Abstract
Due to the heterocyclic structure and distinct conformational profile, proline is unique in the repertoire of the 20 amino acids coded into proteins. Here, we summarize the biochemical work on the replacement of proline with (4R)- and (4S)-fluoroproline as well as 4,4-difluoroproline in proteins done mainly in the last two decades. We first recapitulate the complex position and biochemical fate of proline in the biochemistry of a cell, discuss the physicochemical properties of fluoroprolines, and overview the attempts to use these amino acids as proline replacements in studies of protein production and folding. Fluorinated proline replacements are able to elevate the protein expression speed and yields and improve the thermodynamic and kinetic folding profiles of individual proteins. In this context, fluoroprolines can be viewed as useful tools in the biotechnological toolbox. As a prospect, we envision that proteome-wide proline-to-fluoroproline substitutions could be possible. We suggest a hypothetical scenario for the use of laboratory evolutionary methods with fluoroprolines as a suitable vehicle to introduce fluorine into living cells. This approach may enable creation of synthetic cells endowed with artificial biodiversity, containing fluorine as a bioelement.
Highlights
Nature employs a rather small set of chemical elements for constructing the core biochemical makeup
The unique features created by proline residues in proteins justify the essential role of proline in biochemistry
Our recent theory suggests that proline was one of the first amino acids recruited for protein translation [22]
Summary
Nature employs a rather small set of chemical elements for constructing the core biochemical makeup. It is typical that the incorporation of fluorine into certain molecular fragments changes the local polarity as well as the electronic and conformational properties These factors may translate into an altered structure and stability of a protein containing a fluorinated fragment. What consequences fluorination would have regarding the fitness and survival of the organism relying on fluorine-containing proteins remains an open question In this context, the substitution of the proline residue with fluorinated analogues (fluoroprolines, Figure 1) creates an option for making fluorine a component of a living organism. The effects of fluoroprolines have been examined in a number of protein structures These studies demonstrated an altered stability and altered folding kinetics that occurred upon the proline-to-fluoroproline replacement, as reviewed in [17]. They are not included in this review due to a scarcity of biochemical studies
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