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W1988049211 abstract "Recent studies indicate that the metabolism of diacylglycerol pyrophosphate (DGPP) is involved in a novel lipid signaling pathway. DGPP phosphatases (DGPP phosphohydrolase) fromSaccharomyces cerevisiae and Escherichia colicatalyze the dephosphorylation of DGPP to yield phosphatidate (PA) and then catalyze the dephosphorylation of PA to yield diacylglycerol. We demonstrated that the Mg2+-independent form of PA phosphatase (PA phosphohydrolase, PAP2) purified from rat liver catalyzed the dephosphorylation of DGPP. This reaction was Mg2+-independent, insensitive to inhibition byN-ethylmaleimide and bromoenol lactone, and inhibited by Mn2+ ions. PAP2 exhibited a high affinity for DGPP (Km = 0.04 mol %). The specificity constant (Vmax/Km) for DGPP was 1.3-fold higher than that of PA. DGPP inhibited the ability of PAP2 to dephosphorylate PA, and PA inhibited the dephosphorylation of DGPP. Like rat liver PAP2, the Mg2+-independent PA phosphatase activity of DGPP phosphatase purified from S. cerevisiaewas inhibited by lyso-PA, sphingosine 1-phosphate, and ceramide 1-phosphate. Mouse PAP2 showed homology to DGPP phosphatases fromS. cerevisiae and E. coli, especially in localized regions that constitute a novel phosphatase sequence motif. Collectively, our work indicated that rat liver PAP2 is a member of a phosphatase family that includes DGPP phosphatases from S. cerevisiae and E. coli. We propose a model in which the phosphatase activities of rat liver PAP2 and the DGPP phosphatase of S. cerevisiae regulate the cellular levels of DGPP, PA, and diacylglycerol. Recent studies indicate that the metabolism of diacylglycerol pyrophosphate (DGPP) is involved in a novel lipid signaling pathway. DGPP phosphatases (DGPP phosphohydrolase) fromSaccharomyces cerevisiae and Escherichia colicatalyze the dephosphorylation of DGPP to yield phosphatidate (PA) and then catalyze the dephosphorylation of PA to yield diacylglycerol. We demonstrated that the Mg2+-independent form of PA phosphatase (PA phosphohydrolase, PAP2) purified from rat liver catalyzed the dephosphorylation of DGPP. This reaction was Mg2+-independent, insensitive to inhibition byN-ethylmaleimide and bromoenol lactone, and inhibited by Mn2+ ions. PAP2 exhibited a high affinity for DGPP (Km = 0.04 mol %). The specificity constant (Vmax/Km) for DGPP was 1.3-fold higher than that of PA. DGPP inhibited the ability of PAP2 to dephosphorylate PA, and PA inhibited the dephosphorylation of DGPP. Like rat liver PAP2, the Mg2+-independent PA phosphatase activity of DGPP phosphatase purified from S. cerevisiaewas inhibited by lyso-PA, sphingosine 1-phosphate, and ceramide 1-phosphate. Mouse PAP2 showed homology to DGPP phosphatases fromS. cerevisiae and E. coli, especially in localized regions that constitute a novel phosphatase sequence motif. Collectively, our work indicated that rat liver PAP2 is a member of a phosphatase family that includes DGPP phosphatases from S. cerevisiae and E. coli. We propose a model in which the phosphatase activities of rat liver PAP2 and the DGPP phosphatase of S. cerevisiae regulate the cellular levels of DGPP, PA, and diacylglycerol. PA 1The abbreviations used are: PA, phosphatidate; DG, diacylglycerol; PAP, PA phosphatase; DGPP, diacylglycerol pyrophosphate; NEM, N-ethylmaleimide; LPA, lysophosphatidate; SPP, sphingosine 1-phosphate; CerP, ceramide 1-phosphate. 