Rapid Mining of Novel α-Glucosidase and Lipase Inhibitors from Streptomyces sp. HO1518 Using UPLC-QTOF-MS/MS

Abstract

A rapid and sensitive method using ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) was applied for the analysis of the metabolic profile of acarviostatin-containing aminooligosaccharides derived from Streptomyces sp. HO1518. A total of ninety-eight aminooligosaccharides, including eighty potential new compounds, were detected mainly based on the characteristic fragment ions originating from quinovosidic bond cleavages in their molecules. Following an LC-MS-guided separation technique, seven new aminooligosaccharides (10-16) along with four known related compounds (17-20) were obtained directly from the crude extract of strain HO1518. Compounds 10-13 represent the first examples of aminooligosaccharides with a rare acarviostatin II02-type structure. In addition, all isolates displayed considerable inhibitory effects on three digestive enzymes, which revealed that the number of the pseudo-trisaccharide core(s), the feasible length of the oligosaccharides, and acyl side chain exerted a crucial influence on their bioactivities. These results demonstrated that the UPLC-QTOF-MS/MS-based metabolomics approach could be applied for the rapid identification of aminooligosaccharides and other similar structures in complex samples. Furthermore, this study highlights the potential of acylated aminooligosaccharides with conspicuous α-glucosidase and lipase inhibition for the future development of multi-target anti-diabetic drugs.

Keywords: Streptomyces sp. HO1518; UPLC-QTOF-MS/MS; aminooligosaccharides; diabetes; digestive enzyme inhibitors; metabolic profiling.

Figure 1

The structures of compounds 1–9.

Figure 2

Positive HRESIMS/MS fragmentation and spectrum of 7. (A) Positive-ion HRESIMS/MS fragmentation pattern of 7; (B) HRESIMS/MS spectra of 7.

Figure 3

The general structures of aminooligosaccharides from Streptomyces sp. HO1518. (A) The general structures of acarviostatins with glucoses at the reducing terminus; (B) The general structures of acarviostatins with glucoses at the reducing and non-reducing terminus; (C) The general structures of acarviostatins with an incomplete pseudo-trisaccharide at the non-reducing terminus.

Figure 4

The structures of compounds 10–20.

Figure 5

Key 2D NMR correlations of compounds 10 and 14.

Figure 6

Positive HRESIMS/MS fragmentation and spectra of 10–13. (A) Positive-ion HRESIMS/MS fragmentation patterns of 10–13; (B–E) HRESIMS/MS spectra of 10–13.

Figure 7

The docking results of human PL (PDB ID: 1LPB) with inhibitors. (A) The possible interactions between 1LPB and orlistat; (B) acarbose; (C) acarviostatin I03; (D) acarviostatin II02; (E) acarviostatin II03. Wheat: orlistat; pink: C₇N cyclohexitol; yellow: 4-amino-4,6-dideoxy-d-glucopyranose; cyan: d-glucopyranose.