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Issue 8, 2011
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MS/MS fragmentation-guided search of TMG-chitooligomycins and their structure–activity relationship in specific β-N-acetylglucosaminidase inhibition

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Abstract

The reducing tetrasaccharide TMG-chitotriomycin (1) is an inhibitor of β-N-acetylglucosaminidase (GlcNAcase), produced by the actinomycete Streptomyces anulatusNBRC13369. The inhibitor shows a unique inhibitory spectrum, that is, selectivity toward enzymes from chitin-containing organisms such as insects and fungi. Nevertheless, its structure-selectivity relationship remains to be clarified. In this study, we conducted a structure-guided search of analogues of 1 in order to obtain diverse N,N,N-trimethylglucosaminium (TMG)-containing chitooligosaccharides. In this approach, the specific fragmentation profile of 1 on ESI-MS/MS analysis was used for the selective detection of desired compounds. As a result, two new analogues, named TMG-chitomonomycin (3) and TMG-chitobiomycin (2), were obtained from a culture filtrate of 1-producing Streptomyces. Their enzyme-inhibiting activity revealed that the potency and selectivity depended on the degree of polymerization of the reducing end GlcNAc units. Furthermore, a computational modeling study inspired the inhibitory mechanism of TMG-related compounds as a mimic of the substrate in the Michaelis complex of the GH20 enzyme. This study is an example of the successful application of a MS/MS experiment for structure-guided isolation of natural products.

Graphical abstract: MS/MS fragmentation-guided search of TMG-chitooligomycins and their structure–activity relationship in specific β-N-acetylglucosaminidase inhibition

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Publication details

The article was received on 26 Nov 2010, accepted on 09 Feb 2011 and first published on 04 Mar 2011


Article type: Paper
DOI: 10.1039/C0OB01090A
Org. Biomol. Chem., 2011,9, 2943-2951

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    MS/MS fragmentation-guided search of TMG-chitooligomycins and their structure–activity relationship in specific β-N-acetylglucosaminidase inhibition

    H. Usuki, Y. Yamamoto, Y. Kumagai, T. Nitoda, H. Kanzaki and T. Hatanaka, Org. Biomol. Chem., 2011, 9, 2943
    DOI: 10.1039/C0OB01090A

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