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Structure–Function Analysis of Liver Flavin Monooxygenase 3 that Drives Trimethylaminuria in Humans

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Abstract

Mutations in human flavin monooxygenase-3 (hFMO3) enzyme have been implicated in the rare autosomal recessive disorder called trimethylaminuria (TMAU). In this inheritable disease, patients display elevated levels of trimethylamine (TMA) due to reduced or abolished N-oxygenation activity of the hFMO3 enzyme. TMA is a gas with characteristic fishy odour that is exuded in TMAU patients. Here, we have mapped forty-four TMAU-associated mutations on the atomic model of hFMO3, analyzed their spatial distributions and correlated these data with enzymatic implications of the mutants. The analysis suggests that hFMO3 mutations fall into distinct groups of six spatial clusters. The mutations are distributed throughout hFMO3 three-dimensional structure, and are either surface exposed or buried. In terms of catalytic activity, fifteen mutations abolish it, sixteen diminish it and the remaining thirteen mutations have not been unexplored experimentally. We have collated data on known xenobiotics and metabolites that interact with hFMO3 that can either serve as competitive inhibitors or drive production of secondary metabolites. The present study also reveals biochemical linkages between hFMO3 and few commonly used human drugs. These analyses thus provide a structural platform for understanding hFMO3 mutations and their enzymatic activities within the TMAU disease phenotype.

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Acknowledgements

This work was supported by JC Bose fellowship to Amit P. Sharma. One of the authors is supported by CSIR fellowship. The authors thank CB Indus, I Pantig and AG for constant encouragement. All the authors reviewed and approved the final version of the manuscript.

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Authors and Affiliations

  1. Molecular Medicine Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, 110067, India

    Jyoti Chhibber-Goel, Varsha Singhal, Anamika Gaur, Manickam Yogavel & Amit Sharma

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  1. Jyoti Chhibber-Goel
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  2. Varsha Singhal
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  3. Anamika Gaur
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  4. Manickam Yogavel
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  5. Amit Sharma
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Correspondence to Amit Sharma.

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Significance statement The human flavin monooxygenase 3 enzyme is linked to numerous diseases via its product trimethylamine-N-oxide. In the present study, the authors provide insights that reinforce the significance of understanding hFMO3 mutations and their effect on enzymatic activity.

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Chhibber-Goel, J., Singhal, V., Gaur, A. et al. Structure–Function Analysis of Liver Flavin Monooxygenase 3 that Drives Trimethylaminuria in Humans. Proc. Natl. Acad. Sci., India, Sect. B Biol. Sci. 88, 1681–1690 (2018). https://doi.org/10.1007/s40011-017-0913-5

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  • DOI: https://doi.org/10.1007/s40011-017-0913-5

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