Biochemistry of Fluoroprolines: the Prospect of Making Fluorine a Bioelement

Overview

Journal Beilstein J Org Chem

Specialty Chemistry

Date 2021 Mar 17

PMID 33727970

Citations 7

Authors

Vladimir Kubyshkin

Rebecca Davis

Nediljko Budisa

Affiliations

Soon will be listed here.

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 (4)- and (4)-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.

Citing Articles

Site-Specific Incorporation of Fluorinated Prolines into Proteins and Their Impact on Neighbouring Residues.

Elena-Real C, Urbanek A, Sagar A, Mohanty P, Levy G, Morato A Chemistry. 2024; 31(6):e202403718.

PMID: 39661394 PMC: 11772113. DOI: 10.1002/chem.202403718.

Enzymatic synthesis of mono- and trifluorinated alanine enantiomers expands the scope of fluorine biocatalysis.

Nieto-Dominguez M, Sako A, Enemark-Rasmussen K, Gotfredsen C, Rago D, Nikel P Commun Chem. 2024; 7(1):104.

PMID: 38724655 PMC: 11082193. DOI: 10.1038/s42004-024-01188-1.

4-Thiaproline accelerates the slow folding phase of proteins containing cis prolines in the native state by two orders of magnitude.

O Loughlin J, Zinovjev K, Napolitano S, van der Kamp M, Rubini M Protein Sci. 2023; 33(2):e4877.

PMID: 38115231 PMC: 10804670. DOI: 10.1002/pro.4877.

Fluorine NMR study of proline-rich sequences using fluoroprolines.

Sinnaeve D, Ben Bouzayene A, Ottoy E, Hofman G, Erdmann E, Linclau B Magn Reson (Gott). 2023; 2(2):795-813.

PMID: 37905223 PMC: 10539733. DOI: 10.5194/mr-2-795-2021.

Non-Canonical Amino Acids in Analyses of Protease Structure and Function.

Goettig P, Koch N, Budisa N Int J Mol Sci. 2023; 24(18).

PMID: 37762340 PMC: 10531186. DOI: 10.3390/ijms241814035.

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