Solution Conformations of Mycothiol Bimane, 1-d-GlcNAc-α- (1 → 1)-d-myo-Ins and 1-d-GlcNAc-α-(1 → 1)-l-myo-Ins

• Published in: Journal of organic chemistry 2003-05, Vol.68 (9), p.3380-3386
• Main Authors: MAHADEVAN, Janaki, NICHOLAS, Gillian M., BEWLEY, Carole A.
• Format: Article
• Language: English
• Subjects: Actinomyces - chemistry; Actinomyces - metabolism; Amidohydrolases - genetics; Amidohydrolases - metabolism; Cyclization; Cysteine; Disaccharides - chemistry; Glycopeptides; Inositol; Molecular Conformation; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Pyrazoles - chemistry; Stereoisomerism; Structure-Activity Relationship; Sulfhydryl Compounds - chemistry
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo026872w

Mycothiol is an abundant small molecular weight thiol found only in actinomycetes, which include mycobacteria. Mycothiol biosynthetic and detoxification enzymes are novel and unique to actinomycetes, thereby representing potential antimycobacterial targets. To better guide inhibitor design, we have determined by NMR the solution conformations of mycothiol bimane (MSmB) and the pseudodisaccharide 1-D-GlcNAc-alpha-(1 --> 1)-D-myo-Ins (D-GI), molecules that represent the natural substrates for the mycothiol-dependent detoxification enzyme mycothiol-S-conjugate amidase (MCA) and the mycothiol biosynthetic enzyme D-GlcNAc-alpha-(1 --> 1)-D-myo-Ins deacetylase (AcGI deacetylase), respectively. Comparison of the mean structure of MSmB and the energy-minimized structures of two competitive spiroisoxazoline-containing MCA inhibitors shows striking similarities between these molecules in the region of the scissile amide bond of MSmB and provides structural evidence that those inhibitors are substrate mimics. Owing to our earlier finding that AcGI deacetylase will not deacetylate the unnatural isomer 1-d-GlcNAc-alpha-(1 --> 1)-L-myo-Ins (L-GI), the solution conformation of L-GI was also determined. The interglycosidic bond angles for all three compounds are comparable. When considered together with the observation that a simplified cyclohexyl thioglycoside mycothiol analogue is a good substrate for MCA, it appears that the stereochemistry of the inositol ring is critical for deacetylase function, superceding the importance of the full complement of hydroxyl groups on the "nonreducing" ring.