1The abbreviations used are: PA, phosphatidate; DG, diacylglycerol; PAP, PA phosphatase; DGPP, diacylglycerol pyrophosphate; NEM, N-ethylmaleimide; LPA, lysophosphatidate; SPP, sphingosine 1-phosphate; CerP, ceramide 1-phosphate. phosphatase (3-sn-phosphatidate phosphohydrolase, EC 3.1.3.4) catalyzes the dephosphorylation of PA to yield DG and Pi (1Smith S.W. Weiss S.B. Kennedy E.P. J. Biol. Chem. 1957; 228: 915-922Abstract Full Text PDF PubMed Google Scholar). Two forms of PA phosphatase exist in mammalian cells. Data indicate that one form of PA phosphatase (PAP1) is primarily responsible for the synthesis of phospholipids and triacylglycerols (2Kennedy E.P. Op den Kamp J.A.F. Roelofsen B. Wirtz K.W.A. Lipids and Membranes: Past, Present and Future. Elsevier Science Publishers B. V., Amsterdam1986: 171-206Google Scholar, 3Brindley D.N. Prog. Lipid Res. 1984; 23: 115-133Crossref PubMed Scopus (166) Google Scholar, 4Kocsis M.G. Weselake R.J. Lipids. 1996; 31: 785-802Crossref PubMed Scopus (44) Google Scholar, 5Balsinde J. Dennis E.A. J. Biol. Chem. 1996; 271: 31937-31941Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar), whereas the other form of PA phosphatase (PAP2) is primarily involved in lipid signaling pathways (4Kocsis M.G. Weselake R.J. Lipids. 1996; 31: 785-802Crossref PubMed Scopus (44) Google Scholar, 5Balsinde J. Dennis E.A. J. Biol. Chem. 1996; 271: 31937-31941Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar, 6Jamal Z. Martin A. Gomez-Munoz A. Brindley D.N. J. Biol. Chem. 1991; 266: 2988-2996Abstract Full Text PDF PubMed Google Scholar, 7Brindley D.N. Waggoner D.W. Chem. Phys. Lipids. 1996; 80: 45-57Crossref PubMed Scopus (103) Google Scholar). PA, the substrate of the PA phosphatase reaction, regulates the activity of several lipid-dependent enzymes (8Bae-Lee M. Carman G.M. J. Biol. Chem. 1990; 265: 7221-7226Abstract Full Text PDF PubMed Google Scholar, 9Moritz A. DeGraan P.N.E. Gispen W.H. Wirtz K.W.A. J. Biol. Chem. 1992; 267: 7207-7210Abstract Full Text PDF PubMed Google Scholar, 10Jones G.A. Carpenter G. J. Biol. Chem. 1993; 268: 20845-20850Abstract Full Text PDF PubMed Google Scholar, 11Bhat B.G. Wang P. Coleman R.A. J. Biol. Chem. 1994; 269: 13172-13178Abstract Full Text PDF PubMed Google Scholar, 12English D. Cell. Signalling. 1996; 8: 341-347Crossref PubMed Scopus (178) Google Scholar) and exhibits mitogenic effects in mammalian cells (12English D. Cell. Signalling. 1996; 8: 341-347Crossref PubMed Scopus (178) Google Scholar, 13Moolenaar W.H. Kruijer W. Tilly B.C. Verlaan I. Bierman A.J. de Laat S.W. Nature. 1986; 323: 171-173Crossref PubMed Scopus (378) Google Scholar, 14Yu C.-L. Tsai M.-H. Stacey D.W. Cell. 1988; 52: 63-71Abstract Full Text PDF PubMed Scopus (210) Google Scholar, 15Gomez-Munoz A. Martin A. O'Brien L. Brindley D.N. J. Biol. Chem. 1994; 269: 8937-8943Abstract Full Text PDF PubMed Google Scholar, 16Moolenaar W.H. J. Biol. Chem. 1995; 270: 12949-12952Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar). Thus, the action of PA phosphatase is thought to attenuate the signaling functions of PA (7Brindley D.N. Waggoner D.W. Chem. Phys. Lipids. 1996; 80: 45-57Crossref PubMed Scopus (103) Google Scholar). In addition, Brindley and co-workers (7Brindley D.N. Waggoner D.W. Chem. Phys. Lipids. 1996; 80: 45-57Crossref PubMed Scopus (103) Google Scholar, 17Waggoner D.W. Gomez-Munoz A. Dewald J. Brindley D.N. J. Biol. Chem. 1996; 271: 16506-16509Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar) have shown that PAP2, purified from rat liver, has the ability to dephosphorylate LPA, SPP, and CerP. These substrates and their hydrolysis products have been shown to play a role in signaling pathways in mammalian cells (7Brindley D.N. Waggoner D.W. Chem. Phys. Lipids. 1996; 80: 45-57Crossref PubMed Scopus (103) Google Scholar, 17Waggoner D.W. Gomez-Munoz A. Dewald J. Brindley D.N. J. Biol. Chem. 1996; 271: 16506-16509Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar).The two forms of PA phosphatase have distinguishing enzymological properties that are used to differentiate them. PAP1 has a Mg2+ ion requirement and is inhibited by the thioreactive agent NEM (4Kocsis M.G. Weselake R.J. Lipids. 