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Cloning and characterization of a mammalian lithium-sensitive bisphosphate 3'-nucleotidase inhibited by inositol 1,4-bisphosphate.

Publication ,  Journal Article
Spiegelberg, BD; Xiong, JP; Smith, JJ; Gu, RF; York, JD
Published in: J Biol Chem
May 7, 1999

Discovery of a structurally conserved metal-dependent lithium-inhibited phosphomonoesterase protein family has identified several potential cellular targets of lithium as used to treat manic depression. Here we describe identification of a novel family member using a "computer cloning" strategy. Human and murine cDNA clones encoded proteins sharing 92% identity and were highly expressed in kidney. Native and recombinant protein harbored intrinsic magnesium-dependent bisphosphate nucleotidase activity (BPntase), which removed the 3'-phosphate from 3'-5' bisphosphate nucleosides and 3'-phosphoadenosine 5'-phosphosulfate with Km and Vmax values of 0.5 microM and 40 micromol/min/mg. Lithium uncompetitively inhibited activity with a Ki of 157 microM. Interestingly, BPntase was competitively inhibited by inositol 1,4-bisphosphate with a Ki of 15 microM. Expression of mammalian BPntase complemented defects in hal2/met22 mutant yeast. These data suggest that BPntase's physiologic role in nucleotide metabolism may be regulated by inositol signaling pathways. The presence of high levels of BPntase in the kidney are provocative in light of the roles of bisphosphorylated nucleotides in regulating salt tolerance, sulfur assimilation, detoxification, and lithium toxicity. We propose that inhibition of human BPntase may account for lithium-induced nephrotoxicity, which may be overcome by supplementation of current therapeutic regimes with inhibitors of nucleotide biosynthesis, such as methionine.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

May 7, 1999

Volume

274

Issue

19

Start / End Page

13619 / 13628

Location

United States

Related Subject Headings

  • Sequence Homology, Amino Acid
  • Saccharomyces cerevisiae
  • Nucleotidases
  • Molecular Sequence Data
  • Mice
  • Lithium
  • Kinetics
  • Inositol Phosphates
  • Humans
  • Genetic Complementation Test
 

Citation

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Spiegelberg, B. D., Xiong, J. P., Smith, J. J., Gu, R. F., & York, J. D. (1999). Cloning and characterization of a mammalian lithium-sensitive bisphosphate 3'-nucleotidase inhibited by inositol 1,4-bisphosphate. J Biol Chem, 274(19), 13619–13628. https://doi.org/10.1074/jbc.274.19.13619
Spiegelberg, B. D., J. P. Xiong, J. J. Smith, R. F. Gu, and J. D. York. “Cloning and characterization of a mammalian lithium-sensitive bisphosphate 3'-nucleotidase inhibited by inositol 1,4-bisphosphate.J Biol Chem 274, no. 19 (May 7, 1999): 13619–28. https://doi.org/10.1074/jbc.274.19.13619.
Spiegelberg BD, Xiong JP, Smith JJ, Gu RF, York JD. Cloning and characterization of a mammalian lithium-sensitive bisphosphate 3'-nucleotidase inhibited by inositol 1,4-bisphosphate. J Biol Chem. 1999 May 7;274(19):13619–28.
Spiegelberg, B. D., et al. “Cloning and characterization of a mammalian lithium-sensitive bisphosphate 3'-nucleotidase inhibited by inositol 1,4-bisphosphate.J Biol Chem, vol. 274, no. 19, May 1999, pp. 13619–28. Pubmed, doi:10.1074/jbc.274.19.13619.
Spiegelberg BD, Xiong JP, Smith JJ, Gu RF, York JD. Cloning and characterization of a mammalian lithium-sensitive bisphosphate 3'-nucleotidase inhibited by inositol 1,4-bisphosphate. J Biol Chem. 1999 May 7;274(19):13619–13628.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

May 7, 1999

Volume

274

Issue

19

Start / End Page

13619 / 13628

Location

United States

Related Subject Headings

  • Sequence Homology, Amino Acid
  • Saccharomyces cerevisiae
  • Nucleotidases
  • Molecular Sequence Data
  • Mice
  • Lithium
  • Kinetics
  • Inositol Phosphates
  • Humans
  • Genetic Complementation Test