Modulation of mammalian cardiac AMP deaminase by protein kinase C-mediated phosphorylation

Thakkar, Jay K.; Janero, David R.; Yarwood, C; Sharif, H.

doi:10.1042/bj2910523

Cited by 24 publications

(12 citation statements)

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“…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). Regarding the latter, polyphosphates (32) and inositol (1,2,3,4,5,6)-hexakisphosphate (10) inhibit AMPD, whereas inositol (1,3,4,5)-tetrakisphosphate (Ins(1,3,4,5)P 4 ) modestly stimulates AMPD activity (11).…”

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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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confidence: 99%

Regulation of AMP Deaminase by Phosphoinositides

Sims

Mahnke-Zizelman

Profit

et al. 1999

Journal of Biological Chemistry

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“…AMPD can also be regulated via reversible protein phosphorylation by the Ca2+ and phospholipid-dependent protein kinase C (PKC) (Hu et al, 1991;Tovmasian et al, 1990;Thakkar et al, 1993). The enzyme also is inhibited by phosphoinositides (Sims et al, 1999).…”

Section: Enzymes Of Adenylate Energy Metabolismmentioning

confidence: 99%

Regulation of enzymes of energy metabolism - AMP deaminase and creatine kinase - in an anoxia tolerant turtle

Zhou¹

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“…Stimulation of a-adrenergic cascade and the protein kinase C activators were shown to decrease AMPD activity in experiments with rat cardiomyocytes subjected to metabolic poisoning. It was suggested that it may be modulated by phosphorylation-dependent reactions [2,31]. The endothelium represents a minor cell population in the heart, but its strategic location at vessel wall borders underlies its importance.…”

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Inhibition of AMP deaminase as therapeutic target in cardiovascular pathology

Zabielska

Borkowski

Słomińska

et al. 2015

Pharmacological Reports

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AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. This reaction helps to maintain healthy cellular energetics by removing excess AMP that accumulates in energy depleted cells. Furthermore, AMPD permits the synthesis of guanine nucleotides from the larger adenylate pool. This enzyme competes with cytosolic 5'-nucleotidases (c5NT) for AMP. Adenosine, a product of c5NT is a vasodilator, antagonizes inotropic effects of catecholamines and exerts anti-platelet, anti-inflammatory and immunosuppressive activities. The ratio of AMPD/c5NT defines the amount of adenosine produced in adenine nucleotide catabolic pathway. Inhibition of AMPD could alter this ratio resulting in increased adenosine production. Besides the potential effect on adenosine production, elevation of AMP due to inhibition of AMPD could also lead to activation of AMP regulated protein kinase (AMPK) with myriad of downstream events including enhanced energetic metabolism, mitochondrial biogenesis and cytoprotection. While the benefits of these processes are well appreciated in cells such as skeletal or cardiac myocytes its role in protection of endothelium could be even more important. Therapeutic use of AMPD inhibition has been limited due to difficulties with obtaining compounds with adequate characteristics. However, endothelium seems to be the easiest target as effective inhibition of AMPD could be achieved at much lower concentration than in the other types of cells. New generation of AMPD inhibitors has recently been established and its testing in context of endothelial and organ protection could provide important basic knowledge and potential therapeutic tools.

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Modulation of mammalian cardiac AMP deaminase by protein kinase C-mediated phosphorylation

Cited by 24 publications

References 32 publications

Regulation of AMP Deaminase by Phosphoinositides

Regulation of AMP Deaminase by Phosphoinositides

Regulation of enzymes of energy metabolism - AMP deaminase and creatine kinase - in an anoxia tolerant turtle

Inhibition of AMP deaminase as therapeutic target in cardiovascular pathology

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