is not, however, the focus of this question. I'm struggling to understand for sure whether, in its soluble state, biotinyl-5'-AMP is likely to adsorb or donate (further) protons to its immediate chemical neighbours in the cell, particularly weak bases or acids.

Question

How can I intuitively understand the acid-base properties of an organic molecule in solution with multiple functional groups? Biotinyl-5'-AMP is deprotonated in solution, as far as I am aware. Would this deprotonated species then have further ability to donate or adsorb protons? I have found database information about this molecule suggesting the pKa of the strongest acid and strongest basic groups (0.83 and 4.99 respectively), and a line that the molecule is likely to be a 'strong basic compound'.

Given those database figures and the structure/functional groups (figure below): How can I intuitively understand the acid-base properties of this compound in solution? How should I interpret and rationalise those database pKa values? How should I then predict the propensity of biotinyl-5'-AMP to influence the pKa of immediately-adjacent weak acids and bases in the cell?

biotinyl-5'-AMP

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  • $\begingroup$ It's essentially just another amino acid. It's a zwitterion around pH=5. This pKa about 1 is for cation (its protonated form). $\endgroup$
    – Mithoron
    Nov 17, 2022 at 1:21

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How can I intuitively understand the acid-base properties of an organic molecule in solution with multiple functional groups?

You should view the molecule as a set of different acids and bases that just happen to be connected in the same molecule. Some of those acidic groups like the phosphate anhydride might have low pKas; some of those basic groups like the exocyclic amine might have high pKas. If you understand how mixtures of strong and weak acids and bases work you understand how this molecule works. The only additional constraint is that because all the groups are connected in the same molecule, all the different acid/base species here have the same concentration, instead of independent concentrations.

Biotinyl-5'-AMP is deprotonated in solution...

Well that depends entirely on the pH! (Although at low pH where the phosphate is less likely to be protonated I would expect the rate of degradation via hydrolysis to be fairly significant...but that's just an technicality of this particular molecule that's not relevant to acid/base chemistry of "big" molecules in general...)

How should I interpret and rationalise those database pKa values?

With extreme caution. The folks who compute these pKas aren't always right, and even when they are right it's not always clear what acid/base equilibrium they are characterizing with their prediction.

How should I then predict the propensity of biotinyl-5'-AMP to influence the pKa of immediately-adjacent weak acids and bases in the cell?

The same way any other mixture of acids and bases would...if you are trying to understand how this molecule affects a single molecule to which it is bound, it will be more helpful to think of H-bond donating and accepting. "Acidic" and "basic" make a bit more sense as bulk solution ideas

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  • $\begingroup$ Re: 'deprotonated in solution' : As a biochemist I momentarily forgot that pHs actually exist outside of the 7.2--7.8 range :D Thanks for the correction. $\endgroup$
    – steve_b
    Nov 17, 2022 at 10:02
  • $\begingroup$ This answer is very useful and explains the landscape I was trying to understand very clearly. Regarding your last paragraph, I think that I more trying to ask a question along the lines of, "would a high local concentration of this molecule induce an increase or decrease in pH at a point within a cell" (starting pH ~ 7.4). Can you include a briefly reasoned approximation based on the prominent ionisable groups which you see? Or, is it too complex to be able to approximate? It would be useful to know the degree to which one can intuitively answer this problem without a rigorous calculation. $\endgroup$
    – steve_b
    Nov 17, 2022 at 10:12
  • $\begingroup$ The diffusion time of protons is very fast. For cells that are 10 microns big, the diffusion time is approximately ~5 milliseconds. So whatever perturbation this molecule has on a local area in the cell, it isn't going to last long. Or, if you like, treat the relevant length scale as 10 nm. This is probably (ballpark) the hydrodynamic radius of biotinyl-ATP. The diffusion time over 10 nm for protons is like 5 nanoseconds. So whatever "local concentration" of this metabolite exists at a point might perturb the pH, but not for very long. $\endgroup$
    – Curt F.
    Nov 17, 2022 at 22:14

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