This enzyme belongs to the adenosine and AMP deaminase family. This enzyme is homologous to guanine deaminase (EC 3.5.4.3; D00873 in EzCatDB) and cytosine deaminase (EC 3.5.4.1; D00675 in EzCatDB), sharing a similar catalytic site. This enzyme catalyzes two successive reactions (as in cytidine deaminase (D00406 in EzCatDB), according to the literature [6], [10] & [20]. (A) Additive double-bond deformation; Addition of water to purine C6-carbon to form a tetrahedral intermediate (I00018). (B) Eliminative double-bond formation; Elimination of amine group from the intermediate, forming a carbonyl group. #### Although literature [10] suggested that His238 is a general base to activate the water in the first reaction (A), other papers gave the evidence against it. Instead of His238, Asp295 seems more likely base (see [6], [14] & [15]). Moreover, in the second reaction, some papers ([14] & [15]) suggested that His238 might act as a general acid to protonate the eliminated amine group, it is too distant from the group. Instead of the residue, hydrophobic cluster composed of Leu58, Phe61, Thr269 & Phe300 seems to facilitate the elimination (see [20]). However, these hydrophobic residues are not so conserved among the homologous enzymes (guanine deaminase and cytosine deaminase). In analogy with cytosine deaminase (D00675 in EzCatDB), which adopts Fe2+ ion as cofactor, and guanine deaminase, which uses the same cofactor, zinc ion, as this enzyme, this enzyme may catalyzes the following reactions (addition and elimination): (A) Additive double-bond deformation; Addition of water to purine C6-carbon, forming a tetrahedral intermediate (I00018): (A1) Asp295 acts as a general base to deprotonate the Zinc-bound water. Here, the positive charge of His238 seems to stabilize the activated water. (A2) The activated water makes a nucleophilic attack on the C6 atom, whilst Glu217 acts as a general acid to protonate the N1 atom (protonation site) of the purine. This reaction leads to the formation of tetrahedral intermediate at the C6 atom, transforming the N1-C6 bond from double bond to single bond (I00018). (B) Eliminative double-bond formation; Elimination of amine group from the intermediate, forming a carbonyl group. (B1) Asp295 acts as a general acid to protonate the eliminated amine group, releasing the ammonia. (B2) Asp295 acts as a general base to deprotonate the hydroxyl group, bound to the zinc ion and His238. (Here, His238 may assist the catalytic function of Asp295 as well.) This reaction leads to the enol form of the product, inosine. (This may be an E1-like reaction, as amine elimination occurs prior to deprotonation.)
HIS 15;HIS 17;HIS 214;ASP 295(Zinc binding)
HIS 515;HIS 517;HIS 714;ASP 795(Zinc binding)
HIS 1015;HIS 1017;HIS 1214;ASP 1295(Zinc binding)
HIS 1515;HIS 1517;HIS 1714;ASP 1795(Zinc binding)
HIS 15;HIS 17;HIS 214; (Zinc binding)
HIS 12;HIS 14;HIS 211;ASP 292(Zinc binding)
Crystallographic observation of a trapped tetrahedral intermediate in a metalloenzyme.
Enzyme-substrate complexes of adenosine and cytidine deaminases: absence of accumulation of water adducts.
Site-directed mutagenesis of histidine 238 in mouse adenosine deaminase: substitution of histidine 238 does not impede hydroxylate formation.
Functional residues at the active site of bovine brain adenosine deaminase.
Structure-based de novo design of non-nucleoside adenosine deaminase inhibitors.
Adenosine deaminase converts purine riboside into an analogue of a reactive intermediate: a 13C NMR and kinetic study.
Evidence from nitrogen-15 and solvent deuterium isotope effects on the chemical mechanism of adenosine deaminase.
Preliminary X-ray analysis of crystals of murine adenosine deaminase.
Transition-state stabilization by adenosine deaminase: 1,6-addition of water to purine ribonucleoside, the enzyme's affinity for 6-hydroxy-1,6-dihydropurine ribonucleoside, and the effective concentration of substrate water at the active site.
Structural and conformational analysis of pentostatin (2'-deoxycoformycin), a potent inhibitor of adenosine deaminase.
Atomic structure of adenosine deaminase complexed with a transition-state analog: understanding catalysis and immunodeficiency mutations.
A transition state in pieces: major contributions of entropic effects to ligand binding by adenosine deaminase.
The rate of formation of transition-state analogues in the active site of adenosine deaminase is encounter-controlled: implications for the mechanism.
Refined 2.5 A structure of murine adenosine deaminase at pH 6.0.
A pre-transition-state mimic of an enzyme: X-ray structure of adenosine deaminase with bound 1-deazaadenosine and zinc-activated water.
Site-directed mutagenesis of active site glutamate-217 in mouse adenosine deaminase.
Probing the functional role of two conserved active site aspartates in mouse adenosine deaminase.
An adenosine deaminase (ADA) allele contains two newly identified deleterious mutations (Y97C and L106V) that interact to abolish enzyme activity.
Effect of a chemical modification on the hydrated adenosine intermediate produced by adenosine deaminase and a model reaction for a potential mechanism of action of 5-aminoimidazole ribonucleotide carboxylase.
Characterization of hydrogen bonding in the complex of adenosine deaminase with a transition state analogue: a Raman spectroscopic study.
Complexes of adenosine deaminase with two potent inhibitors: X-ray structures in four independent molecules at pH of maximum activity.
Probing the active site of adenosine deaminase by a pH responsive fluorescent competitive inhibitor.
Adenosine deaminase prefers a distinct sugar ring conformation for binding and catalysis: kinetic and structural studies.
3'-Beta-ethynyl and 2'-deoxy-3'-beta-ethynyl adenosines: first 3'-beta-branched-adenosines substrates of adenosine deaminase.
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.
Clustered charged amino acids of human adenosine deaminase comprise a functional epitope for binding the adenosine deaminase complexing protein CD26/dipeptidyl peptidase IV.
The stability curve of bovine adenosine deaminase is bimodal.
Structure of bovine adenosine deaminase complexed with 6-hydroxy-1,6-dihydropurine riboside.
A highly potent non-nucleoside adenosine deaminase inhibitor: efficient drug discovery by intentional lead hybridization.
Crystal structure of CD26/dipeptidyl-peptidase IV in complex with adenosine deaminase reveals a highly amphiphilic interface.
Structure-based design, synthesis, and structure-activity relationship studies of novel non-nucleoside adenosine deaminase inhibitors.
Structure-based design and synthesis of non-nucleoside, potent, and orally bioavailable adenosine deaminase inhibitors.
Crystal structures of HIV-1 Tat derived nonapeptides Tat(1-9) and Trp2-Tat(1-9) bound to the active site of dipeptidyl peptidase IV (CD26).