The Stability of C_α Peptide Radicals: Why Glycyl Radical Enzymes?

Abstract

The conformational space of dipeptide models derived from glycine, alanine, phenylalanine, proline, tyrosine, and cysteine has been searched extensively and compared with the corresponding C(α) dipeptide radicals at the G3(MP2)-RAD level of theory. The results indicate that the (least-substituted) glycine dipeptide radical is the thermochemically most stable of these species. Analysis of the structural parameters indicates that this is due to repulsive interactions between the C(α) substituents and peptide units in the radical. A comparison of the conformational preferences of dipeptide radicals and their closed-shell parents also indicates that radical stability is a strongly conformation-dependent property.

1,2-Propanediol Dehydration in Roseburia inulinivorans

“…The functional diversity of glycyl radical enzymes is impressive (9,37,38) and has important implications for many aspects of human health and general quality of life. For example, the inhibition of some of these reactions will prevent anaerobic growth by certain pathogenic microorganisms (39).…”

Dissociation energies of Cα–H bonds in amino acids – a re-examination

“…1 are all based on the reference system CH 4 / ? CH 3 . In order to test whether different reference systems lead to substantially different results, BDE(C a -H) values in glycine and alanine dipeptide models and anhydrides 2H-6H were recalculated using the CH 3 NH 2 / ?…”

“…[1][2][3][4] Together with BDE data for other dipeptide radicals this was taken to reflect steric interactions between the C a substituents and the amide groups present on the N-and C-terminal side of the central amino acid radicals. …”

Structure and Reactivity of theN-Acetyl-Cysteine Radical Cation and Anion: Does Radical Migration Occur?

“…T here are numerous examples where radicals play key roles in the active site of enzymes [1][2][3][4][5][6][7][8][9][10][11][12]. These radicals are normally located on a reactive amino acid side chain (cysteine [2], methionine, tyrosine, or tryptophan [10]) or on the peptide backbone, namely at the α-carbon positon of glycine [13].…”

“…In some instances, it has also been shown that the radical migrates to different positions in the inactive form [4,5,9]. In those cases, the radical is relocated to the less reactive positions of the sulfur atom on a cysteine residue [4,5,9] or to the glycine α-carbon [6,11]. In most enzymes, such radical rearrangement is considered to be a protective mechanism.…”