Plant Derived Iminosugars as Metabolic and Therapeutic Modulators Advances in Biosynthesis Mechanisms and Clinical Potential 2015 2025

A class of naturally occurring or synthetically produced “azasugars” also known as iminosugars are carbohydrate compounds that resemble carbohydrates in structure but contain nitrogen instead of oxygen in their ring. The substitution of nitrogen results in significant changes to the physiochemical and biological properties of the compounds. The nitrogen ring providing basicity to the compounds and increases the ability of hydrogen bonds formation and cationic characteristics at physiological pH. Iminosugars mimic carbohydrates and competitively inhibit the activity of carbohydrate processing enzymes, such as glycosidases or glycosyltransferases due to their ability to mimic the transition state of hydrolysis by enzymes [1, 2]. Iminosugars are generally considered polyhydroxylated nitrogen heterocycles, depending on the size and architecture of their rings; are classified into piperidine, pyrrolidine, pyrrolizidine and indolizidine, respectively; and have a stereochemical arrangement of their hydroxyl groups that resemble the stereochemistry of naturally occurring monosaccharides (i.e., glucose, mannose or galactose). Changes in the orientation of hydroxyl groups or N-alkyl substitution have a significant effect on the selective recognition of iminosugars by enzymes such as α-glycosidase, β-glycosidase, mannosidase or glucosylceramide synthase.Iminosugars make up categories of secondary metabolites produced within different families of higher plant species such as Moraceae + (Morus alba), Fabaceae + (Castanospermum australe), Solanaceae + (Hyoscyamus albus). Secondary metabolites can often provide defence or modulation services to higher plants and are therefore naturally abundant sources for drug discovery [3, 4]. Iminosugars can be defined by their unique nitrogen substitution and sugar-like structure and can provide molecular tools to explore and/or modify carbohydrate dependent biological processes. Further, due to H-bonding capacity, iminosugars tightly interact with constituent residues at biologically active sites of enzymes that utilizes glycans in their biochemical pathway(s). In this way, iminosugars can provide a method for guiding glycoprotein folding, glycolipid production, & lysosomal breakdown of biomolecules [5, 6]. Due to biological activity of iminosugars, several clinically relevant drugs have been developed such as miglitol and miglustat for the treatment of type 2 diabetes and lysosomal storage disorders, respectively [7]. The two most researched naturally occurring iminosugars are 1-deoxynojirimycin (DNJ) and castanospermine isolated from Morus alba (Mulberry) and Castanospermum australe are active ingredient found in the plant. Both have been shown to be effective inhibitors of an enzyme α-glucosidase. The antihyperglycemic effects of mulberry leaves are due to presence of DNJ [8] and castanospermine, a bicyclic indolizidine alkaloid with high levels of inhibition for both endoplasmic reticulum α-glucosidases I and II [9]. Swainsonine, another indolizidine alkaloid, has significant effects on the inhibition of α-mannosidase and the regulation of glycoprotein maturation pathways. In addition to their ability to modulate the enzymatic reactions, iminosugars have a variety of biological effects, including affecting carbohydrate metabolism, glycoprotein folding, glycolipid biosynthesis, and lysosomal degradation pathways [10] and these biological effects translate into numerous therapeutic applications. Thus, the present review aims to investigate the role of plant derived iminosugars in metabolic pathways and to explore their pharmacological potential as promising therapeutic leads.

2. MATERIAL AND METHOD

A comprehensive literature search was conducted using scientific databases including PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar. Articles published between January 2015 and March 2025 were considered. The keywords used for literature review are “iminosugars”, “aza sugars”, “carbohydrate mimic”, therapeutic use of Imino sugars”, “DNJ analog”, “β-glycosidases” etc.

3. RESULT AND DISCUSSION

Classification of Iminosugars

Iminosugars are a diverse group of nitrogen-based carbohydrate analogues that mimic the structure and reactivity of monosaccharides. Iminosugar classification depends on the size of the ring, number of hydroxyl groups, and the method of nitrogen incorporation will also affect the selectivity of the enzymes that they affect and their biological activity. These characteristics contribute to the pharmacological potential of iminosugars. Iminosugars can be grouped into several structural categories: piperidine, pyrrolidine, indolizidine, nortropaine, pyrrolizidine and fused bicyclic derivatives as presented (Table 1).

