Dehydrogenase MnGutB1 catalyzes 1-deoxynojirimycin biosynthesis in mulberry

Abstract

As the prevalence of diabetes continues to increase, the number of individuals living with diabetes complications will reach an unprecedented magnitude. Continuous use of some synthetic agents to reduce blood glucose levels causes severe side effects, and thus, the demand for non-toxic, affordable drugs persists. Naturally occurring compounds, such as iminosugars derived from the mulberry (Morus spp.), have been shown to reduce blood glucose levels. In mulberry, 1-deoxynojirimycin (DNJ) is the predominant iminosugar. However, the mechanism underlying DNJ biosynthesis is not completely understood. Here, we showed that DNJ in mulberry is derived from sugar and catalyzed through 2-amino-2-deoxy-D-mannitol dehydrogenase MnGutB1. Combining both targeted and nontargeted metabolite profiling methods, DNJ and its precursors 2-amino-2-deoxy-D-mannitol (ADM) and nojirimycin (NJ) were quantified in mulberry samples from different tissues. Purified His-tagged MnGutB1 oxidized the hexose derivative ADM to form the 6-oxo compound DNJ. The mutant MnGutB1 D283N lost this remarkable capability. Furthermore, in contrast to virus-induced gene silencing (VIGS) of MnGutB1 in mulberry leaves that disrupted the biosynthesis of DNJ, overexpression of MnGutB1 in hairy roots and light-induced upregulation of MnGutB1 enhanced DNJ accumulation. Our results demonstrated that hexose derivative ADM, rather than lysine derivatives, is the precursor in DNJ biosynthesis, and it is catalyzed by MnGutB1 to form the 6-oxo compound. These results represent a breakthrough in producing DNJ and its analogs for medical use by metabolic engineering or synthetic biology.

PHB3 interacts with BRI1 and BAK1 to mediate brassinosteroid signal transduction in Arabidopsis and tomato

“…BRs regulate plant cell elongation and division, light sensing, vascular differentiation, flowering, male reproduction, and stress resistance (Clouse, 2011;Fabregas et al, 2018;Gupta et al, 2020). Moreover, BR regulates organ boundary determination, stomatal differentiation, root meristem maintenance, immune response, root hair formation, shoot branching, and leaf angle control in monocots (Shang et al, 2016;Nolan et al, 2017;Xia et al, 2021;Zhang et al, 2023).…”

Am-aza-ing antidiabetic: Mulberry dehydrogenase MnGUTB1 contributes to the biosynthesis of 1-deoxynojirimycin

“…In summary, Yang et al (2023) identified an amino-polyol dehydrogenase in mulberry that participates in the biosynthesis of antihyperglycemia azasugar DNJ. They provided evidence for its biochemical activity, presented data on tissue localization of DNJ biosynthesis, and supplied an explanation for the photoperiodical dependency of DNJ contents in mulberry.…”

“…In this issue of Plant Physiology , Yang et al (2023) provide clear evidence that a 2-amino-2-deoxy-D-mannitol (ADM) dehydrogenase, MnGUTB1, participates in the biosynthesis of the azasugar DNJ, catalyzing the oxidation of ADM to NJ in mulberry ( Fig. 1 ).…”

“…In plants like mulberry, DNJ is likely derived from D-glucose via ADM (2-amino-2-deoxy-D-mannitol) and NJ (nojirimycin). The amino-polyol dehydrogenase MnGUTB1, identified and characterized by Yang et al (2023) , catalyzes the conversion of ADM to NJ in mulberry, an essential step in the biosynthesis of the antihyperglycemia DNJ. Dotted arrows depict reactions for which no enzymes are currently described to catalyze them in plants.…”

“…Several enzymes involved in DNJ biosynthesis await their identification and characterization, regardless of the exact pathway. Besides the open questions, Yang et al (2023) provide valuable insights to increase the production of DNJ by optimizing mulberry cultivation, molecular-assisted breeding, synthetic biology, and metabolic engineering.…”