Structure of Dihydromethanopterin Reductase, a Cubic Protein Cage for Redox Transfer

Structure of Dihydromethanopterin Reductase, a Cubic Protein Cage for Redox Transfer

Dihydromethanopterin reductase (Dmr) is a redox enzyme that plays a key role in generating tetrahydromethanopterin (H4MPT) for use in one-carbon metabolism by archaea and some bacteria. DmrB is a bacterial enzyme understood to reduce dihydromethanopterin (H2MPT) to H4MPT using flavins as the source...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry Vol. 289; no. 13; pp. 8852 - 8864
Main Authors: McNamara, Dan E., Cascio, Duilio, Jorda, Julien, Bustos, Cheene, Wang, Tzu-Chi, Rasche, Madeline E., Yeates, Todd O., Bobik, Thomas A.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 28-03-2014
American Society for Biochemistry and Molecular Biology
Subjects:
Archaea
Burkholderia
Burkholderia - enzymology
Catalytic Domain
Crystallography, X-Ray
Dihydromethanopterin Reductase
Electron Transport
Flavin Mononucleotide - metabolism
Flavoproteins
Methanopterin
Molecular Docking Simulation
Nanotechnology
Obesity
Oxidation-Reduction
Oxidoreductases - chemistry
Oxidoreductases - metabolism
Protein Structure and Folding
Pterin
Pterins - chemistry
Pterins - metabolism
Sequence Homology
Obesity
Dihydromethanopterin Reductase
Pterin
Archaea
Methanopterin
Burkholderia
Flavoproteins
Nanotechnology
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Dihydromethanopterin reductase (Dmr) is a redox enzyme that plays a key role in generating tetrahydromethanopterin (H4MPT) for use in one-carbon metabolism by archaea and some bacteria. DmrB is a bacterial enzyme understood to reduce dihydromethanopterin (H2MPT) to H4MPT using flavins as the source of reducing equivalents, but the mechanistic details have not been elucidated previously. Here we report the crystal structure of DmrB from Burkholderia xenovorans at a resolution of 1.9 Å. Unexpectedly, the biological unit is a 24-mer composed of eight homotrimers located at the corners of a cubic cage-like structure. Within a homotrimer, each monomer-monomer interface exhibits an active site with two adjacently bound flavin mononucleotide (FMN) ligands, one deeply buried and tightly bound and one more peripheral, for a total of 48 ligands in the biological unit. Computational docking suggested that the peripheral site could bind either the observed FMN (the electron donor for the overall reaction) or the pterin, H2MPT (the electron acceptor for the overall reaction), in configurations ideal for electron transfer to and from the tightly bound FMN. On this basis, we propose that DmrB uses a ping-pong mechanism to transfer reducing equivalents from FMN to the pterin substrate. Sequence comparisons suggested that the catalytic mechanism is conserved among the bacterial homologs of DmrB and partially conserved in archaeal homologs, where an alternate electron donor is likely used. In addition to the mechanistic revelations, the structure of DmrB could help guide the development of anti-obesity drugs based on modification of the ecology of the human gut. Background: Dihydromethanopterin reductase catalyzes the final step of methanopterin biosynthesis. Results: The crystal structure is a 24-subunit cubic protein cage with 48 molecules of bound FMN. Conclusion: Analyses indicate a reaction mechanism in which distinct FMNs act as cofactor and electron donor. Significance: The structures illuminate a new mechanism for pterin reduction and reveal an extraordinarily elaborate assembly for electron transfer in the cell.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M113.522342