1996; 31: 785-802Crossref PubMed Scopus (44) Google Scholar, 6Jamal Z. Martin A. Gomez-Munoz A. Brindley D.N. J. Biol. Chem. 1991; 266: 2988-2996Abstract Full Text PDF PubMed Google Scholar, 7Brindley D.N. Waggoner D.W. Chem. Phys. Lipids. 1996; 80: 45-57Crossref PubMed Scopus (103) Google Scholar). PAP2 does not have a Mg2+ ion requirement and is insensitive to NEM (4Kocsis M.G. Weselake R.J. Lipids. 1996; 31: 785-802Crossref PubMed Scopus (44) Google Scholar, 6Jamal Z. Martin A. Gomez-Munoz A. Brindley D.N. J. Biol. Chem. 1991; 266: 2988-2996Abstract Full Text PDF PubMed Google Scholar, 7Brindley D.N. Waggoner D.W. Chem. Phys. Lipids. 1996; 80: 45-57Crossref PubMed Scopus (103) Google Scholar). PAP2, purified from rat liver (18Waggoner D.W. Martin A. Dewald J. Gomez-Munoz A. Brindley D.N. J. Biol. Chem. 1995; 270: 19422-19429Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 19Fleming I.N. Yeaman S.J. Biochem. J. 1995; 308: 983-989Crossref PubMed Scopus (42) Google Scholar, 20Siess E.A. Hofstetter M.M. FEBS Lett. 1996; 381: 169-173Crossref PubMed Scopus (26) Google Scholar) and porcine thymus (21Kanoh H. Imai S. Yamada K. Sakane F. J. Biol. Chem. 1992; 267: 25309-25314Abstract Full Text PDF PubMed Google Scholar, 22Kai M. Wada I. Imai S. Sakane F. Kanoh H. J. Biol. Chem. 1996; 271: 18931-18938Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar), shares enzymological properties that are strikingly similar to a PA phosphatase activity exhibited by a DGPP phosphatase (DGPP phosphohydrolase) that has recently been isolated from Saccharomyces cerevisiae (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar) and Escherichia coli (24Dillon D.A. Wu W.-I. Riedel B. Wissing J.B. Dowhan W. Carman G.M. J. Biol. Chem. 1996; 271: 30548-30553Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). DGPP phosphatase catalyzes the dephosphorylation of the novel lipid DGPP to form PA and Pi(23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 25Riedel, B., Morr, M., Wu, W.-I., Carman, G. M., and Wissing, J. B. (1997) Plant Sci. in press.Google Scholar). When DGPP is supplied as a substrate in vitro, the enzyme removes the β phosphate of DGPP to generate PA and then removes the phosphate of PA to generate DG (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 24Dillon D.A. Wu W.-I. Riedel B. Wissing J.B. Dowhan W. Carman G.M. J. Biol. Chem. 1996; 271: 30548-30553Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). Although DGPP phosphatase utilizes PA as a substrate in the absence of DGPP, the enzyme has a preference for DGPP as a substrate (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 24Dillon D.A. Wu W.-I. Riedel B. Wissing J.B. Dowhan W. Carman G.M. J. Biol. Chem. 1996; 271: 30548-30553Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). This PA phosphatase activity (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar) is distinctly different from that of the PAP1 enzymes that have been purified from S. cerevisiae (26Lin Y.-P. Carman G.M. J. Biol. Chem. 1989; 264: 8641-8645Abstract Full Text PDF PubMed Google Scholar, 27Morlock K.R. McLaughlin J.J. Lin Y.-P. Carman G.M. J. Biol. Chem. 1991; 266: 3586-3593Abstract Full Text PDF PubMed Google Scholar) but does resemble that of the mammalian PAP2 enzymes. Like PAP2, the PA phosphatase activity catalyzed by DGPP phosphatase is Mg2+-independent and NEM-insensitive (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 24Dillon D.A. Wu W.-I. Riedel B. Wissing J.B. Dowhan W. Carman G.M. J. Biol. Chem. 1996; 271: 30548-30553Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). In addition, the PAP2 (18Waggoner D.W. Martin A. Dewald J. Gomez-Munoz A. Brindley D.N. J. Biol. Chem. 1995; 270: 19422-19429Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar) and DGPP phosphatase (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 24Dillon D.A. Wu W.