A comparative investigation of catalytic mechanism and domain between catechol-O-methyltransferase isoforms by isomeric shikonin and alkannin.
Int J Biol Macromol
; 242(Pt 1): 124758, 2023 Jul 01.
Article
em En
| MEDLINE
| ID: mdl-37150367
ABSTRACT
The differences in catalytic mechanism and domain between the soluble (S-COMT) and membrane-bound catechol-O-methyltransferase (MB-COMT) are poorly documented due to the unavailable crystal structure of MB-COMT. Considering the enzymatic nature of S-COMT and MB-COMT, the challenge could be solvable by probing the interactions between the enzymes with the ligands with minor differences in structures. Herein, isomeric shikonin and alkannin bearing a R/S -OH group in side chain at the C2 position were used for domain profiling of COMTs. Human and rat liver-derived COMTs showed the differences in inhibitory response (human's IC50 and Ki values for S-COMT < rat's, 5.80-19.56 vs. 19.56-37.47 µM; human's IC50 and Ki values for MB-COMT > rat's) and mechanism (uncompetition vs. noncompetition) towards the two isomers. The inhibition of the two isomers against human and rat S-COMTs was stronger than those for MB-COMTs (S-COMT's IC50 and Ki values < MB-COMT's, 5.80-37.47 vs. 40.01-111.8 µM). Additionally, the inhibition response of alkannin was higher than those of shikonin in no matter human and rat COMTs. Molecular docking stimulation was used for analysis. The inhibitory effects observed in in vitro and in silico tests were confirmed in vivo. These findings would facilitate further COMT-associated basic and applied research.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Catecol O-Metiltransferase
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article