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Identification of a cyclic nucleotide as a cryptic intermediate in molybdenum cofactor biosynthesis.

Publication ,  Journal Article
Hover, BM; Loksztejn, A; Ribeiro, AA; Yokoyama, K
Published in: J Am Chem Soc
May 8, 2013

The molybdenum cofactor (Moco) is a redox cofactor found in all kingdoms of life, and its biosynthesis is essential for survival of many organisms, including humans. The first step of Moco biosynthesis is a unique transformation of guanosine 5'-triphosphate (GTP) into cyclic pyranopterin monophosphate (cPMP). In bacteria, MoaA and MoaC catalyze this transformation, although the specific functions of these enzymes were not fully understood. Here, we report the first isolation and structural characterization of a product of MoaA. This molecule was isolated under anaerobic conditions from a solution of MoaA incubated with GTP, S-adenosyl-L-methionine, and sodium dithionite in the absence of MoaC. Structural characterization by chemical derivatization, MS, and NMR spectroscopy suggested the structure of this molecule to be (8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate (3',8-cH2GTP). The isolated 3',8-cH2GTP was converted to cPMP by MoaC or its human homologue, MOCS1B, with high specificities (Km < 0.060 μM and 0.79 ± 0.24 μM for MoaC and MOCS1B, respectively), suggesting the physiological relevance of 3',8-cH2GTP. These observations, in combination with some mechanistic studies of MoaA, unambiguously demonstrate that MoaA catalyzes a unique radical C-C bond formation reaction and that, in contrast to previous proposals, MoaC plays a major role in the complex rearrangement to generate the pyranopterin ring.

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Published In

J Am Chem Soc

DOI

EISSN

1520-5126

Publication Date

May 8, 2013

Volume

135

Issue

18

Start / End Page

7019 / 7032

Location

United States

Related Subject Headings

  • Pteridines
  • Nucleotides, Cyclic
  • Molybdenum Cofactors
  • Molecular Conformation
  • Models, Molecular
  • Metalloproteins
  • Hydrolases
  • Humans
  • General Chemistry
  • Crystallography, X-Ray
 

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Hover, B. M., Loksztejn, A., Ribeiro, A. A., & Yokoyama, K. (2013). Identification of a cyclic nucleotide as a cryptic intermediate in molybdenum cofactor biosynthesis. J Am Chem Soc, 135(18), 7019–7032. https://doi.org/10.1021/ja401781t
Hover, Bradley M., Anna Loksztejn, Anthony A. Ribeiro, and Kenichi Yokoyama. “Identification of a cyclic nucleotide as a cryptic intermediate in molybdenum cofactor biosynthesis.J Am Chem Soc 135, no. 18 (May 8, 2013): 7019–32. https://doi.org/10.1021/ja401781t.
Hover BM, Loksztejn A, Ribeiro AA, Yokoyama K. Identification of a cyclic nucleotide as a cryptic intermediate in molybdenum cofactor biosynthesis. J Am Chem Soc. 2013 May 8;135(18):7019–32.
Hover, Bradley M., et al. “Identification of a cyclic nucleotide as a cryptic intermediate in molybdenum cofactor biosynthesis.J Am Chem Soc, vol. 135, no. 18, May 2013, pp. 7019–32. Pubmed, doi:10.1021/ja401781t.
Hover BM, Loksztejn A, Ribeiro AA, Yokoyama K. Identification of a cyclic nucleotide as a cryptic intermediate in molybdenum cofactor biosynthesis. J Am Chem Soc. 2013 May 8;135(18):7019–7032.
Journal cover image

Published In

J Am Chem Soc

DOI

EISSN

1520-5126

Publication Date

May 8, 2013

Volume

135

Issue

18

Start / End Page

7019 / 7032

Location

United States

Related Subject Headings

  • Pteridines
  • Nucleotides, Cyclic
  • Molybdenum Cofactors
  • Molecular Conformation
  • Models, Molecular
  • Metalloproteins
  • Hydrolases
  • Humans
  • General Chemistry
  • Crystallography, X-Ray