Is the anomeric effect an important factor in the rate of adenosine deaminase catalyzed hydrolysis of purine nucleosides? A direct comparison of nucleoside analogues constructed on ribose and carbocyclic templates with equivalent heterocyclic bases selected to promote hydration.
The aglycone of (North)-methanocarbadeoxyadenosine [(N)-MCdA, (5)], a relatively weak substrate for adenosine deaminase (ADA)-relative rate of deamination ca. 100 times lower than adenosine-was modified with substitutions at positions 6 (6-fluoro, compound 6) and 8 (8-aza, compound 7) with the intent to improve the level of hydration and hence hydrolysis by ADA. In these substrates the fused cyclopropane moiety constrains the cyclopentane ring to mimic the conformation of a furanose sugar in the North hemisphere of the pseudorotational cycle, which matches the conformation of the ribose ring of adenosine in complex with ADA. The order of susceptibility to ADA hydrolysis was adenosine>>(N)-MCdA (5) approximately equal to(N)-6F-MCdP (6)>(N)-8-aza-MCdA (7). Despite the known fact that 8-azaadenosine is hydrolyzed twice as fast as adenosine, the corresponding carbocyclic analogue 7 was hydrolyzed at approximately half the rate of the parent 5. These results argue in favor of the critical role of the O(4') oxygen atom and its associated anomeric effect in assisting hydrolysis by ADA.
Hernandez
Susana
S
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, 376 Boyles St., Frederick, MD 21701, USA.
Ford
Harry
H
Marquez
Victor E
VE
D000243:Adenosine Deaminase / Q000737:chemistry / Q000378:metabolism*; D002384:Catalysis; D006868:Hydrolysis; D007700:Kinetics; D011684:Purine Nucleosides / Q000737:chemistry / Q000378:metabolism*; D012266:Ribose; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
D011684:Purine Nucleosides; D014867:Water; D012266:Ribose; D000243:Adenosine Deaminase