Elevated adenosine monophosphate deaminase activity in Alzheimer’s disease brain

Sims, Brian; Powers, Richard E.; Sabina, Richard L.; Theibert, Anne B.

doi:10.1016/s0197-4580(98)00083-9

Cited by 32 publications

(25 citation statements)

References 51 publications

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“…6). These values are comparable with those measured in fresh whole rat brain (27 and 25 nmol/min/mg protein) and to the activities of control soluble and membrane-associated forms of AMPD from human cerebellum, which were 33 and 28 nmol/min/mg protein, respectively (25). These activities are similar to those reported in sheep, rat, and fetal human brain (25).…”

Section: Journal Of Biological Chemistry 3837supporting

confidence: 85%

“…AMPD Activity Assay-The enzyme activities of the freshly prepared zebrafish homogenates (free and bound zebrafish AMPD) were assayed by quantifying the amount of ammonia liberated during the reaction using the colorimetric indophenol method (25). The complete incubation mixture (300 l) consisted of 5 l of zebrafish homogenate, 50 mM sodium citrate (pH 7), 50 mM KCl, and 4 mM AMP.…”

Section: Methodsmentioning

confidence: 99%

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Vitamin C Deficiency Activates the Purine Nucleotide Cycle in Zebrafish

Kirkwood

Lebold

Miranda

et al. 2012

Journal of Biological Chemistry

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Background:We investigated the effects of vitamin C status on the metabolome of adult zebrafish. Results: Levels of inosine monophosphate (IMP) and AMP deaminase (AMPD) activity were enhanced in vitamin C-deficient zebrafish. Conclusion: Vitamin C deficiency activates the purine nucleotide cycle in zebrafish. Significance: The link between vitamin C deficiency and elevated AMPD activity is relevant to metabolic diseases.

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Section: Journal Of Biological Chemistry 3837supporting

confidence: 85%

Section: Methodsmentioning

confidence: 99%

Vitamin C Deficiency Activates the Purine Nucleotide Cycle in Zebrafish

Kirkwood

Lebold

Miranda

et al. 2012

Journal of Biological Chemistry

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“…1C) indicated a single strongly immunoreactive band at approximately 80 kDa. Because both AMPD2 and AMPD3 are expressed in brain (21,22) and all the AMPD activity was recovered in a single peak, the AMPD2 and AMPD3 isoforms appear to behave similarly in this purification. Thus, comparable with other high affinity inositide-binding proteins, endogenous rat brain AMPD is effectively purified using an inositide affinity resin (3-9, 45, 46).…”

Section: Endogenous Brain Ampd Binds Inositide Affinity Probes-mentioning

confidence: 98%

“…All human AMPD isoforms contain similar C-terminal regions and substantially divergent N-terminal domains. The AMPD1 isoform is found almost exclusively in skeletal muscle, whereas the AMPD2 and AMPD3 isoforms are widely expressed in many tissues and cells (19,20), including mammalian brain (21,22). AMPD activity is highly regulated through interactions with other proteins (23)(24)(25), phosphorylation (26,27), and small molecules (10, 11, 28 -32).…”

mentioning

confidence: 99%

Regulation of AMP Deaminase by Phosphoinositides

Sims

Mahnke-Zizelman

Profit

et al. 1999

Journal of Biological Chemistry

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AMP deaminase (AMPD) converts AMP to IMP and is a diverse and highly regulated enzyme that is a key component of the adenylate catabolic pathway. In this report, we identify the high affinity interaction between AMPD and phosphoinositides as a mechanism for regulation of this enzyme. We demonstrate that endogenous rat brain AMPD and the human AMPD3 recombinant enzymes specifically bind inositide-based affinity probes and to mixed lipid micelles that contain phosphatidylinositol 4,5-bisphosphate. Moreover, we show that phosphoinositides specifically inhibit AMPD catalytic activity. Phosphatidylinositol 4,5-bisphosphate is the most potent inhibitor, effecting pure noncompetitive inhibition of the wild type human AMPD3 recombinant enzyme with a K i of 110 nM. AMPD activity can be released from membrane fractions by in vitro treatment with neomycin, a phosphoinositide-binding drug. In addition, in vivo modulation of phosphoinositide levels leads to a change in the soluble and membrane-associated pools of AMPD activity. The predicted human AMPD3 sequence contains pleckstrin homology domains and (R/ K)X n (R/K)XKK sequences, both of which are characterized phosphoinositide-binding motifs. The interaction between AMPD and phosphoinositides may mediate membrane localization of the enzyme and function to modulate catalytic activity in vivo.Phosphoinositides and inositol polyphosphates (referred to collectively as inositides) are components of many pathways in eukaryotic cells, functioning in second messenger cascades, acting as regulators of many proteins, and operating as membrane localization signals (1-3). Numerous protein and lipid kinases, adaptor proteins, ion channels, phospholipases, modulators of small GTPases, and actin-binding proteins are regulated by inositides (1-3). To identify novel targets for inositides, our laboratories and others have used purification schemes employing affinity resins that contain tethered inositol polyphosphate head groups (3-9). These affinity purifications were successful in the identification of inositide binding in the clathrin adaptor/assembly protein AP-2 (6), centaurin ␣ (7), a centaurin ␣ orthologue (8), and a phospholipase C (PLC) 1 -related protein (9). In addition to AP-2 and centaurin ␣, we isolated several other proteins from rat brain, one of which was approximately 80 kDa (5). Published reports show that inositol polyphosphates modulate the activity of the enzyme AMP deaminase (EC 3.5.4.6) (AMPD) (10, 11), an enzyme family whose endogenous, purified subunit molecular masses are between 66 and 88 kDa. Therefore, we hypothesized that AMPD could be the 80-kDa protein isolated using the inositide affinity resin.AMPD is a diverse and highly regulated enzyme located at a branchpoint in the adenine nucleotide catabolic pathway and is important in regulating nucleotide pools. AMPD is also a component of the purine nucleotide cycle, an energy-generating pathway reportedly operative in many animal tissues (reviewed in Ref. 12). The AMPD1 gene encodes human isoform M and rat iso...

