An Unusual Protector-Protégé Strategy for the Biosynthesis of Purine Nucleoside Antibiotics

Cell Chem Biol. 2017 Feb 16;24(2):171-181. doi: 10.1016/j.chembiol.2016.12.012. Epub 2017 Jan 19.


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.

Keywords: arabinofuranosyladenine; biosynthesis; gene cluster; pentostatin; protector-protégé strategy; purine nucleoside antibiotics.

MeSH terms

  • Adenosine Deaminase / metabolism
  • Anti-Bacterial Agents / biosynthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Base Sequence
  • Cluster Analysis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Pentostatin / biosynthesis*
  • Pentostatin / chemistry
  • Pentostatin / pharmacology
  • Sequence Analysis, DNA
  • Streptomyces antibioticus / genetics
  • Vidarabine / biosynthesis*
  • Vidarabine / chemistry
  • Vidarabine / pharmacology


  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Pentostatin
  • Adenosine Deaminase
  • Vidarabine