Plant-Derived Iminosugars: Biosynthesis and Metabolic Interactions

Iminosugars are a unique class of alkaloid-like carbohydrate mimetics that originate from plant sources. They have been characterized by having a nitrogen atom in the place of the endocyclic oxygen, providing them with significant glycosidase inhibitory potential and wide-ranging pharmacological applications. Recently there has been increased understanding about how iminosugars are biosynthesized in plants such as mulberry (Morus spp), buckthorn (Rhamnus spp), and numerous other medicinal species. The one most well-studied iminosugar to date, 1-deoxynojirimycin (DNJ), has an established canonical pathway for biosynthesis starting from either glucose or fructose intermediates that enter the Polyol Pathway [11, 12]. In this pathway there are specific dehydrogenases and aminotransferases that participate in the incorporation of nitrogen into the compound. Research has revealed that one of the relevant classes of dehydrogenases that can drive nitrogen incorporation into the pathway for the formation of iminosugars is represented by MnGutB1 in mulberry. This dehydrogenase promotes the conversion of N-hydroxy-L-arginine derivatives into DNJ precursors and demonstrates that specialized oxidoreductases function as excellent regulatory mechanisms to direct flux towards iminosugars biosynthesis[11].Similar studies from different organisms showed us that same enzymes (in plant–microbe interactions) are used by pathogens that synthesize iminosugars to manipulate host's glycobiology. This suggest that the synthesis of iminosugars has been evolutionarily conserved between different biological kingdoms [13]. Biosynthetically, the process is characterized by making sugar based polyhydroxyl compounds, which undergo cyclization followed by amination and stereochemical modifications of those polyhydroxyls to form heterocycles with nitrogen atoms like monosaccharides. Metabolomic and isotope labelling studies show that iminosugar biosynthesis is closely related to primary carbohydrate metabolism as they arise from intermediates of glycolysis and the pentose phosphate pathway. This locates iminosugars synthesis at a junction between major modes of carbon metabolism [14].

Plant-derived iminosugars exhibit nutraceutical property and have marked impact on metabolic pathways in humans after they have been synthesized. Iminosugars exerts their action through competitive inhibition of glycosidases, which are the enzymes responsible for the hydrolysis of glycosidic bonds within oligosaccharides and glycoconjugates. For e.g., DNJ and similar compounds inhibit the intestinal α-glucosidases and results in delaying carbohydrate digestion and glucose absorption, thus decreasing the post-prandial hyperglycaemia—an attribute that has been utilized for diabetes treatment[15]. Likely, iminosugars are also able to influence lipid metabolic pathways through their ability to modulate ceramide and glycosphingolipid biosynthesis. Through inhibition of glucosylceramide synthase, iminosugars can decrease the accumulation of glycosphingolipids, demonstrating the potential for therapeutic application with lysosomal storage disorders, such as Gaucher and Fabry disease. Furthermore, by inhibiting the activity of ER α-glucosidases I and II, which are essential for the proper processing of N-glycosylated proteins, iminosugars can affect protein folding and quality control in the ER [16, 17]. Further, it was observed that iminosugars have an impact on immune recognition by disrupting glycoprotein maturation and have been targeted as an antiviral strategy against HIV and other hepatitis viruses where HIV-type viruses have their glycoproteins disrupted from assembly [18, 19]. In addition, iminosugars may also modulate gut-brain axis signalling through carbohydrate digestion and changes in microbiome and SCFA levels leads to indirect neurocognitive effects such as “brain fog” seen in post-COVID syndrome[19].The biochemical properties of iminosugars enables them to function as transition state-mimetic analogs of the oxocarbenium ion intermediate of a glycosidase-catalyzed reaction. The structural resemblance contributes to the wide-ranging inhibitory effects of iminosugars on various glycosidase enzymes. The biological effects of iminosugars have translated to changes in the metabolic pathways of humans by altering the flow of carbohydrates through a greater rate of catabolism, reduced production of glycoproteins, and decreased lipid glycosylation [18, 20]. Study indicates that DNJ inhibit the activity of maltase and sucrase in the gut, decreasing glucose levels in the body while enhancing the ability of cells to utilize insulin[14]. In the liver also, iminosugars interfere with the activity of glycosyltransferases which decreases the potential of liver damage due to fat accumulation and enhances the functioning of mitochondria and therefore may reduce the development of non-alcoholic fatty liver disease [14, 21, 22].In addition, iminosugars compounds also interact with inflammatory pathways through their ability to modulate the release of pro-inflammatory cytokines, and when glycosidase-dependent glycoprotein maturation is inhibited, this process disrupts immune receptor signaling and dampens the pro-inflammatory cascade of molecular signals that the body produces. In similar context, recent studies have suggested that iminosugars can serve as adjunctive therapies for individuals with neuroinflammation and metabolic dysregulation, to help restore the state of glycol-homeostasis. Recently published clinical nutrition studies have also identified the role of the plant-derived iminosugars from mulberry leaf tissue (rich in DNJ; a key iminosugars) to improve glycaemic control in individuals and to affect the composition of gut microbial flora, which has downstream effects on both digestive tract health and mood regulation. These studies also support that iminosugars has both medicinal and dietary benefit due to unique interaction with the human metabolic framework. The interactions between iminosugars and gastrointestinal (GI) pathways demonstrate a bi-directional connection because iminosugars alter the digestion of carbohydrates and subsequently change the ecology of the microbial flora residing in the intestinal tract. Wherein the metabolic products produced by the microbial flora influence the metabolism of glucose and lipids by the host [15, 18, 23-25]. Such studies provide an integrative model which positions iminosugars as metabolic modulators and serve as intermediate links between the plant secondary metabolites and the physiology of the human body.In summary, the biosynthesis of plant-derived iminosugars relies on specialized dehydrogenases, aminotransferases and cyclization reactions branching from central carbohydrate metabolism and produce nitrogen-containing sugar mimetics that have potent glycosidase inhibitory activity. These compounds interact with human metabolic pathways at multiple levels including carbohydrate digestion, lipid glycosylation, glycoprotein folding, immune signalling and gut-brain axis regulation. Their dual function as nutraceuticals and pharmacological agents highlights their potential therapeutic benefit for diabetes, lysosomal storage disorders, viral infections and post-COVID metabolic syndromes. Cohesive research on plant biochemistry, human metabolism and clinical nutrition will enhance our understanding of iminosugars as trans-kingdom metabolic modulators.

