Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.5.4.4 (
adenosine deaminase
)
5,136
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
2'-Chloropentostatin (2'-Cl
PTN
, 2'-chloro-2'-deoxycoformycin) and 2'-amino-2'-deoxyadenosine (2'-amino dA) are two adenosine-derived nucleoside antibiotics coproduced by
Actinomadura
sp. strain ATCC 39365. 2'-Cl
PTN
is a potent
adenosine deaminase
(
ADA
) inhibitor featuring an intriguing 1,3-diazepine ring, as well as a chlorination at C-2' of ribose, and 2'-amino dA is an adenosine analog showing bioactivity against RNA-type virus infection. However, the biosynthetic logic of them has remained poorly understood. Here, we report the identification of a single gene cluster (
ada
) essential for the biosynthesis of 2'-Cl
PTN
and 2'-amino dA. Further systematic genetic investigations suggest that 2'-Cl
PTN
and 2'-amino dA are biosynthesized by independent pathways. Moreover, we provide evidence that a predicted cation/H
+
antiporter, AdaE, is involved in the chlorination step during 2'-Cl
PTN
biosynthesis. Notably, we demonstrate that 2'-amino dA biosynthesis is initiated by a Nudix hydrolase, AdaJ, catalyzing the hydrolysis of ATP. Finally, we reveal that the host
ADA
(designated ADA1), capable of converting adenosine/2'-amino dA to inosine/2'-amino dI, is not very sensitive to the powerful
ADA
inhibitor pentostatin. These findings provide a basis for the further rational pathway engineering of 2'-Cl
PTN
and 2'-amino dA production.
IMPORTANCE
2'-Cl
PTN
/
PTN
and 2'-amino dA have captivated the great interests of scientists, owing to their unusual chemical structures and remarkable bioactivities. However, the precise logic for their biosynthesis has been elusive for decades. Actually, the identification and elucidation of their biosynthetic pathways not only enrich the biochemical repertoire of novel enzymatic reactions but may also lay solid foundations for the pathway engineering and combinatorial biosynthesis of this family of purine nucleoside antibiotics to generate novel hybrid analogs with improved features.
...
PMID:Biosynthesis of 2'-Chloropentostatin and 2'-Amino-2'-Deoxyadenosine Highlights a Single Gene Cluster Responsible for Two Independent Pathways in
Actinomadura
sp. Strain ATCC 39365. 2825 48
