New perspectives for pharmacological chaperoning treatment in methylmalonic aciduria cblB type |
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Authors: | S Brasil A Briso-Montiano A Gámez J Underhaug MI Flydal L Desviat B Merinero M Ugarte A Martinez B Pérez |
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Institution: | 1. Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, 28049 Madrid/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Investigación Sanitaria IdiPAZ, Madrid, Spain;2. Department of Chemistry, University of Bergen, Norway;3. Department of Biomedicine, University of Bergen, Norway;4. KG Jebsen Center for Neuropsychiatric Disorders, University of Bergen, Norway. |
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Abstract: | Methylmalonic aciduria cblB type (MMA cblB) is caused by the impairment of ATP:cob(I)alamin adenosyltransferase (ATR), the enzyme responsible for the synthesis of adenosylcobalamin (AdoCbl) from cob(I)alamin. No definitive treatment is available for patients with this condition and novel therapeutic strategies are therefore much needed. Recently, we described a proof-of-concept regarding the use of pharmacological chaperones as a treatment. This work describes the effect of two potential pharmacological chaperones - compound V (N-{(4-chlorophenyl)carbamothioyl]amino}-2-phenylacetamide) and compound VI (4-(4-(4-fluorophenyl)-5-methyl-1H-pyrazol-3-yl)benzene-1,3-diol) - on six ATR mutants, including the most common, p.Arg186Trp. Comprehensive functional analysis identified destabilizing (p.Arg186Gln, p.Arg190Cys, p.Arg190His, p.Arg191Gln and p.Glu193Lys) and oligomerization (p.Arg186Trp and p.Arg191Gln) mutations. In a cellular model overexpressing the destabilizing/oligomerization mutations, compounds V and VI had a positive effect on the stability and activity of all ATR variants. When provided in combination with hydroxocobalamin a more positive effect was obtained than with the compounds alone, even in mutations previously described as B12 non-responsive. In addition, a normal oligomerization profile was recovered after treatment of the p.Arg186Trp mutant with both compounds. These promising results confirm MMA cblB type as a conformational disorder and hence, pharmacological chaperones as a new therapeutic option alone or in combination with hydroxocobalamin for many patients with MMA cblB. |
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Keywords: | AdoCbl adenosylcobalamin ATR ATP:cob(I)alamin adenosyltransferase DSF differential scanning fluorimetry HGMD Human Gene Mutation Database HTS high-throughput screening iPSCs induced pluripotent stem cells MMA methylmalonic aciduria MUT methylmalonyl-CoA mutase OHCbl hydroxocobalamin PAINS pan assay interference compounds PCs pharmacological chaperones PR proteostasis regulators SMARTS Smiles Arbitrary Target Specifications Pharmacological chaperones ATR MMAB Destabilizing mutations |
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