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Journal of Internal Medicine May 2022Acute hepatic porphyria (AHP) is a group of inherited metabolic disorders that affect hepatic heme biosynthesis. They are associated with attacks of neurovisceral... (Review)
Review
Acute hepatic porphyria (AHP) is a group of inherited metabolic disorders that affect hepatic heme biosynthesis. They are associated with attacks of neurovisceral manifestations that can be life threatening and constitute what is considered an acute porphyria attack. Until recently, the sole specific treatment for acute porphyria attacks consisted of the intravenous administration of hemin. Although attacks are often sporadic, some patients develop recurrent acute attacks, with devastating effects on quality of life. Liver transplantation has historically been the sole curative treatment option. The clinical manifestations of AHP are attributed to the accumulation of the heme precursor 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Advances in molecular engineering have provided new therapeutic possibilities for modifying the heme synthetic pathway. We reviewed the background and current status of AHP treatment using liver-directed small interfering RNA targeting ALAS1. The therapeutic aim was to normalize the levels of ALAS1, which is highly upregulated during acute porphyria attacks. Givosiran is now an approved drug for use in adults and adolescents aged 12 years and older. The results of clinical trials have shown that givosiran treatment leads to a rapid and sustained reduction of ALAS1 mRNA, decreased heme precursor levels, and a decreased rate of acute attacks compared with placebo. The clinical trials (phases I, II, and III) were all randomized and placebo controlled. Many patients enrolled in the initial clinical trials have continued treatment in open label extension and extended/compassionate-use programs in countries where givosiran is not yet commercially available.
Topics: Acetylgalactosamine; Adolescent; Adult; Heme; Humans; Incidence; Porphobilinogen Synthase; Porphyria, Acute Intermittent; Porphyrias, Hepatic; Pyrrolidines; Quality of Life; RNAi Therapeutics
PubMed: 35067977
DOI: 10.1111/joim.13443 -
Pharmacological Research Nov 2021The growing use of short-interfering RNA (siRNA)-based therapeutics for viral diseases reflects the most recent innovations in anti-viral vaccines and drugs. These drugs... (Review)
Review
The growing use of short-interfering RNA (siRNA)-based therapeutics for viral diseases reflects the most recent innovations in anti-viral vaccines and drugs. These drugs play crucial roles in the fight against many hitherto incurable diseases, the causes, pathophysiologies, and molecular processes of which remain unknown. Targeted liver drug delivery systems are in clinical trials. The receptor-mediated endocytosis approach involving the abundant asialoglycoprotein receptors (ASGPRs) on the surfaces of liver cells show great promise. We here review N-acetylgalactosamine (GalNAc)-siRNA conjugates that treat viral diseases such as hepatitis B infection, but we also mention that novel, native conjugate-based, targeted siRNA anti-viral drugs may also cure several life-threatening diseases such as hemorrhagic cystitis, multifocal leukoencephalopathy, and severe acute respiratory syndrome caused by coronaviruses and human herpes virus.
Topics: Acetylgalactosamine; Animals; Humans; RNA Interference; RNA, Small Interfering; Virus Diseases; Viruses
PubMed: 34474100
DOI: 10.1016/j.phrs.2021.105864 -
Journal of Inherited Metabolic Disease Jul 2021
Topics: Acetylgalactosamine; Homocysteine; Humans; Porphyria, Acute Intermittent; Pyrrolidines
PubMed: 34145602
DOI: 10.1002/jimd.12411 -
The Journal of Physical Chemistry. A Oct 2022In the present work, we report the first rotational study of -acetylgalactosamine, a cancer-associated sugar derivative, by means of high-resolution rotational...
In the present work, we report the first rotational study of -acetylgalactosamine, a cancer-associated sugar derivative, by means of high-resolution rotational spectroscopy. Two different conformers have been conclusively characterized using broadband Fourier transform microwave spectroscopy coupled with a laser ablation vaporization system. Additionally, we performed a comprehensive analysis of the intramolecular interactions that govern these structures, which allowed us to both characterize the existence of intramolecular hydrogen bond networks that drive the intrinsic conformation panorama of -acetylgalactosamine and further rationalize the biological role of this aminosugar derivative as part of the Tn antigen.
