Transition-state analogs as inhibitors of human and malarial hypoxanthine-guanine phosphoribosyltransferases.
Nat Struct Biol
; 6(6): 582-7, 1999 Jun.
Article
en En
| MEDLINE
| ID: mdl-10360365
ABSTRACT
The proposed transition state for hypoxanthine-guanine phosphoribosyltransferases (HGPRTs) has been used to design and synthesize powerful inhibitors that contain features of the transition state. The iminoribitols (1S)-1-(9-deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol 5-phosphate (immucillinHP) and (1S)-1-(9-deazaguanin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol 5-phosphate (immucillinGP) are the most powerful inhibitors yet reported for both human and malarial HGPRTs. Equilibrium binding constants are >1,000-fold tighter than the binding of the nucleotide substrate. The NMR spectrum of malaria HGXPRT in the Michaelis complex reveals downfield hydrogen-bonded protons. The chemical shifts move farther downfield with bound inhibitor. The inhibitors are lead compounds for species-specific antibiotics against parasitic protozoa. The high-resolution crystal structure of human HGPRT with immucillinGP is reported in the companion paper.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Plasmodium falciparum
/
Pirimidinonas
/
Pirroles
/
Inhibidores Enzimáticos
/
Hipoxantina Fosforribosiltransferasa
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Struct Biol
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
1999
Tipo del documento:
Article
País de afiliación:
Estados Unidos