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Article

Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes

by
Simona Alibrandi
1,2,
Fabiana Nicita
1,
Luigi Donato
1,3,*,
Concetta Scimone
1,3,
Carmela Rinaldi
1,
Rosalia D’Angelo
1 and
Antonina Sidoti
1
1
Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, 98125 Messina, Italy
2
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98125 Messina, Italy
3
Department of Biomolecular Strategies, Genetics, Cutting-Edge Therapies, I.E.ME.S.T., 90139 Palermo, Italy
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(22), 7045; https://doi.org/10.3390/molecules26227045
Submission received: 23 July 2021 / Revised: 10 November 2021 / Accepted: 19 November 2021 / Published: 22 November 2021
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications)
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Abstract

Background: Trimethylaminuria (TMAU) is a rare genetic disease characterized by the accumulation of trimethylamine (TMA) and its subsequent excretion trough main body fluids, determining the characteristic fish odour in affected patients. We realized an experimental study to investigate the role of several coding variants in the causative gene FMO3, that were only considered as polymorphic or benign, even if the available literature on them did not functionally explain their ineffectiveness on the encoded enzyme. Methods: Mutational analysis of 26 TMAU patients was realized by Sanger sequencing. Detected variants were, subsequently, deeply statistically and in silico characterized to determine their possible effects on the enzyme activity. To achieve this goal, a docking prediction for TMA/FMO3 and an unbinding pathway study were performed. Finally, a TMAO/TMA urine quantification by 1H-NMR spectroscopy was performed to support modelling results. Results: The FMO3 screening of all patients highlighted the presence of 17 variants distributed in 26 different haplotypes. Both non-sense and missense considered variants might impair the enzymatic kinetics of FMO3, probably reducing the interaction time between the protein catalytic site and TMA, or losing the wild-type binding site. Conclusions: Even if further functional assays will confirm our predictive results, considering the possible role of FMO3 variants with still uncertain effects, might be a relevant step towards the detection of novel scenarios in TMAU etiopathogenesis.
Keywords: FMO3; TMAU; in silico; proteomics; genetic variants FMO3; TMAU; in silico; proteomics; genetic variants
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MDPI and ACS Style

Alibrandi, S.; Nicita, F.; Donato, L.; Scimone, C.; Rinaldi, C.; D’Angelo, R.; Sidoti, A. Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes. Molecules 2021, 26, 7045. https://doi.org/10.3390/molecules26227045

AMA Style

Alibrandi S, Nicita F, Donato L, Scimone C, Rinaldi C, D’Angelo R, Sidoti A. Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes. Molecules. 2021; 26(22):7045. https://doi.org/10.3390/molecules26227045

Chicago/Turabian Style

Alibrandi, Simona, Fabiana Nicita, Luigi Donato, Concetta Scimone, Carmela Rinaldi, Rosalia D’Angelo, and Antonina Sidoti. 2021. "Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes" Molecules 26, no. 22: 7045. https://doi.org/10.3390/molecules26227045

APA Style

Alibrandi, S., Nicita, F., Donato, L., Scimone, C., Rinaldi, C., D’Angelo, R., & Sidoti, A. (2021). Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes. Molecules, 26(22), 7045. https://doi.org/10.3390/molecules26227045

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