Topics: Humans; Acetylgalactosamine; Molecular Conformation; Hydrogen Bonding; Organic Chemicals; Neoplasms; Sugars
PubMed: 36099577
DOI: 10.1021/acs.jpca.2c04595 -
Blood Jan 2019Regular prophylaxis with factor VIII (FVIII) or FIX products to prevent bleeding in patients with severe hemophilia A (HA) and HB, respectively, results in marked... (Review)
Review
Regular prophylaxis with factor VIII (FVIII) or FIX products to prevent bleeding in patients with severe hemophilia A (HA) and HB, respectively, results in marked suppression of the onset of arthropathy and contributes greatly to improvements in quality of life. Some issues remain with the use of clotting factor replacement therapy, however. The need for multiple IV infusions is associated with a substantial mental and physical burden, and the hemostatic effect of bypassing agents (BPAs) in patients with inhibitor is inconsistent. The development of subcutaneous products with prolonged hemostatic efficiency, irrespective of the presence of inhibitors, has been a longtime wish for patients. A new class of therapeutic agents that act by enhancing coagulation (emicizumab) and inhibiting anticoagulant pathways (fitusiran and concizumab) have been established, and clinical trials using these nonfactor products are ongoing. The current findings have demonstrated that prophylaxis by nonfactor products supports marked reductions of bleeding episodes in hemophilia patients with or without inhibitor. Emicizumab has already been approved for use internationally. Some concerns are evident, however. Thrombotic microangiopathy and thromboembolism have occurred in 5 emicizumab-treated patients receiving repeated infusions of activated prothrombin complex concentrates, and a sinus vein thrombosis has occurred in a fitusiran-treated patient receiving repeated infusions of FVIII product. Moreover, reliable techniques to monitor hemostatic function in patients receiving nonfactor products with concomitant BPA or FVIII/FIX therapies require further assessment. These novel therapeutic agents have promising hemostatic properties, although wider experience in hemophilia centers is warranted to establish appropriate therapeutic strategies.
Topics: Acetylgalactosamine; Animals; Antibodies, Bispecific; Antibodies, Monoclonal, Humanized; Blood Coagulation; Coagulants; Hemophilia A; Hemophilia B; Hemostasis; Humans; RNA, Small Interfering; Thromboembolism
PubMed: 30559263
DOI: 10.1182/blood-2018-07-820712 -
Advanced Healthcare Materials May 2023Peptide nucleic acids (PNAs) are used/applied in various studies to target genomic DNA and RNA to modulate gene expression. Non-specific targeting and rapid elimination...
Peptide nucleic acids (PNAs) are used/applied in various studies to target genomic DNA and RNA to modulate gene expression. Non-specific targeting and rapid elimination always remain a challenge for PNA-based applications. Here, the synthesis, characterization, in vitro and in vivo study of di lactobionic acid (diLBA) and tris N-acetyl galactosamine (tGalNAc) conjugated PNAs for liver-targeted delivery are reported. For proof of concept, diLBA, and tGalNAc conjugated PNAs (anti-miR-122 PNAs) were synthesized to target microRNA-122 (miR-122) which is over-expressed in the hepatic tissue. Different lengths of anti-miR-122 PNAs conjugated with diLBA and tGalNAc are tested. Cell culture and in vivo analyses to determine biodistribution, efficacy, and toxicity profile are performed. This work indicates that diLBA conjugates show significant retention in hepatocytes in addition to tGalNAc conjugates after in vivo delivery. Full-length PNA conjugates show significant downregulation of miR-122 levels and subsequent de-repression of its downstream targets with no evidence of toxicity. The results provide a robust framework for ligand-conjugated delivery systems for PNAs that can be explored for broader biomedical applications.
Topics: Peptide Nucleic Acids; Acetylgalactosamine; Tissue Distribution; Antagomirs; Hepatocytes
PubMed: 36636995
DOI: 10.1002/adhm.202202859 -
Nature Communications May 2024β-N-Acetylgalactosamine-containing glycans play essential roles in several biological processes, including cell adhesion, signal transduction, and immune responses....
β-N-Acetylgalactosamine-containing glycans play essential roles in several biological processes, including cell adhesion, signal transduction, and immune responses. β-N-Acetylgalactosaminidases hydrolyze β-N-acetylgalactosamine linkages of various glycoconjugates. However, their biological significance remains ambiguous, primarily because only one type of enzyme, exo-β-N-acetylgalactosaminidases that specifically act on β-N-acetylgalactosamine residues, has been documented to date. In this study, we identify four groups distributed among all three domains of life and characterize eight β-N-acetylgalactosaminidases and β-N-acetylhexosaminidase through sequence-based screening of deep-sea metagenomes and subsequent searching of public protein databases. Despite low sequence similarity, the crystal structures of these enzymes demonstrate that all enzymes share a prototype structure and have diversified their substrate specificities (oligosaccharide-releasing, oligosaccharide/monosaccharide-releasing, and monosaccharide-releasing) through the accumulation of mutations and insertional amino acid sequences. The diverse β-N-acetylgalactosaminidases reported in this study could facilitate the comprehension of their structures and functions and present evolutionary pathways for expanding their substrate specificity.
