Rational Design of the Spatial Effect in a Fe(II)/α-Ketoglutarate-Dependent Dioxygenase Reverses the Regioselectivity of C(sp3)-H Bond Hydroxylation in Aliphatic Amino Acids.
Angew Chem Int Ed Engl
; 63(32): e202406060, 2024 08 05.
Article
en En
| MEDLINE
| ID: mdl-38789390
ABSTRACT
The hydroxylation of remote C(sp3)-H bonds in aliphatic amino acids yields crucial precursors for the synthesis of high-value compounds. However, accurate regulation of the regioselectivity of remote C(sp3)-H bonds hydroxylation in aliphatic amino acids continues to be a common challenge in chemosynthesis and biosynthesis. In this study, the Fe(II)/α-ketoglutarate-dependent dioxygenase from Bacillus subtilis (BlAH) was mined and found to catalyze hydroxylation at the γ and δ sites of aliphatic amino acids. Crystal structure analysis, molecular dynamics simulations, and quantum chemical calculations revealed that regioselectivity was regulated by the spatial effect of BlAH. Based on these results, the spatial effect of BlAH was reconstructed to stabilize the transition state at the δ site of aliphatic amino acids, thereby successfully reversing the γ site regioselectivity to the δ site. For example, the regioselectivity of L-Homoleucine (5 a) was reversed from the γ site (1 12) to the δ site (>99 1). The present study not only expands the toolbox of biocatalysts for the regioselective functionalization of remote C(sp3)-H bonds, but also provides a theoretical guidance for the precision-driven modification of similarly remote C(sp3)-H bonds in complex molecules.
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Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Bacillus subtilis
/
Dioxigenasas
/
Aminoácidos
/
Ácidos Cetoglutáricos
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Año:
2024
Tipo del documento:
Article
País de afiliación:
China