title: Femtomolar inhibitors bind to 5'-methylthioadenosine nucleosidases with favorable enthalpy and entropy.
abstract: 5'-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) catalyzes the hydrolytic cleavage of adenine from methylthioadenosine (MTA). Inhibitor design and synthesis informed by transition state analysis have developed femtomolar inhibitors for MTANs, among the most powerful known noncovalent enzyme inhibitors. Thermodynamic analyses of the inhibitor binding reveals a combination of highly favorable contributions from enthalpic (-24.7 to -4.0 kcal mol(-1)) and entropic (-10.0 to 6.4 kcal mol(-1)) interactions. Inhibitor binding to similar MTANs from different bacterial species gave distinct energetic contributions from similar catalytic sites. Thus, binding of four transition state analogues to EcMTAN and SeMTAN is driven primarily by enthalpy, while binding to VcMTAN is driven primarily by entropy. Human MTA phosphorylase (hMTAP) has a transition state structure closely related to that of the bacterial MTANs, and it binds tightly to some of the same transition state analogues. However, the thermodynamic signature of binding of an inhibitor to hMTAP differs completely from that with MTANs. We conclude that factors other than first-sphere catalytic residue contacts contribute to binding of inhibitors because the thermodynamic signature differs between bacterial species of the same enzyme.
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
authors.forename: Keisha
authors.initials: K
authors.lastname: Thomas
authors.forename: Antti M
authors.initials: AM
authors.lastname: Haapalainen
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Burgos
authors.forename: Gary B
authors.initials: GB
authors.lastname: Evans
authors.forename: Peter C
authors.initials: PC
authors.lastname: Tyler
authors.forename: Shivali
authors.initials: S
authors.lastname: Gulab
authors.forename: Rong
authors.initials: R
authors.lastname: Guan
authors.forename: Vern L
authors.initials: VL
authors.lastname: Schramm
mesh_terms: D001483:Base Sequence; D002151:Calorimetry; D002384:Catalysis; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006860:Hydrogen Bonding; D009699:N-Glycosyl Hydrolases / Q000737:chemistry*; D016133:Polymerase Chain Reaction; D013816:Thermodynamics
chemical_list: D017931:DNA Primers; D004791:Enzyme Inhibitors; D009699:N-Glycosyl Hydrolases