Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes.
FMO3
TMAU
genetic variants
in silico
proteomics
Journal
Molecules (Basel, Switzerland)
ISSN: 1420-3049
Titre abrégé: Molecules
Pays: Switzerland
ID NLM: 100964009
Informations de publication
Date de publication:
22 Nov 2021
22 Nov 2021
Historique:
received:
23
07
2021
revised:
10
11
2021
accepted:
19
11
2021
entrez:
27
11
2021
pubmed:
28
11
2021
medline:
15
12
2021
Statut:
epublish
Résumé
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 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. The Even if further functional assays will confirm our predictive results, considering the possible role of
Sections du résumé
BACKGROUND
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
METHODS
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
RESULTS
The
CONCLUSIONS
CONCLUSIONS
Even if further functional assays will confirm our predictive results, considering the possible role of
Identifiants
pubmed: 34834137
pii: molecules26227045
doi: 10.3390/molecules26227045
pmc: PMC8618768
pii:
doi:
Substances chimiques
Methylamines
0
Oxygenases
EC 1.13.-
dimethylaniline monooxygenase (N-oxide forming)
EC 1.14.13.8
trimethylamine
LHH7G8O305
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Références
J Comput Chem. 2005 Dec;26(16):1701-18
pubmed: 16211538
Drug Metab Rev. 2002 Aug;34(3):523-32
pubmed: 12214664
Eur Heart J. 2019 Feb 14;40(7):583-594
pubmed: 30535398
J Inherit Metab Dis. 2006 Feb;29(1):162-72
pubmed: 16601883
Nat Methods. 2015 Jan;12(1):7-8
pubmed: 25549265
Drug Discov Today. 2020 Sep;25(9):1710-1717
pubmed: 32615074
J Pers Med. 2021 Jan 31;11(2):
pubmed: 33572540
Clin Chim Acta. 1997 Sep 8;265(1):85-97
pubmed: 9352132
Pharmacogenetics. 2003 Aug;13(8):495-500
pubmed: 12893987
Methods Mol Biol. 1999;112:531-52
pubmed: 10027275
JIMD Rep. 2020 Oct 06;57(1):67-75
pubmed: 33473342
Proc Natl Acad Sci U S A. 2011 Oct 25;108(43):17791-6
pubmed: 22006322
Mol Biol Rep. 2018 Oct;45(5):1349-1355
pubmed: 30099685
J Dig Dis. 2016 Sep;17(9):628-632
pubmed: 27335202
Expert Rev Mol Med. 2016 Apr 29;18:e8
pubmed: 27126549
Gene. 2013 Feb 25;515(2):410-5
pubmed: 23266626
J Nerv Ment Dis. 2013 Jun;201(6):537-8
pubmed: 23719328
J Biochem. 1980 Dec;88(6):1895-8
pubmed: 7462208
JIMD Rep. 2019 Mar 25;47(1):35-40
pubmed: 31240165
J Med Case Rep. 2014 Oct 06;8:328
pubmed: 25288227
Phys Rev Lett. 2006 Oct 27;97(17):170201
pubmed: 17155444
Drug Metab Dispos. 2016 Nov;44(11):1839-1850
pubmed: 27190056
Protein Sci. 2021 Jan;30(1):70-82
pubmed: 32881101
Arch Biochem Biophys. 2021 Jan 15;697:108663
pubmed: 33152328
Mol Genet Metab. 2001 Jul;73(3):224-9
pubmed: 11461189
Life Sci. 2004 Apr 16;74(22):2739-47
pubmed: 15043988
J Comput Chem. 2010 Jan 30;31(2):455-61
pubmed: 19499576
Mutat Res. 2006 Jun;612(3):165-171
pubmed: 16481213
JIMD Rep. 2012;5:71-5
pubmed: 23430919
J Comput Aided Mol Des. 2019 Aug;33(8):705-727
pubmed: 31435895
JIMD Rep. 2014;12:11-5
pubmed: 23821320
J Mol Graph Model. 2018 Sep;84:134-144
pubmed: 29975864
Horm Mol Biol Clin Investig. 2014 Dec;20(3):99-109
pubmed: 25460299
J Clin Pharm Ther. 2021 Apr;46(2):304-309
pubmed: 33247860
PLoS One. 2013 Aug 05;8(8):e70166
pubmed: 23940542