Mechanism of pyranopterin ring formation in molybdenum cofactor biosynthesis
Abstract
The molybdenum cofactor (Moco) is essential for all kingdoms of life, plays central roles in various biological processes, and must be biosynthesized de novo. During Moco biosynthesis, the characteristic pyranopterin ring is constructed by a complex rearrangement of guanosine 5'-triphosphate (GTP) into cyclic pyranopterin (cPMP) through the action of two enzymes, MoaA and MoaC (molybdenum cofactor biosynthesis protein A and C, respectively). Conventionally, MoaA was considered to catalyze the majority of this transformation, with MoaC playing little or no role in the pyranopterin formation. Recently, this view was challenged by the isolation of 3',8-cyclo-7,8-dihydro-guanosine 5'-triphosphate (3',8-cH2GTP) as the product of in vitro MoaA reactions. To elucidate the mechanism of formation of Moco pyranopterin backbone, in this paper we performed biochemical characterization of 3',8-cH2GTP and functional and X-ray crystallographic characterizations of MoaC. These studies revealed that 3',8-cH2GTP is the only product of MoaA that can be converted to cPMP by MoaC. Our structural studies captured the specific binding of 3',8-cH2GTP in the active site of MoaC. These observations provided strong evidence that the physiological function of MoaA is the conversion of GTP to 3',8-cH2GTP (GTP 3',8-cyclase), and that of MoaC is to catalyze the rearrangement of 3',8-cH2GTP into cPMP (cPMP synthase).more »
- Authors:
-
- Duke Univ., Durham, NC (United States). Medical Center. Dept. of Biochemistry
- Publication Date:
- Research Org.:
- Duke Univ., Durham, NC (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Inst. of Health (NIH) (United States)
- OSTI Identifier:
- 1182324
- Grant/Contract Number:
- W-31-109-Eng-38; GM074815
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Proceedings of the National Academy of Sciences of the United States of America
- Additional Journal Information:
- Journal Volume: 112; Journal Issue: 20; Journal ID: ISSN 0027-8424
- Publisher:
- National Academy of Sciences, Washington, DC (United States)
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; molybdenum cofactor; pterin biosynthesis; radical SAM enzyme; enzymatic rearrangement; cPMP synthase
Citation Formats
Hover, Bradley M., Tonthat, Nam K., Schumacher, Maria A., and Yokoyama, Kenichi. Mechanism of pyranopterin ring formation in molybdenum cofactor biosynthesis. United States: N. p., 2015.
Web. doi:10.1073/pnas.1500697112.
Hover, Bradley M., Tonthat, Nam K., Schumacher, Maria A., & Yokoyama, Kenichi. Mechanism of pyranopterin ring formation in molybdenum cofactor biosynthesis. United States. https://doi.org/10.1073/pnas.1500697112
Hover, Bradley M., Tonthat, Nam K., Schumacher, Maria A., and Yokoyama, Kenichi. Mon .
"Mechanism of pyranopterin ring formation in molybdenum cofactor biosynthesis". United States. https://doi.org/10.1073/pnas.1500697112. https://www.osti.gov/servlets/purl/1182324.