Therapeutic Potential of Plant-Derived Iminosugars in Metabolic Disorders: A Decade of Advances (2015–2025)

1. Diabetes Mellitus

Plant-derived iminosugars are competitive inhibitors of α-glucosidases (maltase, sucrase, isomaltase) within the small intestine. They mimic the transition state of glycosidase-catalyzed reactions, thereby slowing the hydrolysis of carbohydrates, and reducing glucose absorption, resulting in reduced postprandial hyperglycemia. This is like the mechanism of action exhibit by synthetic α-glucosidase inhibitors like acarbose, although iminosugars tend to be better tolerated and have fewer side effects [25]. Iminosugars, specifically 1-deoxynojirimycin (DNJ) have been extensively studied over the past ten years for their potential role in the treatment of diabetes. Preclinical research shows that extracts of mulberry leaves, which are rich in DNJ, can improve fasting glucose levels, improve insulin sensitivity, increase hepatocellular glycogen storage, decrease oxidative stress, and decrease release of pro-inflammatory cytokines, indicating that iminosugars can play crucial in glycemic control and immunometabolic regulation[26]. In other study, DNJ was found effective on inhibition of sucrose and maltose and decreases the speed of carbohydrate breakdown[27]. The similar results were found in human studies as well. The supplementation of diabetes (type 2) with mulberry leaf extract decreases HbA1c and glucose levels after eating foods high in carbohydrates [28]. Additionally, in patients with type II diabetes, supplementation with DNJ was effective in improving fasting blood sugar levels, decreasing insulin resistance, and delaying progression to full-blown diabetes [29]. Evidences compiled from last 10 years has demonstrated the multiple therapeutic uses of plant-based iminosugars for diabetes, making them good candidates for nutraceutical and pharmaceutical agents. The main challenges for plant-based iminosugars are their low natural abundance in plants, their ability to broadly inhibit glycosidases causing off-target effects and the necessity of large scale, long-term clinical trials to confirm their efficacy and safety. Future research will be necessary for the metabolic engineering of plants to develop faster growing plants, developing structure/effect relationships for specificity and evaluating iminosugars for inclusion as functional foods in diabetes prevention.

