Ancestral-sequence reconstruction unveils the structural basis of function in mammalian FMOs

Nicoll, Callum R.; Bailleul, Gautier; Fiorentini, Filippo; Mascotti, María Laura; Fraaije, Marco W.; Mattevi, Andrea

doi:10.1038/s41594-019-0347-2

Cited by 78 publications

(98 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This establishment of three-dimensional structures of BFMOs guides the intimate understanding of substrate preference and can ultimately aid in the prediction of potential substrates, or the identification of key residues for enzyme function modification. Regarding the reconstructed human FMOs, enzyme structure revealed an apparent substrate tunnel and enables the docking of candidate molecules based on their size and hydrophobicity [107]. Similarly, crystallization of a BVMO facilitated insights in cofactor binding and orientation.…”

Section: A Need For Structural Insights Of Plant Fmosmentioning

confidence: 99%

“…It was then not until 2018, that a BFMO from a multicellular organism was crystalized: The ZNO pyrrolizidine alkaloids monooxygenase from the grasshopper species Zonocerus variegatus [106]. Most recently, ancestral reconstructed human FMO1, 3 and 5 were crystalized [107]. Here, the ancestral sequences are 90 percent identical to extant versions and maintain their functions completely.…”

Section: A Need For Structural Insights Of Plant Fmosmentioning

confidence: 99%

“…Notably, all published structures of Class B flavin-dependent monooxygenase suggest they operate in a homo-dimeric organization [32,[104][105][106][107]. Albeit this oligomerization is not reported directly for plant FMOs, such organization is very plausible and should be considered when plant FMOs are handled (e.g., enzyme purification and screening).…”

Section: A Need For Structural Insights Of Plant Fmosmentioning

confidence: 99%

“…While FMOs are relatively underused in industry at present, several bacterial FMOs are exploited for commercial pursuits, for example, in the pharmaceutical and dye industries [20,122]. The relatively limited use of FMOs as biocatalysts today is partly due to the restricted availability of enzymes, both in terms of their expression and isolation [1], although some successful strategies have be employed to address these limitations [107].…”

Section: The Unexploited Potential Of Plant Fmos For Agriculture and mentioning

confidence: 99%

See 3 more Smart Citations

The “Green” FMOs: Diversity, Functionality and Application of Plant Flavoproteins

Thodberg

Neilson

2020

Catalysts

View full text Add to dashboard Cite

Flavin-dependent monooxygenases (FMOs) are ancient enzymes present in all kingdoms of life. FMOs typically catalyze the incorporation of an oxygen atom from molecular oxygen into small molecules. To date, the majority of functional characterization studies have been performed on mammalian, fungal and bacterial FMOs, showing that they play fundamental roles in drug and xenobiotic metabolism. By contrast, our understanding of FMOs across the plant kingdom is very limited, despite plants possessing far greater FMO diversity compared to both bacteria and other multicellular organisms. Here, we review the progress of plant FMO research, with a focus on FMO diversity and functionality. Significantly, of the FMOs characterized to date, they all perform oxygenation reactions that are crucial steps within hormone metabolism, pathogen resistance, signaling and chemical defense. This demonstrates the fundamental role FMOs have within plant metabolism, and presents significant opportunities for future research pursuits and downstream applications.

show abstract

Section: A Need For Structural Insights Of Plant Fmosmentioning

confidence: 99%

Section: A Need For Structural Insights Of Plant Fmosmentioning

confidence: 99%

Section: A Need For Structural Insights Of Plant Fmosmentioning

confidence: 99%

Section: The Unexploited Potential Of Plant Fmos For Agriculture and mentioning

confidence: 99%

See 2 more Smart Citations

The “Green” FMOs: Diversity, Functionality and Application of Plant Flavoproteins

Thodberg

Neilson

2020

Catalysts

View full text Add to dashboard Cite

show abstract

“…FMO3 and FMO6 arose from a more recent duplication that took place early during mammalian evolution 9 . Based on a phylogenetic analysis, Nicoll et al 8 reconstructed ancestral sequences for three mammalian FMOs: FMO2, FMO5 and the precursor of FMO3/6. The ancestral FMOs, which have 83-92% amino-acid sequence identity with the corresponding extant human FMO, were expressed in E. coli as holoenzymes, bound to their prosthetic group FAD.…”

mentioning

confidence: 99%

Flavin-containing monooxygenases: new structures from old proteins

Phillips

Shephard

2019

Nat Struct Mol Biol

View full text Add to dashboard Cite

A recent study reports the structures of reconstructed ancestral mammalian flavin-containing monooxygenases (FMOs), which are the first to be solved for membrane-bound FMOs. The resulting models provide a structural basis for the mechanism of action of these enzymes and greatly enhance our understanding of how the proteins interact with membranes and how they permit access of substrates to their active site. FMOs catalyze the oxidative metabolism of a range of chemicals, which include drugs, pesticides and compounds derived from the diet by the action of gut bacteria 1-4. The enzymes act at the interface between an organism and its chemical environment to play an important role in protection against potentially harmful foreign chemicals. Some FMOs are also involved in endogenous metabolic processes: in the regulation of energy balance 5 , metabolic ageing 6 and glucose homeostasis 7. In vertebrates FMOs are located in the membranes of the endoplasmic reticulum and have proved, to date, impossible to crystallize. Recently, based on the reconstruction of ancestral mammalian FMO sequences, Nicoll et al. 8 reported the crystallization and structures of three membrane-bound FMOs. This major advance provides a structural basis for the catalytic mechanism of FMOs and gives novel insights into how the enzymes bind to membranes and control access to their catalytic site.

show abstract

Flavoprotein Monooxygenases and Halogenases

Paul

Guarneri

Berkel

2021

Flavin‐Based Catalysis

View full text Add to dashboard Cite

Article 25fa states that the author of a short scientific work funded either wholly or partially by Dutch public funds is entitled to make that work publicly available for no consideration following a reasonable period of time after the work was first published, provided that clear reference is made to the source of the first publication of the work.This publication is distributed under The Association of Universities in the Netherlands (VSNU) 'Article 25fa implementation' project. In this project research outputs of researchers employed by Dutch Universities that comply with the legal requirements of Article 25fa of the Dutch Copyright Act are distributed online and free of cost or other barriers in institutional repositories. Research outputs are distributed six months after their first online publication in the original published version and with proper attribution to the source of the original publication.

show abstract

Ancestral-sequence reconstruction unveils the structural basis of function in mammalian FMOs

Abstract: Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Cited by 78 publications

References 84 publications

The “Green” FMOs: Diversity, Functionality and Application of Plant Flavoproteins

The “Green” FMOs: Diversity, Functionality and Application of Plant Flavoproteins

Flavin-containing monooxygenases: new structures from old proteins

Flavoprotein Monooxygenases and Halogenases

Contact Info

Product

Resources

About