@article{osti_1182324,
title = {Mechanism of pyranopterin ring formation in molybdenum cofactor biosynthesis},
author = {Hover, Bradley M. and Tonthat, Nam K. and Schumacher, Maria A. and Yokoyama, Kenichi},
abstractNote = {The molybdenum cofactor (Moco) is essential for all kingdoms of life, plays central roles in various biological processes, and must be biosynthesized de novo. During Moco biosynthesis, the characteristic pyranopterin ring is constructed by a complex rearrangement of guanosine 5'-triphosphate (GTP) into cyclic pyranopterin (cPMP) through the action of two enzymes, MoaA and MoaC (molybdenum cofactor biosynthesis protein A and C, respectively). Conventionally, MoaA was considered to catalyze the majority of this transformation, with MoaC playing little or no role in the pyranopterin formation. Recently, this view was challenged by the isolation of 3',8-cyclo-7,8-dihydro-guanosine 5'-triphosphate (3',8-cH2GTP) as the product of in vitro MoaA reactions. To elucidate the mechanism of formation of Moco pyranopterin backbone, in this paper we performed biochemical characterization of 3',8-cH2GTP and functional and X-ray crystallographic characterizations of MoaC. These studies revealed that 3',8-cH2GTP is the only product of MoaA that can be converted to cPMP by MoaC. Our structural studies captured the specific binding of 3',8-cH2GTP in the active site of MoaC. These observations provided strong evidence that the physiological function of MoaA is the conversion of GTP to 3',8-cH2GTP (GTP 3',8-cyclase), and that of MoaC is to catalyze the rearrangement of 3',8-cH2GTP into cPMP (cPMP synthase). Furthermore, our structure-guided studies suggest that MoaC catalysis involves the dynamic motions of enzyme active-site loops as a way to control the timing of interaction between the reaction intermediates and catalytically essential amino acid residues. In conclusion, these results reveal the previously unidentified mechanism behind Moco biosynthesis and provide mechanistic and structural insights into how enzymes catalyze complex rearrangement reactions.},
doi = {10.1073/pnas.1500697112},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 20,
volume = 112,
place = {United States},
year = {Mon May 04 00:00:00 EDT 2015},
month = {Mon May 04 00:00:00 EDT 2015}
}
Web of Science
Works referenced in this record:
Insights into molybdenum cofactor deficiency provided by the crystal structure of the molybdenum cofactor biosynthesis protein MoaC
journal, July 2000
- Wuebbens, Margot M.; Liu, Michael TW; Rajagopalan, Kv
- Structure, Vol. 8, Issue 7
Mutations in a polycistronic nuclear gene associated with molybdenum cofactor deficiency
journal, September 1998
- Reiss, Jochen; Cohen, Nadine; Dorche, Claude
- Nature Genetics, Vol. 20, Issue 1
Alterations in the Cytoplasmic Membrane Proteins of Various Chlorate-Resistant Mutants of Escherichia coli
journal, January 1971
- MacGregor, C. H.; Schnaitman, C. A.
- Journal of Bacteriology, Vol. 108, Issue 1
Synthesis of Cyclic Pyranopterin Monophosphate, a Biosynthetic Intermediate in the Molybdenum Cofactor Pathway
journal, February 2013
- Clinch, Keith; Watt, Derek K.; Dixon, Rachel A.
- Journal of Medicinal Chemistry, Vol. 56, Issue 4
Catalysis of a New Ribose Carbon-Insertion Reaction by the Molybdenum Cofactor Biosynthetic Enzyme MoaA
journal, February 2013
- Mehta, Angad P.; Hanes, Jeremiah W.; Abdelwahed, Sameh H.
- Biochemistry, Vol. 52, Issue 7
The history of the discovery of the molybdenum cofactor and novel aspects of its biosynthesis in bacteria
journal, May 2011
- Leimkühler, Silke; Wuebbens, Margot M.; Rajagopalan, K. V.
- Coordination Chemistry Reviews, Vol. 255, Issue 9-10
Crystal structure of the S-adenosylmethionine-dependent enzyme MoaA and its implications for molybdenum cofactor deficiency in humans
journal, August 2004
- Hanzelmann, P.; Schindelin, H.
- Proceedings of the National Academy of Sciences, Vol. 101, Issue 35
Molybdenum cofactor biosynthesis in plants and humans
journal, May 2011
- Mendel, Ralf R.; Schwarz, Günter
- Coordination Chemistry Reviews, Vol. 255, Issue 9-10
Identification of a Cyclic Nucleotide as a Cryptic Intermediate in Molybdenum Cofactor Biosynthesis
journal, April 2013
- Hover, Bradley M.; Loksztejn, Anna; Ribeiro, Anthony A.
- Journal of the American Chemical Society, Vol. 135, Issue 18
The Tetrahydropyranopterin Structure of the Sulfur-free and Metal-free Molybdenum Cofactor Precursor
journal, February 2004
- Santamaria-Araujo, José Angel; Fischer, Berthold; Otte, Tanja
- Journal of Biological Chemistry, Vol. 279, Issue 16
Investigation of the Early Steps of Molybdopterin Biosynthesis in Escherichia coli through the Use of in Vivo Labeling Studies
journal, January 1995
- Wuebbens, Margot M.; Rajagopalan, K. V.
