Adenosine deaminase

3IAR10011486ENSG00000196839ENSMUSG00000017697P00813P03958NM_000022NM_001322050NM_001322051NM_001272052NM_007398NP_000013NP_001308979NP_001308980NP_001258981NP_031424Adenosine deaminase (also known as adenosine aminohydrolase, or ADA) is an enzyme (EC 3.5.4.4) involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues.1krm: Crystal structure of bovine adenosine deaminase complexed with 6-hydroxyl-1,6-dihydropurine riboside1ndv: Crystal Structure of Adenosine Deaminase complexed with FR1170161ndw: Crystal Structure of Adenosine Deaminase Complexed with FR2216471ndy: Crystal Structure of Adenosine Deaminase Complexed with FR2305131ndz: Crystal Structure of Adenosine Deaminase Complexed with FR2359991o5r: Crystal structure of adenosine deaminase complexed with a potent inhibitor1qxl: Crystal structure of Adenosine deaminase complexed with FR2353801uml: Crystal structure of adenosine deaminase complexed with a potent inhibitor FR2336241v79: Crystal structures of adenosine deaminase complexed with potent inhibitors1v7a: Crystal structures of adenosine deaminase complexed with potent inhibitors1vfl: Adenosine deaminase1w1i: CRYSTAL STRUCTURE OF DIPEPTIDYL PEPTIDASE IV (DPPIV OR CD26) IN COMPLEX WITH ADENOSINE DEAMINASE1wxy: Crystal structure of adenosine deaminase ligated with a potent inhibitor1wxz: Crystal structure of adenosine deaminase ligated with a potent inhibitor2bgn: HIV-1 TAT PROTEIN DERIVED N-TERMINAL NONAPEPTIDE TRP2-TAT (1-9) BOUND TO THE ACTIVE SITE OF DIPEPTIDYL PEPTIDASE IV (CD26)2e1w: Crystal structure of adenosine deaminase complexed with potent inhibitors Adenosine deaminase (also known as adenosine aminohydrolase, or ADA) is an enzyme (EC 3.5.4.4) involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues. Its primary function in humans is the development and maintenance of the immune system. However, the full physiological role of ADA is not yet completely understood. ADA exists in both small form (as a monomer) and large form (as a dimer-complex). In the monomer form, the enzyme is a polypeptide chain, folded into eight strands of parallel α/β barrels, which surround a central deep pocket that is the active site. In addition to the eight central β-barrels and eight peripheral α-helices, ADA also contains five additional helices: residues 19-76 fold into three helices, located between β1 and α1 folds; and two antiparallel carboxy-terminal helices are located across the amino-terminal of the β-barrel. The ADA active site contains a zinc ion, which is located in the deepest recess of the active site and coordinated by five atoms from His15, His17, His214, Asp295, and the substrate. Zinc is the only cofactor necessary for activity. The substrate, adenosine, is stabilized and bound to the active site by nine hydrogen bonds. The carboxyl group of Glu217, roughly coplanar with the substrate purine ring, is in position to form a hydrogen bond with N1 of the substrate. The carboxyl group of Asp296, also coplanar with the substrate purine ring, forms hydrogen bond with N7 of the substrate. The NH group of Gly184 is in position to form a hydrogen bond with N3 of the substrate. Asp296 forms bonds both with the Zn2+ ion as well as with 6-OH of the substrate. His238 also hydrogen bonds to substrate 6-OH. The 3'-OH of the substrate ribose forms a hydrogen bond with Asp19, while the 5'-OH forms a hydrogen bond with His17. Two further hydrogen bonds are formed to water molecules, at the opening of the active site, by the 2'-OH and 3'-OH of the substrate. Due to the recessing of the active site inside the enzyme, the substrate, once bound, is almost completely sequestered from solvent. The surface exposure of the substrate to solvent when bound is 0.5% the surface exposure of the substrate in the free state. ADA irreversibly deaminates adenosine, converting it to the related nucleoside inosine by the substitution of the amino group for a keto group. Inosine can then be deribosylated (removed from ribose) by another enzyme called purine nucleoside phosphorylase (PNP), converting it to hypoxanthine. The proposed mechanism for ADA-catalyzed deamination is stereospecific addition-elimination via tetrahedral intermediate. By either mechanism, Zn2+ as a strong electrophile activates a water molecule, which is deprotonated by the basic Asp295 to form the attacking hydroxide. His238 orients the water molecule and stabilizes the charge of the attacking hydroxide. Glu217 is protonated to donate a proton to N1 of the substrate.