Topics: Metagenome; Substrate Specificity; Acetylgalactosamine; Glycoside Hydrolases; beta-N-Acetylhexosaminidases; Phylogeny; Crystallography, X-Ray; Amino Acid Sequence; Animals
PubMed: 38730244
DOI: 10.1038/s41467-024-47653-2 -
Molecules (Basel, Switzerland) Jul 2011N-Acetylhexosamine 1-kinase (NahK) catalyzes the direct addition of a phosphate from adenosine 5'-triphosphate (ATP) to the anomeric position of N-acetylhexosamine and...
N-Acetylhexosamine 1-kinase (NahK) catalyzes the direct addition of a phosphate from adenosine 5'-triphosphate (ATP) to the anomeric position of N-acetylhexosamine and shows similar activity towards N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc). Herein we report the cloning, characterization, and substrate specificity studies of two NahKs from Bifidobacterium infantis ATCC15697 and Bifidobacterium longum ATCC55813, respectively. A new capillary electrophoresis assay method has been developed for enzyme activity assays. Both enzymes have a good expression level in E. coli (180-185 mg/L culture) and can tolerate diverse modifications at C2 of GlcNAc and GalNAc. Various GlcNAc derivatives with C6, both C2 and C6, as well as both C2 and C3 modifications are tolerable substrates for the newly cloned NahKs. Quite interestingly, despite of their low activities toward glucose and galactose, the activities of both NahKs are much higher for mannose and some of its C2, C4, and C6 derivatives. These NahKs are excellent catalysts for enzymatic and chemoenzymatic synthesis of carbohydrates.
Topics: Acetylgalactosamine; Acetylglucosamine; Adenosine Triphosphate; Amino Acid Sequence; Bifidobacterium; Carbohydrate Conformation; Cloning, Molecular; Electrophoresis, Capillary; Electrophoresis, Polyacrylamide Gel; Escherichia coli; Galactose; Glucose; Hydrogen-Ion Concentration; Isoenzymes; Kinetics; Mannose; Molecular Sequence Data; Phosphates; Phosphotransferases; Plasmids; Protein Engineering; Recombinant Proteins; Substrate Specificity; Transformation, Bacterial
PubMed: 21799473
DOI: 10.3390/molecules16086396 -
Biomolecules Jan 2022The brain N-glycome is known to be crucial for many biological functions, including its involvement in neuronal diseases. Although large structural studies of brain...
The brain N-glycome is known to be crucial for many biological functions, including its involvement in neuronal diseases. Although large structural studies of brain N-glycans were recently carried out, a comprehensive isomer-specific structural analysis has still not been achieved, as indicated by the recent discovery of novel structures with galactosylated bisecting GlcNAc. Here, we present a detailed, isomer-specific analysis of the human brain N-glycome based on standardized porous graphitic carbon (PGC)-LC-MS/MS. To achieve this goal, we biosynthesized glycans with substitutions typically occurring in the brain N-glycome and acquired their normalized retention times. Comparison of these values with the standardized retention times of neutral and desialylated N-glycan fractions of the human brain led to unambiguous isomer specific assignment of most major peaks. Profound differences in the glycan structures between naturally neutral and desialylated glycans were found. The neutral and sialylated N-glycans derive from diverging biosynthetic pathways and are biosynthetically finished end products, rather than just partially processed intermediates. The focus on structural glycomics defined the structure of human brain N-glycans, amongst these are HNK-1 containing glycans, a bisecting sialyl-lactose and structures with fucose and -acetylgalactosamine on the same arm, the so-called LDNF epitope often associated with parasitic worms.
Topics: Acetylgalactosamine; Brain; Brain Chemistry; Chromatography, Liquid; Fucose; Glycomics; Graphite; Humans; Lactose; Sialic Acids; Tandem Mass Spectrometry
PubMed: 35053234
DOI: 10.3390/biom12010085 -
Communications Biology May 2022The genetic capacity to synthesize the biofilm matrix exopolysaccharide Pel is widespread among Gram-negative and Gram-positive bacteria. However, its exact chemical...
The genetic capacity to synthesize the biofilm matrix exopolysaccharide Pel is widespread among Gram-negative and Gram-positive bacteria. However, its exact chemical structure has been challenging to determine. Using a Pseudomonas aeruginosa strain engineered to overproduce Pel, improvements to the isolation procedure, and selective hydrolysis with the glycoside hydrolase PelA, we demonstrate that Pel is a partially de-N-acetylated linear polymer of α-1,4-N-acetylgalactosamine comprised predominantly of dimeric repeats of galactosamine and N-acetylgalactosamine.
Topics: Acetylgalactosamine; Biofilms; Galactosamine; Polymers; Polysaccharides, Bacterial
PubMed: 35618750
DOI: 10.1038/s42003-022-03453-2