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

Hirokazu Usuki, Yukihiro Yamamoto, Yuya Kumagai, Teruhiko Nitoda, Hiroshi Kanzaki, Tadashi Hatanaka

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The reducing tetrasaccharide TMG-chitotriomycin (1) is an inhibitor of β-N-acetylglucosaminidase (GlcNAcase), produced by the actinomycete Streptomyces anulatus NBRC13369. 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.

Original languageEnglish
Pages (from-to)2943-2951
Number of pages9
JournalOrganic and Biomolecular Chemistry
Volume9
Issue number8
DOIs
Publication statusPublished - Apr 21 2011

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Acetylglucosaminidase
Structure-Activity Relationship
fragmentation
selectivity
Streptomyces
inhibitors
Chitin
enzymes
Enzyme activity
actinomycetes
Enzymes
Biological Products
Fungi
chitin
analogs
enzyme activity
insects
fungi
Actinobacteria
Polymerization

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Biochemistry

Cite this

MS/MS fragmentation-guided search of TMG-chitooligomycins and their structure-activity relationship in specific β-N-acetylglucosaminidase inhibition. / Usuki, Hirokazu; Yamamoto, Yukihiro; Kumagai, Yuya; Nitoda, Teruhiko; Kanzaki, Hiroshi; Hatanaka, Tadashi.

In: Organic and Biomolecular Chemistry, Vol. 9, No. 8, 21.04.2011, p. 2943-2951.

Research output: Contribution to journalArticle

Usuki, Hirokazu ; Yamamoto, Yukihiro ; Kumagai, Yuya ; Nitoda, Teruhiko ; Kanzaki, Hiroshi ; Hatanaka, Tadashi. / MS/MS fragmentation-guided search of TMG-chitooligomycins and their structure-activity relationship in specific β-N-acetylglucosaminidase inhibition. In: Organic and Biomolecular Chemistry. 2011 ; Vol. 9, No. 8. pp. 2943-2951.
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