-I. Riedel B. Wissing J.B. Dowhan W. Carman G.M. J. Biol. Chem. 1996; 271: 30548-30553Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar) enzymes can utilize LPA as a substrate. Given these similarities, we hypothesized that mammalian PAP2 would display DGPP phosphatase activity. Using purified PAP2 from rat liver we demonstrated that PAP2 catalyzed the DGPP phosphatase reaction. Recent data indicate that DGPP and the enzymes responsible for its metabolism are involved in a novel lipid signaling pathway (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar,28Wissing J.B. Behrbohm H. FEBS Lett. 1993; 315: 95-99Crossref PubMed Scopus (47) Google Scholar, 29Munnik T. de Vrije T. Irvine R.F. Musgrave A. J. Biol. Chem. 1996; 271: 15708-15715Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). The implications of PAP2 having DGPP phosphatase activity are discussed in relation to lipid signaling pathways.DISCUSSIONDGPP phosphatase is a recently discovered enzyme that has been identified in C. roseus, E. coli, S. cerevisiae, rat liver, pig liver, pig brain, and bovine brain (25Riedel, B., Morr, M., Wu, W.-I., Carman, G. M., and Wissing, J. B. (1997) Plant Sci. in press.Google Scholar). The discovery of DGPP phosphatase in such a wide range of organisms suggests that it plays an important role in phospholipid metabolism and cell growth. DGPP phosphatase has been purified to homogeneity from S. cerevisiae and characterized with respect to its enzymological and kinetic properties (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). DGPP phosphatase has been partially purified from E. coli and shown to be the product of the pgpB gene (24Dillon D.A. Wu W.-I. Riedel B. Wissing J.B. Dowhan W. Carman G.M. J. Biol. Chem. 1996; 271: 30548-30553Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). The DGPP phosphatases isolated from S. cerevisiae (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar) and E. coli (24Dillon D.A. Wu W.-I. Riedel B. Wissing J.B. Dowhan W. Carman G.M. J. Biol. Chem. 1996; 271: 30548-30553Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar) catalyze the dephosphorylation of the β phosphate of DGPP to yield PA and then catalyze the dephosphorylation of the PA product to yield DG. The DGPP phosphatase and PA phosphatase activities of the DGPP phosphatase enzymes from S. cerevisiae (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar) andE. coli (24Dillon D.A. Wu W.-I. Riedel B. Wissing J.B. Dowhan W. Carman G.M. J. Biol. Chem. 1996; 271: 30548-30553Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar) are Mg2+-independent and NEM-insensitive (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 24Dillon D.A. Wu W.-I. Riedel B. Wissing J.B. Dowhan W. Carman G.M. J. Biol. Chem. 1996; 271: 30548-30553Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). In addition, these DGPP phosphatase activities are potently inhibited by Mn2+ ions (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar,24Dillon D.A. Wu W.-I. Riedel B. Wissing J.B. Dowhan W. Carman G.M. J. Biol. Chem. 1996; 271: 30548-30553Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar).In this study we examined the hypothesis that PAP2 purified from rat liver would display DGPP phosphatase activity. One impetus for this study was the fact that the characteristic properties of PAP2 (i.e. Mg2+-independent and NEM-insensitive PA phosphatase activity) (4Kocsis M.G. Weselake R.J. Lipids. 1996; 31: 785-802Crossref PubMed Scopus (44) Google Scholar, 6Jamal Z. Martin A. Gomez-Munoz A. Brindley D.N. J. Biol. Chem. 1991; 266: 2988-2996Abstract Full Text PDF PubMed Google Scholar, 18Waggoner D.W. Martin A. Dewald J. Gomez-Munoz A. Brindley D.N. J. Biol. Chem. 1995; 270: 19422-19429Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 19Fleming I.N. Yeaman S.J. Biochem. J. 1995; 308: 983-989Crossref PubMed Scopus (42) Google Scholar, 21Kanoh H. Imai S. Yamada K. Sakane F. J. Biol. Chem. 1992; 267: 25309-25314Abstract Full Text PDF PubMed Google Scholar) are the same as those of the PA phosphatase activities described for the DGPP phosphatase enzymes from S. cerevisiae (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar) and E. coli (24Dillon D.A. Wu W.