title: The rationale for targeting the NAD/NADH cofactor binding site of parasitic S-adenosyl-L-homocysteine hydrolase for the design of anti-parasitic drugs.
abstract: Trypanosomal S-adenoyl-L-homocysteine hydrolase (Tc-SAHH), considered as a target for treatment of Chagas disease, has the same catalytic mechanism as human SAHH (Hs-SAHH) and both enzymes have very similar x-ray structures. Efforts toward the design of selective inhibitors against Tc-SAHH targeting the substrate binding site have not to date shown any significant promise. Systematic kinetic and thermodynamic studies on association and dissociation of cofactor NAD/H for Tc-SAHH and Hs-SAHH provide a rationale for the design of anti-parasitic drugs directed toward cofactor-binding sites. Analogues of NAD and their reduced forms show significant selective inactivation of Tc-SAHH, confirming that this design approach is rational.
authors.affiliation: Department of Molecular Biosciences, The University of Kansas, Lawrence, Kansas, USA.
authors.forename: Sumin
authors.initials: S
authors.lastname: Cai
authors.forename: Qing-Shan
authors.initials: QS
authors.lastname: Li
authors.forename: Jianwen
authors.initials: J
authors.lastname: Fang
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Borchardt
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kuczera
authors.forename: C Russell
authors.initials: CR
authors.lastname: Middaugh
authors.forename: Richard L
authors.initials: RL
authors.lastname: Schowen
mesh_terms: D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D014355:Chagas Disease / Q000188:drug therapy*; D006801:Humans; D008958:Models, Molecular; D009243:NAD / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D013379:Substrate Specificity; D013816:Thermodynamics; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D014344:Trypanocidal Agents; D009243:NAD; D043383:Adenosylhomocysteinase