Nicotiana benthamiana α-galactosidase A1.1 can functionally complement human α-galactosidase A deficiency associated with Fabry disease

Abstract

ABSTRACTα-Galactosidases (EC 3.2

Effects of Enzyme Replacement Therapy and Antidrug Antibodies in Patients with Fabry Disease

“…The increased t 1/2 of 80 hours of pegunigalsidase a (the result of PEG-mediated crosslinking of the GLA homodimer) is especially promising. 122 Another potentially promising approach is the identification of GLA enzymes, as recently described by Kytidou et al 123 who reported a GLA homolog from Nicotiana benthamiana that did not crossreact with ADAs from patients treated with currently approved ERT. It will be of interest whether these approaches or the infusion of a nonapproved double-dose (infused every 4 weeks) might also lead to a reduction of existing ADA titers.…”

Plant Glycosides and Glycosidases: A Treasure-Trove for Therapeutics

“…Enzymes of several families have been identified and functionally characterized using ABPs, such as serine hydrolases (Kaschani et al, 2009), papain-like cysteine proteases (Richau et al, 2012) and cysteine proteases (Lu et al, 2015). In addition, retaining glycosidases of different plant species have been characterized and identified (Chandrasekar et al, 2014;Husaini et al, 2018;Kytidou et al, 2018). The use of ABPs as functional tool for studying retaining glycosidases in plants was first reported by the group of Chandrasekar et al (2014).…”

“…The enzyme was then overexpressed in N. benthamiana leaves, purified and further biochemically characterized. One of the most important findings was that A1.1 proves to be able to hydrolyze human glycosphingolipids in vitro and in situ and might find applications in the treatment of Fabry disease, caused by deficiency of the human α-galactosidase (Kytidou et al, 2018). Therapeutic application of a plant enzyme, discovered with an ABP, for treatment of a human metabolic disease can be thus be envisioned (Figures 3B,C).…”

“…The ubiquitous plant glycosidases themselves might conceivably find therapeutic applications in humans and might have potential to treat inherited glycosidase deficiencies in man (Kytidou et al, 2018). Overall, ABPs may help to identify plant glycosidases of interest.…”

Recombinant production and characterization of six novel GH27 and GH36 α-galactosidases from Penicillium subrubescens and their synergism with a commercial mannanase during the hydrolysis of lignocellulosic biomass

“…4) Based on homology with an α-galactosidase of Nicotania benthamiana (PDB ID: 6F4C) from GH27, whose catalytic residues have been identified, it is highly probable that the catalytic residues of AglA are Asp 131 and Asp 201 , whereas in the active site other amino acids appear involved in substrate recognition (Table 4, Fig. 5A) (Kytidou et al, 2018). Nonetheless, a short insertion of seven residues (PAYFSEN) located in the position β27 of the vicinity of the catalytic site was observed in the AglA structure (Fig.…”