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Multiple sulfatase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
The enzyme, formylglycine-generating enzyme (FGE), catalyzes the oxidization of the cysteine residue at position 64 to 2-amino-3-oxopropionic acid. This is the amino acid which enables the sulfate ester hydrolysis. It is located in the ER [8].
Enzyme replacement combinational therapy: effective treatments for mucopolysaccharidoses
Published in Expert Opinion on Biological Therapy, 2021
Azam Safary, Hakimeh Moghaddas-Sani, Mostafa Akbarzadeh-Khiavi, Alireza Khabbazzi, Mohammad A. Rafi, Yadollah Omidi
Idursulfase (I2S, IDS, Elaprase®, α-L-iduronate sulfate sulfatase, EC: 3.1.6.13), as a recombinant form of human iduronate-2-sulfatase, has received FDA approval in 2006 for the treatment of MPS II. This enzyme is produced using genetic engineering in a continuous human cell line and is being intravenously injected at a dose of 0.5 mg/kg per week [11]. The idursulfase is a glycoprotein composed of 525 amino acids, containing eight N-linked glycosylation sites that are occupied by 2 bis-M6P containing oligosaccharide chains. All members of the sulfatase family undergo PTMs in the endoplasmic reticulum (ER). Cα-formylglycine (Cα-FGly) is a catalytic residue in the active site of the sulfatase enzymes and plays an essential role in their catalytic activity. In eukaryotes, it is generated in the rough ER of a conserved cysteine residue by a formylglycine-generating enzyme (FGE). Idursulfase as a member of the sulfatase family catalyzes the removal of the sulfate group from the 2-position of L-iduronic acid in DS and HS in the lysosomes [75]. Idursulfase beta is another approved ERT for Hunter syndrome, which is produced in the CHO cell line. Based on the biochemical and physicochemical comparison of two recombinant enzymes, idursulfase beta has a higher content of formylglycine and exhibits significantly greater specific enzymatic activity compared to the idursulfase. However, further clinical evaluations should be conducted to demonstrate the long-term efficacy and differentiation between these enzymes [76].
Antibody-drug conjugate library prepared by scanning insertion of the aldehyde tag into IgG1 constant regions
Published in mAbs, 2018
Betty C. B. Huang, Yun Cheol Kim, Stefanie Bañas, Robyn M. Barfield, Penelope M. Drake, Igor Rupniewski, William E. Haskins, David Rabuka
Since its introduction more than 10 years ago,1 the aldehyde tag has become accepted as a convenient, facile method for the site-specific introduction of a bioorthogonal chemical handle into a protein of interest. The chemical handle can be selectively ligated to a compatible linker/payload to yield a defined protein conjugate. Specifically, the aldehyde tag comprises a six amino acid sequence (LCTPSR) that serves as a recognition sequence for formylglycine generating enzyme (FGE). FGE oxidizes the cysteine (Cys) in the context of the recognition sequence to a formylglycine (fGly) residue containing an aldehyde, which serves as the bioorthogonally-reactive group. Compatible conjugation chemistries include the Hydrazinyl Iso-Pictet-Spengler (HIPS) ligation and the trapped-Knoevenagel ligation, both of which result in stable C-C bonds.2,3
Adeno-associated virus (AAV) capsid engineering in liver-directed gene therapy
Published in Expert Opinion on Biological Therapy, 2021
Esther Rodríguez-Márquez, Nadja Meumann, Hildegard Büning
An alternative strategy used an aldehyde tag – inserted at I-587 of the AAV2 capsid – as acceptor. The inserted sequence is sensed by the cellular formylglycine generating enzyme, which converts cysteine to an aldehyde-bearing formylglycine residue. This residue then allows for site-specific and chemoselective modification of the capsid with hydrazide- or aminooxy-functionalized partners, such as peptides, antibodies, and fluorophores. Applying this strategy, Liu and colleagues labeled AAV2 with the fluorophore Alexa488-hydrazide or targeted the capsid to HLA-expressing cells via a mouse monoclonal antibody against human leukocyte antigen (HLA) [110].