title: Linking distinct conformations of nicotinamide adenine dinucleotide with protein fold/function.
abstract: Nicotinamide adenine dinucleotide (NAD or NADP) are essential cofactor/substrate for enzymes that catalyze redox or nonredox reactions. Because several enzymes involved in NAD(P) metabolism have been implicated in a wide array of diseases, there is great interest in designing inhibitors/activators of these NAD(P)-dependent enzymes based on their structures. Hence, we have elucidated the various distinct enzyme-bound NAD(P) conformations and their correlation with the respective protein fold and function using hierarchical clustering methods. Torsion angles distinguishing enzyme-bound NAD versus NADP conformations and NAD(P) conformations bound to redox versus nonredox enzymes were identified. Although an unusually small χ(N) in diphtheria toxin-bound NAD(+) had been postulated to strain the N-glycosidic bond, thus facilitating catalysis, toxin-bound NAD(+) molecules with χ(N) varying from 0 to 60° were found to exhibit similar C(1D)-N(1N) bond cleavage barriers in water. The findings herein provide useful guidelines in the design of inhibitors/activators of NAD(P)-dependent enzymes that are therapeutic targets.
authors: Chemical Biology & Molecular Biophysics, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan.
authors: Gopi
authors: G
authors: Kuppuraj
authors: Karen
authors: K
authors: Sargsyan
authors: Yun-Hao
authors: YH
authors: Hua
authors: A Rod
authors: AR
authors: Merrill
authors: Carmay
authors: C
authors: Lim