Nucleoside Triphosphate Pyrophosphohydrolase
Adenosine diphosphoribose pyrophosphatase
ALA 96(Magnesium-1);GLU 112(Magnesium-2 & 3);GLU 116(Magnesium-1 & 2);GLU 166(Magnesium-2)
X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF NATIVE ENZYME, COMPLEX WITH ADP-RIBOSE, COMPLEX WITH GADOLINIUM.
The structure of ADP-ribose pyrophosphatase reveals the structural basis for the versatility of the Nudix family.
X-RAY CRYSTALLOGRAPHY (2.07 ANGSTROMS), CATALYTIC MECHANISM.
Mechanism of the Escherichia coli ADP-ribose pyrophosphatase, a Nudix hydrolase.
The crystal structure and mutational analysis of human NUDT9.
Structure and mechanism of MT-ADPRase, a nudix hydrolase from Mycobacterium tuberculosis.
Structural insights into the Thermus thermophilus ADP-ribose pyrophosphatase mechanism via crystal structures with the bound substrate and metal.
Structures and mechanisms of Nudix hydrolases.
Molecular mechanism of the Thermus thermophilus ADP-ribose pyrophosphatase from mutational and kinetic studies.
Crystal structures of human NUDT5 reveal insights into the structural basis of the substrate specificity.
Structural basis for different substrate specificities of two ADP-ribose pyrophosphatases from Thermus thermophilus HB8.
Molecular mechanism of ADP-ribose hydrolysis by human NUDT5 from structural and kinetic studies.
Diverse substrate recognition and hydrolysis mechanisms of human NUDT5.
This enzyme belongs to Nudix (nucleoside diphosphate linked to x) hydrolase family. There are several types of ADP-ribose pyrophosphatases from various organisms (EzCatDB; S00814, S00921, S00922, S00923, D00880), in terms of substrate specificities, metal binding, active sites and reaction mechanisms. This enzyme also hydrolyzes 8-oxo-dGDP as well as ADP-ribose (see [11]). The magnesium numbering is based on the literature [8], in contrast to those homologous enzymes (EzCatDB; S00814, S00921, S00922), whose numberings are opposite, based on literature [6]. Magnesium-3 is bound to Glu112 and alpha-phosphate of ADP-ribose, whereas Magnesium-2 is bound to Glu112, Glu116, Glu166 and alpha-phosphate. Magnesium-1 is bound to mainchain carbonyl of Ala96, Glu116 and both of the phosphate groups. The water that is bound to magnesium-2 and magnesium-3 is the nucleophile, which attacks on the alpha-phosphate of ADP-ribose(see [10]). On the other hand, for the hydrolysis of 8-oxo-dGDP, the beta-phosphate is attacked by the activated water (see [11]). According to the literature [11], 8-oxo-dGDP adopts a Z-shaped conformation, whereas ADP-ribose adopts a horse-shoe conformation. The difference in the adopted conformations of the substrates leads to the different nucleophilic substitution sites (see [11]). According to the literature [6] and [9], the reaction for ADP-ribose proceeds as follows: (0) A water molecule is bound to Magnesium-2 and -3. These magnesium ions may lower the pKa of the water molecule so that the water molecule can be a better nucleophile, and also stabilize the negative charge on the alpha-phosphate group. On the other hand, magnesium-1 that bridges the two phosphate groups may stabilize the negative charge of the leaving group, beta-phosphate. (1) Glu166 may act as a weak base to deprotonate the water molecule, forming a hydroxide ion. (The contribution of this general base is smaller than those acidic residues, Glu112 and Glu116, which bind magnesium-2 and -3, according to the literature [9].) (2) The hydroxide ion makes a nucleophilic attack on the alpha-phosphate of ADP-ribose. (SN2-like reaction) (3) Arg84 and magnesium-1 may stabilize the negative charge on the leaving beta-phosphate group. For the hydrolysis of 8-oxo-dGDP, alpha-phosphate group is the leaving group, whereas beta-phosphate is the nucleophilic substitution site. Otherwise, the reaction mechanism must be similar to that for ADP-ribose.