PMID- 10224133
OWN - NLM
STAT- MEDLINE
DCOM- 19990603
LR  - 20190508
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 19
DP  - 1999 May 7
TI  - Cloning and characterization of a mammalian lithium-sensitive bisphosphate
      3'-nucleotidase inhibited by inositol 1,4-bisphosphate.
PG  - 13619-28
AB  - 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.
FAU - Spiegelberg, B D
AU  - Spiegelberg BD
AD  - Departments of Pharmacology & Cancer Biology and Biochemistry, Duke University
      Medical Center, Durham, North Carolina 27710, USA.
FAU - Xiong, J P
AU  - Xiong JP
FAU - Smith, J J
AU  - Smith JJ
FAU - Gu, R F
AU  - Gu RF
FAU - York, J D
AU  - York JD
LA  - eng
SI  - GENBANK/AF125042
SI  - GENBANK/AF125043
GR  - R01-HL 55672/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (DNA, Complementary)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Inositol Phosphates)
RN  - 47055-78-7 (inositol 1,4-bis(phosphate))
RN  - 9FN79X2M3F (Lithium)
RN  - EC 3.1.3.- (Nucleotidases)
RN  - EC 3.1.3.7 (bisphosphoadenylate 3'-nucleotidase)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Base Sequence
MH  - Cloning, Molecular
MH  - DNA, Complementary
MH  - Enzyme Inhibitors/*pharmacology
MH  - Genetic Complementation Test
MH  - Humans
MH  - Inositol Phosphates/*pharmacology
MH  - Kinetics
MH  - Lithium/*metabolism
MH  - Mice
MH  - Molecular Sequence Data
MH  - Nucleotidases/antagonists & inhibitors/*genetics/metabolism
MH  - Saccharomyces cerevisiae/genetics
MH  - Sequence Homology, Amino Acid
EDAT- 1999/05/01 00:00
MHDA- 1999/05/01 00:01
CRDT- 1999/05/01 00:00
PHST- 1999/05/01 00:00 [pubmed]
PHST- 1999/05/01 00:01 [medline]
PHST- 1999/05/01 00:00 [entrez]
AID - 10.1074/jbc.274.19.13619 [doi]
PST - ppublish
SO  - J Biol Chem. 1999 May 7;274(19):13619-28. doi: 10.1074/jbc.274.19.13619.