An Unusual Protector-Protégé Strategy for the Biosynthesis of Purine Nucleoside Antibiotics.
Cell Chem Biol
; 24(2): 171-181, 2017 Feb 16.
Article
en En
| MEDLINE
| ID: mdl-28111097
ABSTRACT
Pentostatin (PTN, deoxycoformycin) and arabinofuranosyladenine (Ara-A, vidarabine) are purine nucleoside antibiotics used clinically to treat hematological cancers and human DNA virus infections, respectively. PTN has a 1,3-diazepine ring, and Ara-A is an adenosine analog with an intriguing epimerization at the C-2' hydroxyl group. However, the logic underlying the biosynthesis of these interesting molecules has long remained elusive. Here, we report that the biosynthesis of PTN and Ara-A employs an unusual protector-protégé strategy. To our surprise, we determined that a single gene cluster governs PTN and Ara-A biosynthesis via two independent pathways. Moreover, we verified that PenB functions as a reversible oxidoreductase for the final step of PTN. Remarkably, we provided the first direct biochemical evidence that PTN can protect Ara-A from deamination by selective inhibition of the host adenosine deaminase. These findings expand our knowledge of natural product biosynthesis and open the way for target-directed genome mining of Ara-A/PTN-related antibiotics.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Vidarabina
/
Pentostatina
/
Inhibidores Enzimáticos
/
Antibacterianos
Idioma:
En
Revista:
Cell Chem Biol
Año:
2017
Tipo del documento:
Article
País de afiliación:
China