-I. Riedel B. Wissing J.B. Dowhan W. Carman G.M. J. Biol. Chem. 1996; 271: 30548-30553Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). We showed in this study that PAP2 did indeed catalyze the DGPP phosphatase reaction. Like the DGPP phosphatases from S. cerevisiae (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar) and E. coli (24Dillon D.A. Wu W.-I. Riedel B. Wissing J.B. Dowhan W. Carman G.M. J. Biol. Chem. 1996; 271: 30548-30553Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar), the DGPP phosphatase activity of PAP2 was Mg2+-independent, NEM-insensitive, and inhibited by Mn2+ ions. The latter effect probably reflects a specific interaction of DGPP with Mn2+ ions that is not exhibited with PA. The rat liver and S. cerevisiae DGPP phosphatase activities were also insensitive to inhibition by bromoenol lactone, which has recently been used to distinguish between the Mg2+-dependent and Mg2+-independent forms of PA phosphatase (5Balsinde J. Dennis E.A. J. Biol. Chem. 1996; 271: 31937-31941Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar). Furthermore, the S. cerevisiae(23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 24Dillon D.A. Wu W.-I. Riedel B. Wissing J.B. Dowhan W. Carman G.M. J. Biol. Chem. 1996; 271: 30548-30553Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar) and E. coli (24Dillon D.A. Wu W.-I. Riedel B. Wissing J.B. Dowhan W. Carman G.M. J. Biol. Chem. 1996; 271: 30548-30553Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 42Icho T. J. Bacteriol. 1988; 170: 5117-5124Crossref PubMed Google Scholar, 43Funk C.R. Zimniak L. Dowhan W. J. Bacteriol. 1992; 174: 205-213Crossref PubMed Google Scholar) DGPP phosphatases and the rat liver PAP2 (17Waggoner D.W. Gomez-Munoz A. Dewald J. Brindley D.N. J. Biol. Chem. 1996; 271: 16506-16509Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar) were similar in that they used other lipid phosphate compounds such as LPA and CerP as substrates.Although our studies revealed similarities between rat liver PAP2 and the DGPP phosphatases of S. cerevisiae and E. coli, there were also differences among these enzymes. Interestingly, the affinity of PAP2 for DGPP and PA as substrates was much greater than the affinities of the DGPP phosphatases of S. cerevisiae and E. coli for these substrates (TableI). The specificity constant (Vmax/Km) of rat liver PAP2 for DGPP was slightly higher (1.3-fold) than that for PA (Table I). PA inhibited the dephosphorylation of DGPP by rat liver PAP2, and DGPP inhibited the dephosphorylation of PA by PAP2. The inhibitor constants for PA and DGPP of rat liver PAP2 were similar, and these constants were similar to their respective Km values as substrates (Table I). Thus, the specificity of PAP2 for DGPP and PA was essentially the same. On the other hand, the DGPP phosphatases fromS. cerevisiae (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar) and E. coli (24Dillon D.A. Wu W.-I. Riedel B. Wissing J.B. Dowhan W. Carman G.M. J. Biol. Chem. 1996; 271: 30548-30553Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar) clearly demonstrate a preference for DGPP as a substrate. For these enzymes, the specificity constants for DGPP are about 9-fold higher than those for PA (Table I) (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 24Dillon D.A. Wu W.