- Journal of Biological Chemistry, Vol. 270, Issue 3
Molybdopterin Biosynthesis: Trapping of Intermediates for the MoaA-Catalyzed Reaction Using 2′-DeoxyGTP and 2′-ChloroGTP as Substrate Analogues.
journal, July 2014
- Mehta, Angad P.; Abdelwahed, Sameh H.; Xu, Hui
- Journal of the American Chemical Society, Vol. 136, Issue 30
The Radical SAM Superfamily
journal, January 2008
- Frey, Perry A.; Hegeman, Adrian D.; Ruzicka, Frank J.
- Critical Reviews in Biochemistry and Molecular Biology, Vol. 43, Issue 1
Structural characterization of a molybdopterin precursor
journal, June 1993
- Wuebbens, M. M.; Rajagopalan, K. V.
- Journal of Biological Chemistry, Vol. 268, Issue 18
Works referencing / citing this record:
At the confluence of ribosomally synthesized peptide modification and radical S -adenosylmethionine (SAM) enzymology
journal, August 2017
- Latham, John A.; Barr, Ian; Klinman, Judith P.
- Journal of Biological Chemistry, Vol. 292, Issue 40
DMSO Reductase Family: Phylogenetics and Applications of Extremophiles
journal, July 2019
- Miralles-Robledillo, Jose María; Torregrosa-Crespo, Javier; Martínez-Espinosa, Rosa María
- International Journal of Molecular Sciences, Vol. 20, Issue 13
A tool named Iris for versatile high-throughput phenotyping in microorganisms
journal, February 2017
- Kritikos, George; Banzhaf, Manuel; Herrera-Dominguez, Lucia
- Nature Microbiology, Vol. 2, Issue 5
The regulation of Moco biosynthesis and molybdoenzyme gene expression by molybdenum and iron in bacteria
journal, January 2019
- Zupok, Arkadiusz; Iobbi-Nivol, Chantal; Méjean, Vincent
- Metallomics, Vol. 11, Issue 10
Reconstitution and substrate specificity for isopentenyl pyrophosphate of the antiviral radical SAM enzyme viperin
journal, July 2018
- Chakravarti, Arpita; Selvadurai, Kiruthika; Shahoei, Rezvan
- Journal of Biological Chemistry, Vol. 293, Issue 36
On the Role of Additional [4Fe-4S] Clusters with a Free Coordination Site in Radical-SAM Enzymes
journal, March 2017
- Mulliez, Etienne; Duarte, Victor; Arragain, Simon
- Frontiers in Chemistry, Vol. 5
DMSO Reductase Family: Phylogenetics and Applications of Extremophiles
journal, July 2019
- Miralles-Robledillo, Jose María; Torregrosa-Crespo, Javier; Martínez-Espinosa, Rosa María
- International Journal of Molecular Sciences, Vol. 20, Issue 13
Genetic dissection of cyclic pyranopterin monophosphate biosynthesis in plant mitochondria
journal, January 2018
- Kruse, Inga; Maclean, Andrew E.; Hill, Lionel
- Biochemical Journal, Vol. 475, Issue 2
C–C bond forming radical SAM enzymes involved in the construction of carbon skeletons of cofactors and natural products
journal, January 2018
- Yokoyama, Kenichi; Lilla, Edward A.
- Natural Product Reports, Vol. 35, Issue 7
A tool named Iris for versatile high-throughput phenotyping in microorganisms
journal, February 2017
- Kritikos, George; Banzhaf, Manuel; Herrera-Dominguez, Lucia
- Nature Microbiology, Vol. 2, Issue 5
Therapeutic potential of pteridine derivatives: A comprehensive review
journal, October 2018
- Carmona‐Martínez, Violeta; Ruiz‐Alcaraz, Antonio J.; Vera, María
- Medicinal Research Reviews, Vol. 39, Issue 2
On the Role of Additional [4Fe-4S] Clusters with a Free Coordination Site in Radical-SAM Enzymes
journal, March 2017
- Mulliez, Etienne; Duarte, Victor; Arragain, Simon
- Frontiers in Chemistry, Vol. 5