Biocatalyzed Synthesis of Antidiabetic Drugs
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
FSA was also shown to accept various other N-Cbz-protected aldehydes (Concia et al., 2009) and azido-substituted aldehydes (Sugiyama et al., 2007) (compounds 134, Fig. 11.46) in combination with DHA, hydroxyacetone (HA), 1-hydroxybutan-2-one (HB) or glycolaldehyde (GO) as nucleophiles to provide various structurally related pyrrolidine-type iminocyclitols (e.g., 136 or 137). This route has provided easy access to some interesting drugs; for instance, 1,4-dideoxy-1,4-imino-D-arabinitol (DAB, 138), a potent α-glucosidase inhibitor (Saludes et al., 2007) possessing therapeutic potential as anti-hyperglycemic agent because of its capability to inhibit glycogen phosphorylase and glucagon-stimulated glycogen breakdown (Andersen et al., 1999; Walls et al., 2008; Praly and Vidal, 2010) or 1,4,5-trideoxy-1,4-imino-D-arabinitol (5-DDAB, 139), which was found to have inhibitory properties against α- and β-mannosidase from jack beans and snails, respectively, and α- and β-glucosidase (Sugiyama et al., 2007); its corresponding enantiomer (5-DLAB) is an inhibitor of α-L-rhamnosidase from Penicillium decumbens (Provencher et al., 1994). Chemoenzymatic synthesis of pyrrolidine-type iminocyclitols using FSA.
sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Manuel González-Cuesta, Irene Herrera-González, M. Isabel García-Moreno, Roger A. Ashmus, David J. Vocadlo, José M. García Fernández, Eiji Nanba, Katsumi Higaki, Carmen Ortiz Mellet
Compounds 1–8 were preliminary assayed for their glycosidase inhibitory properties against a panel of commercial glycosidases covering a variety of configurational and anomeric specificities, including bovine and almond β-glucosidase, yeast α-glucosidase and isomaltase, Aspergillus niger amyloglucosidase, Escherichia coli β-galactosidase, green coffee bean α-galactosidase, Helix pomatia β-mannosidase, Jack bean α-mannosidase and β-hexosaminidases from human placenta, bovine kidney and Jack bean. Only the hexosaminidase activity was significantly affected at concentrations below 1 mM of the sp2-iminosugars (Supplementary Table 1). The corresponding Lineweaver-Burk plots were consistent with a competitive inhibition mode in all cases. In the thiourea series, the inhibition constants (Ki) values for the human placenta enzyme were in the low micromolar range (3.0 to 16.0 µM) for the N’-alky substituted members 1–3 and down to nM range (0.24 µM) for the N’-phenyl adduct 4. The notably higher inhibition potency of the aromatic thiourea correlates with its higher hydrogen bond-donating character, strongly suggesting the direct implication of the N’H proton in enzyme-inhibitor complex stabilisation.
Loss-of-function SLC30A2 mutants are associated with gut dysbiosis and alterations in intestinal gene expression in preterm infants
Published in Gut Microbes, 2022
Shannon L Kelleher, Samina Alam, Olivia C Rivera, Shiran Barber-Zucker, Raz Zarivach, Takumi Wagatsuma, Taiho Kambe, David I Soybel, Justin Wright, Regina Lamendella
Despite enrichment of numerous non-commensals, infants harboring Exon7 had a high level of diverse metabolic activity, which may actually have positive consequences on the host. Recent studies implicate propanediol, fucose and rhamnose as cross-feeding metabolites that modulate trophic interactions between symbionts,28 which may serve to promote stability of the microbiome. Additionally, these metabolites may have positive consequences in preterm infants. For example, propionate is taken up by colonocytes29 and used in gluconeogenesis in the liver,30 which is particularly important to glucose regulation in preterm infants.31 Sterate is used for fatty acid biosynthesis and can activate AP111 increasing expression of MUC232 and production of the protective mucus layer in the gut. One of the most significantly enriched microbial genes was formylCoA transferase (LDA = 2.17, p = 1.19^-5; Supplementary Table 1), an oxalate degrading enzyme associated with protection from calcium oxalate urolithiassis.33 Preterm infants are at the risk of development of nephrocalcinosis,34 and thus, enhanced degradation of oxalates may be beneficial. Another interesting gene of note is β-mannosidase (LDA = 3.28, p = 3.5^-5). Mannose is particularly important for infant growth, and free mannose, in addition to mannose in the form of oligosaccharides, is present in high concentrations in breast milk,35 contributes to the establishment of nonpathogenic colonic flora, inhibits binding of pathogens to the intestinal epithelial cell,36 and improves growth in weanling pigs.37 This suggests harboring Exon7 may provide some benefit to the host. Consistent with a potential positive impact, Exon7 was associated with upregulation of numerous host genes that play roles in proliferation, differentiation, migration, and adhesion (JUN, RAF1, PRKCA/KIN27 and MAPKs), cell cycle (CDK1/CDC2), and calcium signaling (GRM1) in the gut. Moreover, expression of GSK3b, critical for Wnt3 signaling, was increased, which may enhance communication between PCs and the intestinal stem cell niche.38 In sum, this expression profile combined with expression of key metabolites suggests infants with Exon7 may be responding to cues that activate tissue remodeling and promoting development of the gut.
