Work

Transition-State Structure of Neisseria meningitides 5‘-Methylthioadenosine/S-Adenosylhomocysteine Nucleosidase

Year: 2007

Type: article

Abstract: 5‘-Methylthioadenosine/ S -adenosylhomocysteine nucleosidase (MTAN) is a bacterial enzyme that is involved in quorum sensing pathways and a potential target for the design of antibiotics. Kinetic isotope effects (KIEs) and computer modeling using density functional theory were used to determine the transition state of N. meningitides MTAN. KIEs were measured for hydrolysis of 5‘- methylthioadenosine (MTA) and were corrected for forward commitment to catalysis to obtain intrinsic KIEs for [1‘- 3 H], [9- 15 N], [1‘- 14 C], [2‘- 3 H], [4‘- 3 H], [5‘- 3 H 2 ], and [Me- 3 H 3 ] MTAs. KIEs support an early S N 1 transition state unlike the dissociative transition states of other MTANs. Computational modeling of intrinsic KIEs places the leaving group adenine at 1.68 Å from the anomeric carbon, a Pauling bond order of 0.50, and no participation of the hydroxide nucleophile. The N7 of adenine is protonated and the leaving group is cationic owing to the significant bond order to the C1‘−N9 bond at the transition state. The 3‘-OH is not strongly polarized or ionized at the transition state, unlike other MTANs. The early transition state of N. meningitides MTAN is supported by its inhibition with transition-state analogues.

Source: Journal of the American Chemical Society

DOI: 10.1021/ja0754204

Authors: Vipender Singh, Minkui Luo, Rosemary L. Brown, Gillian E. Norris, Vern L. Schramm

Institutions: Albert Einstein College of Medicine, Massey University

Language: English

Topic: Chemical Reaction Mechanisms

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: green

Funder: National Institute of General Medical Sciences

Awards: Transition State Analysis of Enzymatic Reactions, Transition State Analysis of Enzymatic Reactions, G521541070