2. Obesity and Lipid Metabolism

1-deoxynojirimycin (DNJ), have gained considerable attention over the past decade for their therapeutic potential in obesity and lipid metabolism. They primarily as glycosidase inhibitors, delaying carbohydrate digestion and reducing postprandial glucose excursions, which indirectly lowers lipogenesis and fat accumulation. Beyond their role in glucose regulation, iminosugars exert direct effects on lipid pathways by inhibiting glucosylceramide synthase, thereby reducing glycosphingolipid accumulation—a mechanism strongly implicated in obesity-related insulin resistance and metabolic dysfunction. Preclinical studies in rodent models have shown that DNJ supplementation reduces body weight gain, improves lipid profiles, and alleviates hepatic steatosis, while also enhancing mitochondrial function and reducing inflammatory cytokine release, linking imino-sugar activity to improved immune-metabolic regulation[30]. In-vitro studies further confirm DNJ’s ability to inhibit adipocyte differentiation and lipid accumulation, suggesting a direct anti-obesity effect at the cellular level [29]. A clinical trial indicates that mulberry leaves extract rich in deoxynojirimycin (DNJ) decreases levels of serum triglycerides and low-density lipoprotein (LDL) cholesterol while improving high-density lipoprotein (HDL) cholesterol in obese individuals. Another study showed improvements in both glycemic variables and lipid parameters [27, 31]. These findings collectively establish the multiple therapeutic options of iminosugars derived from plant sources for obesity and lipid disorders and suggest that their use may be commercially viable for both the pharmaceutical and nutraceutical industries. However, there are still some barriers to overcome, including limited natural availability, broad glycosidase inhibition that may lead to possible gastrointestinal side effects, and the need for large-scale clinical trials. Future research should focus on enhancing yields through metabolic engineering, refining specificity via structure–activity relationship studies and establishing long-term efficacy and safety in managing obesity and lipid metabolism through clinical trials.

3. Lysosomal Storage Disorders

1-deoxynojirimycin (DNJ), have been receiving considerable interest as a therapeutic agent for lysosomal storage disorders (LSD), which are inherited metabolic disorders that occur when there are insufficient amounts of glycosphingolipid in the body because of defects in lysosomal enzymes. By acting as a substrate reduction therapy (SRT) agent, iminosugars function by inhibiting glycosidases and glycosyltransferases, and this way they function by decreasing the production of glycosphingolipids and decrease the accumulation of substrates in lysosomes. Studies in culture and animal models show that DNJ and its analogues have been able to reduce the level of glucosylceramide in cultured and in vivo models of Gaucher and Fabry disease, thus enhancing lysosomal activity and reducing the accumulation of lipids in the lysosome[32].Studies have been carried out to optimise plant-derived DNJ for current therapeutic use. It has been shown to inhibit glucosylceramide synthase, one of the major glycosylation enzymes involved in glycosphingolipid metabolism, providing support for its use in LSD models. Although currently approved SRTs are synthetics (miglustat and eliglustat), the chemical structures of these agents are related to naturally present iminosugars in plants. New evidence is emerging also indicating that plant-derived DNJ may have the potential to function as a nutraceutical adjunct to ERT and thus support metabolic homeostasis by decreasing the accumulation of the substrates of the affected enzymes[31]. Iminosugars may be utilized to modify immunity/inflammation pathways that are altered by LSDs beyond reducing the substrate for enzymes and directly affecting glycoproteins and cytokine selection. There is strong possibility that plant derived therapeutically active iminosugars are good starting point for future research on LSD therapeutics via., evaluating additional possibilities through metabolic manipulation, structure-activity relationship assessment, and clinical use.

4. Immuno metabolic Regulation

1-deoxynojirimycin (DNJ), emerge as significant immuno-metabolic regulatory agent in recent years that connect metabolic homeostasis with immune response signalling. Iminosugars are considered iminosugar nitrogen and their main role is as glycosidase inhibitors and, thus, influence the glycoprotein processing, glycosphingolipid metabolism and cytokine signalling pathways leading to a reduced metabolic inflammatory response which is a key driver of insulin resistance, obesity and associated metabolic disorders[14].Preclinical studies have demonstrated that iminosugars inhibit α-glucosidase activity from the endoplasmic reticulum, resulting in altered N-linked glycoprotein maturation and modulated immune receptor signalling, leading to decreased secretion of pro-inflammatory cytokines and decreased chronic low-grade inflammation that characterises metabolic syndrome[33]. In addition, multivalent imino-sugar derivatives have also demonstrated enhanced glycosidase inhibition and enhanced in vitro immunomodulatory activity, highlighting their potential for fine-tuning immuno-metabolic interactions[7]. Iminosugars have also been examined in viral infection models, where disruption of glycoprotein folding inhibits viral replication while simultaneously changing the host's immune response, thereby supporting their dual role as antiviral agents and immuno-metabolic regulators [34]. Recent studies in translational medicine indicate that DNJ produced from mulberry is effective in reducing systemic inflammation due to decreased accumulation of glycosphingolipids as well as improved insulin sensitivity. Research on clinical nutrition has also demonstrated that functional foods containing DNJ may be able to modulate immune responses through gut microbiota changes by promoting metabolic resilience. As a whole, iminosugars derived from plants are attractive nutraceuticals and pharmacological agents for the treatment of metabolic inflammation and insulin resistance. In the future, research should aim to improve specificity, increase naturally occurring yields, and perform clinical trials to verify immune metabolic efficacy in humans.

