Nucleoside hydrolase

Roberts, M. F., Waller, G. R., N methyltransferases and 7-methyl-N-nucleoside hydrolase activity in Coffea arabica and the biosynthesis of caffeine, Phytochemistry, 18, 451, 1979. (CA92 18866w)... 

This enzyme [EC 3.2.2.9] catalyzes the hydrolysis of 5-adenosylhomocysteine to generate adenine and S-ribosylhomocysteine. The enzyme will also act on 5 -methylthioadenosine to give adenine and 5-methyl-thioribose. See also Methylthioadenosine Nucleoside Hydrolase... 

Thie enzyme [EC 3.2.2.1], also known as inosine-uridine preferring nucleoside hydrolase and lU-nucleoside hydrolase, catalyzes the hydrolysis of an A-o-ribosylpurine to produce a purine and D-ribose. 

Pyrimidine nucleoside hydrolase YeiK from E. coli in complex (PDB 3MKN) with l-(3,4-diaminophenyl)-l,4-dideoxy-l,4-imino-D-ribitol (175, 76 pM Scheme 48)... 

M. Degano, S. C. Almo, J. C. Sacchettini, and V. L. Schramm, Trypanosomal nucleoside hydrolase. A novel mechanism from the structure with a transition-state inhibitor, Biochemistry, 37 (1998) 6277-6285. 

A. Vandemeulebroucke, S. de Vos, E. Van Holsbeke, J. Steyaert, and W. Versees, A flexible loop as a functional element in the catalytic mechanism of nucleoside hydrolase from Trypanosoma vivax, J. Biol. Chem., 283 (2008) 22272-22282. 

M.-C. Ho, W. Shi, A. Rinaldo-Matthis, P. C. Tyler, G. B. Evans, K. Clinch, S. C. Almo, and V. L. Schramm, Four generations of transition-state analogues for human purine nucleoside hydrolase, Proc. Natl. Acad. Sci. USA, 107 (2010) 4805 -812. 

Trypanosomes and other parasitic protozoa are unable to synthesize purines and must obtain them from their hosts using salvage pathway. Selective inhibition of their HGPRT or of nucleoside hydrolases, which are absent from mammalian cells, are goals of drug development.3273 1 ... 

Horenstein BA, Parkin DW, Estupinan B, Schramm VL (1991) Transition-state analysis of nucleoside hydrolase from Crithidia fasciculate. Biochemistry 30 10788-10795... 

Horenstein BA, Schramm VL (1993) ElecUonic nature of the transition state for nucleoside hydrolase. A blueprint for inhibitor design. Biochemistry 32 7089-7097... 

Some other hydrolytic enzymes, in addition to proteases, that are important drug targets include protein phophatases, phosphodiesterases, nucleoside hydrolases, acetylhydolases, glycosylases, and phospholipases. Structure-based inhibitor design is currently being applied to a number of these enzymes. The last three mentioned have been successfully tar-... 

Iminosugar related nucleosides coined immucillins have recently been found to be powerful inhibitors of parasitic nucleoside hydrolases [218]. Compounds such as 84 (Figure 9.28) bind and inhibit protozoan nucleoside hydrolases with dissociation constants in the low nanomolar to picomolar range, thus promising to be antiprotozoan chemotherapeutics against parasite infections such as malaria, sleeping sickness and trypanosomiasis. 

FIGURE 9.28 Potent nucleoside hydrolase inhibitors with antiprotozoan activities. 

The concept of electrostatic catalysis has been applied indirectly by Schramm and coworkers for the design of transition-state analogues in reactions by nucleoside hydrolase (Horenstein et al., 1991 Horenstein and Schramm, 1993) and AMP deaminase (Kline and Schramm, 1994). They stated, in accordance with our previous examples, that the MEP provides novel insight into transition-state structure and the forces associated with substrate binding and release. 

Nucleoside hydrolase has been proposed to participate in purine salvage in the trypanosome Crithidia fasciculata. The enzyme hydrolyses the N-glycosidic linkage of the naturally occurring purine and pyrimidine nucleosides. A geometric model of the transition state for nucleoside hydrolase for the reaction (Horenstein et al., 1991)... 

Transition state mapping with multiple kinetie isotope elfeets has been carried out for a number of nucleoside hydrolases and phosphorylases. Intrinsic effects are given in Table 5.2 for structures of substrates, see Figures 3.14 and 5.31. 

Figure 5.29 Isoenzyme-specific inhibitors of purine nucleoside hydrolases.

Similarly, inosine hydrolysis catalyzed by inosine-uridine-specific nucleoside hydrolase (lU-NH) was modeled by ad hoc methods with Ui q = 0.19 and Nu = 0.005/ but has been reanalyzed recently using structure interpolation, which gives a TS structure with Xlg — and (unpublished results). It... 

Evolutionary pressures have constrained pertussis toxin to a mechanism with significant nucleophile participation while RTA has evolved a catalytic strategy with an oxocarbenium ion intermediate that reacts quickly with nearby water molecules. By this logic, other ADP-ribosylating toxins, such as cholera and diphtheria toxins, would be expected to proceed through relatively synchronous transition states. Nucleoside hydrolases (enzymes that hydrolyze nucleosides to ribose and a purine or pyrimidine base) could use mechanisms with oxocarbenium ion intermediates, though the transition states characterized to date have been A Dn (see below). 

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