Rewriting the Mechanisms of Biological Chemistry: Dehydrons as Chemical Species

If you peruse any of the increasingly bulkier biochemistry textbooks you will notice that a large portion of the reactions depicted correspond mechanistically to transesterifications. Typically in these reactions, nucleophilic attacks are responsible for the breaking and forming of bonds at the catalytic site of the enzyme/substrate transient complex. Yet, something does not look quite right: the chemical formula “H2O” appears in the elementary steps [1] but seems to signify something chemically quite different from what we would identify as water. The underlying acid-base chemistry is usually completely inconsistent with the chemical behavior in a bulk aqueous environment. For example, the functionalization of a nucleophilic group, here generically denoted AH, through deprotonation is often claimed to involve proton transference from AH to water. Yet, at least according to basic chemical intuition, hydronium is invariably more acidic than AH, and so unlikely to accept its proton. Also, the relay mechanisms for proton transference in enzymes – as in the so-called “catalytic triads” [1] – are typically completely at odds with the propensities for proton acceptance as dictated by the respective pKa’s of the groups involved. For instance, aspartate is often shown to nucleophilically functionalize a vicinal histidine by deprotonating it, something completely unrealistic in everyday chemistry.

Ariel Fernandez Books
Books by Ariel Fernandez describing dehydron catalysis.

Recent work by this author entitled “Acid-base chemistry of frustrated water at the protein interface” squarely addressed these paradoxes by adopting an approach that may alter the mechanistic picture of biological chemistry and prompt a rewriting of biochemical reactions in a way consistent with the rules of chemistry. The key point in this paradigm shift is that frustrated water partially occluded by structural defects at the protein interface is shown to turn into a chemical base, a species with radically different chemical properties from what chemists typically mean when they write “H2O” in a chemical reaction. In other words, interfacial water is biochemically functionalized into a new chemical species by nearby defects on the enzyme structure known as dehydrons (脱水元, 中文名)  [2-4]. In this way, dehydrons become catalytic enablers and stimulators of biochemical reactions, realizing an idea first advanced in Ariel Fernandez’ book “Biomolecular Interactions“.

[1] Alan Fersht (1998) Structure and Mechanism in Protein Science. W H Freeman, 1st edition.

[2] Ariel Fernandez (2015) Packing defects functionalize soluble proteins. FEBS Letters 589, 967-973.

[3] Weishi Meng (2015) Ariel Fernandez at the Center of Transformative Biotechnology. Science Transparency, 3/14/2015.

[4] Website for Ariel Fernandez Consultancy.


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