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Mechanism of molybdate insertion into pterin-based molybdenum cofactors

Nature Chemistry volume 13, pages 758–765 (2021)Cite this article

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Abstract

The molybdenum cofactor (Moco) is found in the active site of numerous important enzymes that are critical to biological processes. The bidentate ligand that chelates molybdenum in Moco is the pyranopterin dithiolene (molybdopterin, MPT). However, neither the mechanism of molybdate insertion into MPT nor the structure of Moco prior to its insertion into pyranopterin molybdenum enzymes is known. Here, we report this final maturation step, where adenylated MPT (MPT–AMP) and molybdate are the substrates. X-ray crystallography of the Arabidopsis thaliana Mo-insertase variant Cnx1E S269D D274S identified adenylated Moco (Moco–AMP) as an unexpected intermediate in this reaction sequence. X-ray absorption spectroscopy revealed the first coordination sphere geometry of Moco trapped in the Cnx1E active site. We have used this structural information to deduce a mechanism for molybdate insertion into MPT–AMP. Given their high degree of structural and sequence similarity, we suggest that this mechanism is employed by all eukaryotic Mo-insertases.

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Fig. 1: The four steps of Moco biosynthesis.
Fig. 2: Structure of Cnx1E variant S269D D274S with bound ligands.
Fig. 3: Moco–AMP dihedrals.
Fig. 4: Mo K-edge XAS spectra.
Fig. 5: Proposed reaction mechanism for Cnx1E-catalysed Mo insertion.

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Data availability

The protein structure data that support the findings of this study are publicly available from the Protein Data Bank (https://www.rcsb.org/) with accession code 6Q32. We deposited the protein structure along with the structure factor data file that allows for the re-computing and re-evaluation of the structure. Figures 2 and 3 and Supplementary Figs. 3, 4 and Extended Data Fig. 1 are associated with these raw data. Manuscript datasets are available as Supplementary Data files.

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Acknowledgements

We thank A. Calean (TU Braunschweig) for excellent support with inductively coupled plasma mass spectrometry analysis. M.L.K. gratefully acknowledges support of this research by the National Institutes of Health (grant no. GM-057378). M.L.K. and J.Y. thank the UNM Center for Advanced Research Computing, supported in part by the National Science Foundation, for providing the computing resources used in this work. Work at Caltech was supported by the National Institutes of Health (NIH) grant no. GM045162. We acknowledge the Gordon and Betty Moore Foundation and the Beckman Institute at Caltech for their support of the Molecular Observatory at Caltech and the staff at beamlines 12-2 and 7-3. M.L.K. and J.Y. acknowledge the Stanford Synchrotron Radiation Lightsource, which is supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-76SF00515. R.R.M. and T.K. acknowledge the support of this research by the Deutsche Forschungsgemeinschaft (GRK 2223/1). Correspondence and requests for materials should be addressed to M.L.K. and T.K.

Author information

Author notes

  1. These authors contributed equally: Corinna Probst, Jing Yang, Joern Krausze.

  2. These authors jointly supervised this work: Martin L. Kirk, Tobias Kruse.

Authors and Affiliations

  1. Institute of Plant Biology, Technische Universität Braunschweig, Braunschweig, Germany

    Corinna Probst, Joern Krausze, Thomas W. Hercher, Ralf R. Mendel & Tobias Kruse

  2. Department of Chemistry and Chemical Biology, The University of New Mexico, Albuquerque, NM, USA

    Jing Yang, Casseday P. Richers, Khadanand KC, Logan J. Giles & Martin L. Kirk

  3. Division of Chemistry and Chemical Engineering, Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, USA

    Thomas Spatzal & Douglas C. Rees

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Contributions

C.P. carried out acquisition, analysis and interpretation of data. J.Y. carried out acquisition, analysis and interpretation of XAS data and computed the reaction coordinate. J.K. analysed and interpreted the data. T.W.H. carried out acquisition, analysis and interpretation of data. C.P.R. synthesized and characterized the trioxo- and dioxo-molybdenum model compounds (2, 3 and 4) and analysed spectroscopic data. T.S. carried out acquisition, analysis and interpretation of data. K.K. assisted with the collection of XAS data. L.J.G. assisted with the collection of XAS data. D.C.R. and R.R.M. revised the manuscript. M.L.K. conceived the idea, performed design analysis and interpretation of the data, and drafted the manuscript. T.K. conceived the idea and design, analysed and interpreted the data, and drafted the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Martin L. Kirk or Tobias Kruse.