-I. Riedel B. Wissing J.B. Dowhan W. Carman G.M. J. Biol. Chem. 1996; 271: 30548-30553Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). The PA phosphatase activity of the S. cerevisiae DGPP phosphatase is potently inhibited by DGPP (TableI) (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). However, concentrations of PA up to 16-fold greater than the concentration of DGPP did not inhibit S. cerevisiae DGPP phosphatase activity.Table IKinetic constants for rat liver PAP2 and DGPP phosphatases from S. cerevisiae and E. coliEnzymeDGPPPAV maxK mV max/K m1-aBecause the enzymes from rat liver and E. coli have not been purified to homogeneity, the specificity constants reported in the table cannot be compared.IC50V maxK mV max/K m1-aBecause the enzymes from rat liver and E. coli have not been purified to homogeneity, the specificity constants reported in the table cannot be compared.IC50units/mgmol%mol%units/mgmol%mol%PAP2 (rat liver)1.240.04310.051-bInhibitor constant with respect to PA as the substrate.0.930.04230.071-cInhibitor constant with respect to DGPP as the substrate.DGPP phosphatase1-dData taken from Ref. 23. (S. cerevisiae)1720.553130.351-bInhibitor constant with respect to PA as the substrate.702.232NI1-eNI, not inhibitory.DGPP phosphatase1-fData taken from Ref. 24. (E. coli)2.162.30.94ND1-gND, not determined.0.313.10.1ND1-gND, not determined.1-a Because the enzymes from rat liver and E. coli have not been purified to homogeneity, the specificity constants reported in the table cannot be compared.1-b Inhibitor constant with respect to PA as the substrate.1-c Inhibitor constant with respect to DGPP as the substrate.1-d Data taken from Ref. 23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar.1-e NI, not inhibitory.1-f Data taken from Ref. 24Dillon D.A. Wu W.-I. Riedel B. Wissing J.B. Dowhan W. Carman G.M. J. Biol. Chem. 1996; 271: 30548-30553Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar.1-g ND, not determined. Open table in a new tab A cDNA encoding for PAP2 has been cloned from mouse cells that encodes for a protein with a predicted minimum subunit molecular mass of 31.9 kDa (22Kai M. Wada I. Imai S. Sakane F. Kanoh H. J. Biol. Chem. 1996; 271: 18931-18938Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). DGPP phosphatase activity is associated with a 34-kDa protein that we have purified to homogeneity from S. cerevisiae (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). We have obtained sufficient amino acid sequence information from this 34-kDa protein to identify and isolate the gene (GenBankTM accession no. U51031) encoding for this enzyme. 2G. M. Zeimetz and G. M. Carman, unpublished work. We refer to this gene asDPP1 (diacylglycerol pyrophosphatephosphatase). In addition, we have identified and isolated a second gene (GenBankTM accession no. U33057) from S. cerevisiae that is homologous to DPP1 that we refer to as DPP2.2 The predicted minimum subunit molecular masses of the proteins encoded by these genes are 33.5 and 31.6 kDa, respectively. The subunit molecular mass of the protein encoded by the E. coli pgpB gene is 28 kDa (42Icho T. J. Bacteriol. 1988; 170: 5117-5124Crossref PubMed Google Scholar). The amino acid sequences of DGPP phosphatases of S. cerevisiae andE. coli and the mouse PAP2 proteins show homology to each other. In particular there are localized regions of high homology that constitute a novel phosphatase sequence motif (44Stukey J. Carman G.M. Protein Sci. 1997; 6: 469-472Crossref PubMed Scopus (221) Google Scholar). This motif contains three domains (44Stukey J. Carman G.M. Protein Sci. 1997; 6: 469-472Crossref PubMed Scopus (221) Google Scholar). The alignment of the amino acid sequences of PAP2 and the DGPP phosphatases in these domains is shown in TableII. The size of mammalian PAP2 seems to vary in different tissues (18Waggoner D.W. Martin A. Dewald J. Gomez-Munoz A. Brindley D.N. J. Biol. Chem. 1995; 270: 19422-19429Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar). These different sizes may be attributed to variations in the extent of their glycosylation