Intact carbonic acid is a viable protonating agent for biological bases

Contributed by James T. Hynes, August 28, 2019 (sent for review June 3, 2019; reviewed by Graham R. Fleming and Sharon Hammes-Schiffer)
September 30, 2019
116 (42) 20837-20843

Significance

The paper demonstrates the previously unappreciated feature that, despite its instability, carbonic acid (CA) acts as an effective protonating agent consistent with its pKa value, which is here accurately determined over the full physiological temperature range. The equilibrium concentration of CA in the blood plasma is about 70× larger than (H+)aq, and, given CA’s acidic reactivity established here, it is concluded that, in contrast to current thought, CA should be considered a far more important protonation agent in the blood than is (H+)aq. These conclusions should be also considered when evaluating conditions resulting in CA concentration increase, such as acidosis in the physiological context and the gradual acidification of the oceans in the environmental setting.

Abstract

Carbonic acid H2CO3 (CA) is a key constituent of the universal CA/bicarbonate/CO2 buffer maintaining the pH of both blood and the oceans. Here we demonstrate the ability of intact CA to quantitatively protonate bases with biologically-relevant pKas and argue that CA has a previously unappreciated function as a major source of protons in blood plasma. We determine with high precision the temperature dependence of pKa(CA), pKa(T) = −373.604 + 16,500/T + 56.478 ln T. At physiological-like conditions pKa(CA) = 3.45 (I = 0.15 M, 37 °C), making CA stronger than lactic acid. We further demonstrate experimentally that CA decomposition to H2O and CO2 does not impair its ability to act as an ordinary carboxylic acid and to efficiently protonate physiological-like bases. The consequences of this conclusion are far reaching for human physiology and marine biology. While CA is somewhat less reactive than (H+)aq, it is more than 1 order of magnitude more abundant than (H+)aq in the blood plasma and in the oceans. In particular, CA is about 70× more abundant than (H+)aq in the blood plasma, where we argue that its overall protonation efficiency is 10 to 20× greater than that of (H+)aq, often considered to be the major protonating agent there. CA should thus function as a major source for fast in vivo acid–base reactivity in the blood plasma, possibly penetrating intact into membranes and significantly helping to compensate for (H+)aq’s kinetic deficiency in sustaining the large proton fluxes that are vital for metabolic processes and rapid enzymatic reactions.

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Acknowledgments

This work has been supported by NIH Grant PO 1000125420 (J.T.H. and E.P.).

Supporting Information

Appendix (PDF)

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 116 | No. 42
October 15, 2019
PubMed: 31570591

Classifications

Submission history

Published online: September 30, 2019
Published in issue: October 15, 2019

Keywords

  1. carbonic acid
  2. protonation
  3. blood plasma
  4. biological

Acknowledgments

This work has been supported by NIH Grant PO 1000125420 (J.T.H. and E.P.).

Authors

Affiliations

Daniel Aminov
Department of Chemistry, Ben-Gurion University of the Negev, 84105 Beer-Sheva, Israel;
Dina Pines
Department of Chemistry, Ben-Gurion University of the Negev, 84105 Beer-Sheva, Israel;
Philip M. Kiefer
Department of Chemistry, University of Colorado Boulder, Boulder, CO 80309-0215;
Snehasis Daschakraborty
Department of Chemistry, University of Colorado Boulder, Boulder, CO 80309-0215;
Present address: Department of Chemistry, Indian Institute of Technology (IIT) Patna, Bihta, Patna 801106, India.
Department of Chemistry, University of Colorado Boulder, Boulder, CO 80309-0215;
PASTEUR, Départmente de Chimie, Ecole Normale Supérieure, PSL Research University, Sorbonne Université, UPMC Université Paris 06, CNRS, 75005 Paris, France
Department of Chemistry, Ben-Gurion University of the Negev, 84105 Beer-Sheva, Israel;

Notes

2
To whom correspondence may be addressed. Email: [email protected] or [email protected].
Author contributions: E.P. designed and initiated research; D.A., D.P., P.M.K., S.D., and J.T.H., and E.P. performed research; D.A., D.P., and E.P. analyzed data; D.P. performed kinetic analysis; and J.T.H. and E.P. wrote the paper.
Reviewers: G.R.F., University of California, Berkeley; and S.H.-S, Yale University.

Competing Interests

The authors declare no competing interest.

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    Intact carbonic acid is a viable protonating agent for biological bases
    Proceedings of the National Academy of Sciences
    • Vol. 116
    • No. 42
    • pp. 20797-21332

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