5. Gut–Microbiota Axis

Over the last 10 years, there is growing interest in exploring the effect of 1-deoxynojirimycin (DNJ) on Gut–Microbiota Axis, It has attracted a lot of attention because it works as a competitive α-glucosidase inhibitors, which inhibits the digestion and absorption of carbohydrate-based foods, therefore increasing the amount of undigested polysaccharides reaching the colon and altering the composition and activity of the gut's microbiota. Thus, this causes good glucose levels, improving lipid levels, and reduces general inflammation in the body. In preclinical studies, DNJ supplementation improved gut microbial diversity and stimulated SCFA-producing microorganisms that regulate the immune system and energy balance [35]. In animal models for metabolic syndrome, DNJ-rich extracts improved the integrity of the intestinal barrier in addition to reducing endotoxemia, linking the iminosugars beneficial effect on metabolic inflammation to the use of DNJ[36]. Results from clinical nutrition studies corroborate these findings, with data demonstrating that foods containing DNJ from mulberries decrease postprandial glucose while shifting gut microbiota composition into a significantly more beneficial one[27].The mechanisms of action for these benefits demonstrate that enhanced fermentation of undigested carbohydrates increases the production of short-chain fatty acids (SCFAs), especially butyrate and propionate, both of which are associated with reduced inflammation and increased insulin sensitivity. Iminosugars may help to limit dysbiosis by providing less rapidly absorbable glucose to support pathogen growth when ingested. Additionally, emerging evidence suggests that these components may indirectly affect the gut–brain axis through normalized microbiota compositions resulting in reduced neuroinflammation and greater metabolic resilience. Overall, plant-derived iminosugars represent important nutraceutical and pharmaceutical agents for microbiome-cantered strategies in managing both diabetes and obesity, as well as their associated metabolic diseases. Future research should focus on long-term clinical validation and microbiome-specific mechanistic studies of iminosugars.

CONCLUSION

Plant-derived iminosugars have emerged as structurally unique and biologically powerful carbohydrate mimetics with significant therapeutic relevance. Through selective inhibition of glycosidases and glycosylation-related enzymes, these compounds modulate critical metabolic pathways governing glucose homeostasis, lipid metabolism, glycoprotein maturation, and intracellular signaling. Natural iminosugars i.e., DNJ, DMJ, and castanospermine etc. along with their synthetic derivatives like miglitol and miglustat demonstrates clinically validated benefits in type 2 diabetes and lysosomal storage disorders underscoring their translational potential. Beyond their established role as intestinal α-glucosidase inhibitors, accumulating evidence indicates that iminosugars exert systemic effects, including regulation of oxidative stress responses, mitochondrial metabolism, inflammatory signaling, and host–pathogen interactions. Their emerging antimalarial activity further broadens their pharmacological scope, highlighting their capacity to interfere with glycoprotein-dependent processes essential for parasite development and virulence.Despite these promising outcomes, challenges such as limited bioavailability, gastrointestinal side effects, and enzyme selectivity remain important considerations for future drug development. Advances in medicinal chemistry, biotechnological production, and targeted delivery systems may help overcome these limitations and optimize therapeutic efficacy. In conclusion, plant-derived iminosugars represent a versatile and evolving class of bioactive molecules with substantial potential for the development of next-generation therapeutics addressing metabolic disorders and infectious diseases.

Acknowledgement

Authors are thankful to the director, Amity Institute of Pharmacy, Amity University Uttar Pradesh, Lucknow Campus, Lucknow-226028, UP(India).

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