because treatment of purified PAP2 from rat liver (18Waggoner D.W. Martin A. Dewald J. Gomez-Munoz A. Brindley D.N. J. Biol. Chem. 1995; 270: 19422-19429Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar) and pig thymus (22Kai M. Wada I. Imai S. Sakane F. Kanoh H. J. Biol. Chem. 1996; 271: 18931-18938Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar) withN-glycanase decreases their apparent size from 51–53 kDa and 35 kDa, respectively, to about 30 kDa. There is no evidence ofN-glycosylation of the DGPP phosphatases from S. cerevisiae and E. coli. Collectively, the work presented here indicated that mammalian PAP2 is a member of a phosphatase family that includes DGPP phosphatases from S. cerevisiae and E. coli.Table IIProtein alignments of the phosphatase sequence motif of mouse PAP2 and DGPP phosphatases from S. cerevisiae and E. coli2-aData taken from Ref. 44.2ProteinDomain 12-bThe numbers preceding domain 1 indicate the length in amino acids of the N terminus of the protein. The numbers between domains indicate the amino acids between each domain. The numbers after domain 3 indicate the total amino acids in each protein. Domain 2 Domain 3PAP2 (mouse)119-KYTIGSLRP-39-YSGH-44-SRVSDYKHHWSD-283DGPP phosphatase 1 (S. cerevisiae)117-KNWIGRLRP-39-PSGH-46-SRTQDYRHHFVD-289DGPP phosphatase 2 (S. cerevisiae)135-KLIIGNLRP-41-PSGH-38-SRVIDHRHHWYD-275DGPP phosphatase (E. coli)96-KDKVQEPRP-54-PSGH-36-SRLLLGMHWPRD-2542-a Data taken from Ref. 44Stukey J. Carman G.M. Protein Sci. 1997; 6: 469-472Crossref PubMed Scopus (221) Google Scholar.2-b The numbers preceding domain 1 indicate the length in amino acids of the N terminus of the protein. The numbers between domains indicate the amino acids between each domain. The numbers after domain 3 indicate the total amino acids in each protein. Open table in a new tab DGPP is a novel phospholipid that was first identified as the product of the PA kinase reaction in the plant C. roseus (28Wissing J.B. Behrbohm H. FEBS Lett. 1993; 315: 95-99Crossref PubMed Scopus (47) Google Scholar). DGPP has since been found in a variety of plants (29Munnik T. de Vrije T. Irvine R.F. Musgrave A. J. Biol. Chem. 1996; 271: 15708-15715Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 30Wissing J.B. Behrbohm H. Plant Physiol. 1993; 102: 1243-1249Crossref PubMed Scopus (45) Google Scholar) and in S. cerevisiae (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). The amounts of DGPP in plants and in wild-typeS. cerevisiae are barely detectable (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 29Munnik T. de Vrije T. Irvine R.F. Musgrave A. J. Biol. Chem. 1996; 271: 15708-15715Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). For example, DGPP accounts for only 0.18 mol % of the major phospholipids inS. cerevisiae (23Wu W.-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). The low amount of DGPP is reminiscent of other lipid signaling molecules such as the inositol-containing phospholipids (45Michell R.H. Trends Biochem. Sci. 1992; 17: 274-276Abstract Full Text PDF PubMed Scopus (72) Google Scholar, 46Berridge M.J. Biochim. Biophys. Acta. 1987; 907: 33-45PubMed Google Scholar, 47Majerus P.W. Ross T.S. Cunningham T.W. Caldwell K.K. Jefferson A.B. Bansal V.S. Cell. 1990; 63: 459-465Abstract Full Text PDF PubMed Scopus (203) Google Scholar, 48Downes C.P. Macphee C.H. Eur. J. Biochem. 1990; 193: 1-18Crossref PubMed Scopus (178) Google Scholar, 49Divecha N. Irvine R.F. Cell. 1995; 80: 269-278Abstract Full Text PDF PubMed Scopus (588) Google Scholar). Recent studies have shown that DGPP accumulates in plan" @default.
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W1988049211 title "Mammalian Mg2+-independent Phosphatidate Phosphatase (PAP2) Displays Diacylglycerol Pyrophosphate Phosphatase Activity" @default.
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