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The authors declare no competing interests.

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Peer review information Nature Chemistry thanks Partha Basu, Carola Schulzke and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 The proposed mechanism of molybdate insertion into the MPT dithiolene moiety.

a, Ground state of Cnx1E with a Mg2+-water complex bound. Mg2+ constitutes the cofactor for the Cnx1E catalyzed reaction25,30. b, Conformation of MPT-AMP bound in the active site of Cnx1G26. c, First state of the catalysis with the substrate molybdate bound to the entry site. The presence of molybdate in the entry site induces an unfavorable (tense) backbone conformation in Cnx1E29. d, The conformation of MPT-AMP found in Cnx1G is not compatible with the Cnx1E active site28. Hence, the MPT-AMP pterin moiety must re-orient upon transfer from Cnx1G to Cnx1E, mostly involving two bond rotations. e, Second state of the catalytic cycle with molybdate bound to the entry site and active site bound MPT-AMP. The orientation of the pterin moiety was derived from active site bound Moco-AMP identified in this work. f, The transfer of molybdate from the entry to the insertion site is assisted by the relaxation of the tense backbone conformation29. According to our model of molybdate insertion, one molybdate oxygen ligand is two-fold protonated by the MPT dithiolene function and released as water. Simultaneously, the sulfur to molybdenum bonds are formed: This mechanism begins with a proton transfer from the diacid form of the MPT dithiolene side chain to a molybdate oxygen. A second, less activated protonation on the same oxygen atom would then yield a [(MPT)MoO3(OH2)]2- transition state. This [(MPT)MoO3(OH2)]2-species is expected to possess a highly labile aqua ligand, which would subsequently dissociate from Mo along the reaction coordinate to yield a more stable trioxo [(MPT)MoO3]2- intermediate. A final protonation of basic [(MPT)MoO3]2- by a suitable Cnx1E active site residue (most likely residue Arg369) yields our XAS derived [(MPT)MoO2(OH)]1- structure for Cnx1E Moco-AMP (for details see Fig. 5 and supplementary Fig. 11). The protonated oxygen atom is marked by an asterisk. g, The Cnx1E active site with bound Moco-AMP.

Supplementary information

Supplementary Information

Supplementary Figs 1–11 and Tables 1–5.

Supplementary Data 1

Primary data (dioxo (3)) Fig. 4a.

Supplementary Data 2

Primary data (insertase pH 6) Fig. 4a.

Supplementary Data 3

Primary data (insertase pH 8) Fig. 4a.

Supplementary Data 4

Primary data (molybdate) Fig. 4a.

Supplementary Data 5

Primary data (trioxo (2)) Fig. 4a.

Supplementary Data 6

Evaluated data Fig. 4b.

Supplementary Data 7

Primary data Fig.4c.

Supplementary Data 8

Primary data Fig. 4e.

Supplementary Data 9

Primary data Fig. 4f.

Supplementary Data 10

Primary data Supplementary Fig. 5a.

Supplementary Data 11

Primary data Supplementary Fig. 5b.

Supplementary Data 12

Primary data Supplementary Fig. 5c.

Supplementary Data 13

Primary HPLC data and evaluated data Supplementary Fig. 1a, replicate 1.

Supplementary Data 14

Calibration report replicate 1, Supplementary Fig. 1a.

Supplementary Data 15

Primary HPLC data and evaluated data Supplementary Fig. 1a, replicates 2 and 3.

Supplementary Data 16

Calibration report replicates 2 and 3, Supplementary Fig. 1a.

Supplementary Data 17

Primary ICP-MS Data and evaluated Data Suppl. Fig.1 A, Replicates 1–3.

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Probst, C., Yang, J., Krausze, J. et al. Mechanism of molybdate insertion into pterin-based molybdenum cofactors. Nat. Chem. 13, 758–765 (2021). https://doi.org/10.1038/s41557-021-00714-1

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