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“…p21 also induces t-TGase, which has been described as a pleiotropic mediator of cell differentiation, carcinogenesis, apoptosis, and aging and which plays a role in plaque formation in both Alzheimer's disease and amyloidosis (28,29). p21-induced CTGF and galectin-3 have been implicated in atherosclerosis (53,54), whereas p21-up-regulated complement C3 and AMP deaminase were suggested to play a role in Alzheimer's disease (56,57). In addition, expression of p21-induced proteins cathepsin B, PAI-1, fibronectin, N-acetylgalactosamine-6-sulfate sulfatase, and Mac2-BP has been associated with osteoarthritis and͞or rheumatoid arthritis (58)(59)(60).…”

Section: Induction Of Gene Expression By P21: Correlations With Senesmentioning

confidence: 99%

Effects of p21^{Waf1/Cip1/Sdi1}on cellular gene expression: Implications for carcinogenesis, senescence, and age-related diseases

Chang

Watanabe²,

Broude

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

410

342

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Induction of cyclin-dependent kinase inhibitor p21 Waf1/Cip1/Sdi1 triggers cell growth arrest associated with senescence and damage response. Overexpression of p21 from an inducible promoter in a human cell line induces growth arrest and phenotypic features of senescence. cDNA array hybridization showed that p21 expression selectively inhibits a set of genes involved in mitosis, DNA replication, segregation, and repair. The kinetics of inhibition of these genes on p21 induction parallels the onset of growth arrest, and their reexpression on release from p21 precedes the reentry of cells into cell cycle, indicating that inhibition of cell-cycle progression genes is a mechanism of p21-induced growth arrest. p21 also up-regulates multiple genes that have been associated with senescence or implicated in age-related diseases, including atherosclerosis, Alzheimer's disease, amyloidosis, and arthritis. Most of the tested p21-induced genes were not activated in cells that had been growth arrested by serum starvation, but some genes were induced in both forms of growth arrest. Several p21-induced genes encode secreted proteins with paracrine effects on cell growth and apoptosis. In agreement with the overexpression of such proteins, conditioned media from p21-induced cells were found to have antiapoptotic and mitogenic activity. These results suggest that the effects of p21 induction on gene expression in senescent cells may contribute to the pathogenesis of cancer and age-related diseases.

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Elevated adenosine monophosphate deaminase activity in Alzheimer’s disease brain

Cited by 32 publications

References 51 publications

Vitamin C Deficiency Activates the Purine Nucleotide Cycle in Zebrafish

Vitamin C Deficiency Activates the Purine Nucleotide Cycle in Zebrafish

Regulation of AMP Deaminase by Phosphoinositides

Effects of p21^{Waf1/Cip1/Sdi1}on cellular gene expression: Implications for carcinogenesis, senescence, and age-related diseases

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Elevated adenosine monophosphate deaminase activity in Alzheimer’s disease brain

Cited by 32 publications

References 51 publications

Vitamin C Deficiency Activates the Purine Nucleotide Cycle in Zebrafish

Vitamin C Deficiency Activates the Purine Nucleotide Cycle in Zebrafish

Regulation of AMP Deaminase by Phosphoinositides

Effects of p21Waf1/Cip1/Sdi1on cellular gene expression: Implications for carcinogenesis, senescence, and age-related diseases

Contact Info

Product

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Effects of p21^{Waf1/Cip1/Sdi1}on cellular gene expression: Implications for carcinogenesis, senescence, and age-related diseases