A novel genetic variant potentially altering the expression of MANBA in the cerebellum associated with attention deficit hyperactivity disorder in Han Chinese children
Published in The World Journal of Biological Psychiatry, 2022
Xinzhen Chen, Ting Yao, Jinliang Cai, Qi Zhang, Shanyawen Li, Huiru Li, Xihang Fu, Jing Wu
The MANBA-encoded protein beta-mannosidase is a member of the glycosyl hydrolase 2 family, which functions as the final exo-acting β-glycosidase in the pathway for N-linked glycoprotein oligosaccharide catabolism (Gytz et al. 2019). Expression localisation analysis of MANBA in brain tissues shows that MANBA is primarily restricted to the midbrain and hindbrain, including the cerebellar cortex, medulla and pons (Yu et al. 2015). There is a low level of MANBA expression during all stages of human brain development (Yu et al. 2015), the activity of which decreases with age (Cooper et al. 1987). To date, there have been few studies on MANBA and neuropsychiatric disorders. Previous studies have reported that the expression level of MANBA in hippocampal neurons of schizophrenia patients is reduced (Altar et al. 2005), and genetic variants of MANBA are correlated with treatment response in schizophrenia (Ovenden et al. 2017). Recently, Rodriguez-Fontenla and Carracedo (2021) identified MANBA as a risk gene for autism spectrum disorder (ASD) through TWAS. However, the genetic mechanism and the potential role of beta-mannosidase in the development and progression of these neuropsychiatric diseases have not been reported yet. Similarly, this is the first identification of the association between MANBA genetic variants and childhood ADHD, and the contribution of this gene and its variants to the pathogenesis of ADHD is not yet known. Previous studies have showed that genetic defects in beta-mannosidase protein can result in beta-mannosidosis, a type of lysosomal storage disorder (LSD) (Wenger et al. 1986; Huynh et al. 2011), which is not only associated with a wide spectrum of peripheral neuropathy (Levade et al. 1994) but also implicated in various central nervous system (CNS) lesions, including mineralisation, especially in the cerebellum (Lovell and Jones 1983; 1985). Patients with these LSDs are often accompanied by psychiatric disturbances and cognitive impairments (Staretz-Chacham et al. 2010). Only about 20 severe beta-mannosidosis cases have been reported so far. Patients with beta-mannosidosis present heterogeneous clinical symptoms from childhood, including aggressiveness and hyperactivity (Staretz-Chacham et al. 2010; Gytz et al. 2019), one of the core symptoms of ADHD. In addition, developmental delay, mental retardation, speech impairment and seizures have also been reported (Gytz et al. 2019), all of which are comorbid or associated with ADHD (Bellani et al. 2011; Nickels et al. 2016; Ball et al. 2019; Sun et al. 2019). In addition, beta-mannosidase is very important for the development of the oculomotor nervous system, and its decreased activity is related to autosomal dominant nystagmus (Yu et al. 2015).