Alkaline phosphatase isozymes in cultured human cancer cells

Herz, Fritz

doi:10.1007/bf01949989

Cited by 41 publications

(25 citation statements)

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“…HeLa cells are known for their high expression of PLAP (22,24,25). Furthermore, the enzymatic characteristics observed in HeLa cells in our study indicated that PLAP is the most prominent isoform in these cells.…”

Section: Figure 6 Expression and Isoform-specific Inhibition Of Ap Isupporting

confidence: 57%

“…L-Homoarginine has been reported to inhibit mainly TNAP and has very little effect on the other isoforms (21). In contrast, L-phenylalanine especially inhibits the tissue-specific isoforms and shows little impact on TNAP (22). A third inhibitor, L-leucine, does not affect TNAP activity but strongly reduces the activity of PLAP and GCAP (21,23).…”

Section: Figure 6 Expression and Isoform-specific Inhibition Of Ap Imentioning

confidence: 99%

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Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) Degradation by Alkaline Phosphatase

Schmid

Fliegert

Westphal

et al. 2012

Journal of Biological Chemistry

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Background: Biosynthesis and metabolism of nicotinic acid adenine dinucleotide phosphate (NAADP) are unclear. Results: Alkaline phosphatase (AP) was identified and characterized as enzyme involved in NAADP degradation. Conclusion: In cells not expressing CD38, AP is a valid candidate enzyme for degradation of NAADP to nicotinic acid adenine dinucleotide. Significance: This is the first evidence for identity of the enzyme degrading NAADP in cells not expressing CD38.

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Section: Figure 6 Expression and Isoform-specific Inhibition Of Ap Isupporting

confidence: 57%

Section: Figure 6 Expression and Isoform-specific Inhibition Of Ap Imentioning

confidence: 99%

Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) Degradation by Alkaline Phosphatase

Schmid

Fliegert

Westphal

et al. 2012

Journal of Biological Chemistry

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“…The amino acid side chains of arginine, lysine, aspartate, and glutamate residues were treated as ionized. CAChe molecular modeling software (Fujitsu America, Inc., Beaverton, OR) was used to build the IQ 2-P(I) (10) and IQ 2-P (4) ligand structures (Fig. 2).…”

Section: Methodsmentioning

confidence: 99%

“…The oxygen atom of the carbonyl group in the quinazolinone moiety of IQ 2-P(I) (10) is able to form Hbonds with His 317 and His 153 , two amino acid residues positioned at the upper boundary of the binding pocket. However, unlike the pose of the phosphate group in the PLAP crystal structure, the phosphorus group of IQ 2-P(I) (10) forms only one H-bond with Arg 166 and no H-bonds with His 432 and His 320 (Fig. 4B).…”

Section: Bioinformatics (Data Mining)mentioning

confidence: 97%

“…2). Further studies have shown that IQ 2-P(I) (10) is not hydrolyzed by alkaline phosphatase and the injection of 125 IQ 2-P(I) (7) into normal mice leads to the localization of approximately 10% to 15% ID/g in liver and kidneys. 3 On the other hand, IQ 2-P (4) and 125 IQ 2-P (8) are readily hydrolyzed by alkaline phosphatase and their pharmacokinetics in normal mice following i.v.…”

Section: Introductionmentioning

confidence: 99%

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In silico design, synthesis, and biological evaluation of radioiodinated quinazolinone derivatives for alkaline phosphatase–mediated cancer diagnosis and therapy

Chen

Wang

Kirichian

et al. 2006

Molecular Cancer Therapeutics

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As part of the development of enzyme-mediated cancer imaging and therapy, a novel technology to entrap waterinsoluble radioactive molecules within solid tumors, we show that a water-soluble, radioactive quinazolinone prodrug, ammonium 2-(2 ¶-phosphoryloxyphenyl)-6-[ 125 I]iodo-4-(3H)-quinazolinone ( 125 IQ 2-P ), is hydrolyzed by alkaline phosphatase to a water-insoluble, radiolabeled drug, 2-(2 ¶-hydroxyphenyl)-6-[ 125 I]iodo-4-(3H)-quinazolinone ( 125 IQ 2-OH ). Biodistribution data suggest the existence of two isoforms of the prodrug (IQ 2-P(I) and IQ 2-P ), and this has been confirmed by their synthesis and characterization. Structural differences of the two isoforms have been examined using in silico molecular modeling techniques and docking methods to describe the interaction/binding between the isoforms and human placental alkaline phosphatase (PLAP), a tumor cell, membrane-associated, hydrolytic enzyme whose structure is known by X-ray crystallographic determination. Docking data show that IQ 2-P , but not IQ 2-P(I) , fits the active binding site of PLAP favorably and interacts with the catalytic amino acid Ser 92 , which plays an important role in the hydrolytic process. The binding free energies (#G binding ) of the isoforms to PLAP predict that IQ 2-P will be the better substrate for PLAP. The in vitro incubation of the isoforms with PLAP leads to the rapid hydrolysis of IQ 2-P only and confirms the in silico expectations. Fluorescence microscopy shows that in vitro incubation of IQ 2-P with mouse and human tumor cells causes the extracellular, alkaline phosphatasemediated hydrolysis of the molecule and precipitation of fluorescent crystals of IQ 2-OH . No hydrolysis is seen in the presence of normal mouse and human cells. Furthermore, the intratumoral injection of 125 IQ 2-P into alkaline phosphatase -expressing solid human tumors grown s.c. in nude rats results in efficient hydrolysis of the compound and retention of f70% of the injected radioactivity, whereas similar injection into normal tissues (e.g., muscle) does not produce any measurable hydrolysis (f1%) or retention of radioactivity at the injected site. These studies support the enzyme-mediated cancer imaging and therapy technology and show the potential of such quinazolinone derivatives in the in vivo radiodetection ( 123 I/ 124 I) and therapy ( 131 I) of solid tumors.

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In Situ Localization of Enzyme Activity in Live Cells by a Molecular Probe Releasing a Precipitating Fluorochrome

Liu

et al. 2017

Angewandte Chemie

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Current enzyme-responsive,f luorogenic probes fail to provide in situ information because the released fluorophores tend to diffuse away from the reaction sites.T he problem of diffusive signal dilution can be addressed by designing ap robe that upon enzyme conversion releases afluorophore that precipitates.Anexcited-state intramolecular proton transfer (ESIPT)-based solid-state fluorophore HTPQ was developed that is strictly insoluble in water and emits intense fluorescence in the solid state,with l ex/em = 410/550 nm, thus making it far better suited to use with ac ommercial confocal microscope.HTPQ was further utilized in the design of an enzyme-responsive,f luorogenic probe (HTPQA), targeting alkaline phosphatase (ALP) as am odel enzyme. HTPQA makes possible diffusion-resistant in situ detection of endogenous ALP in live cells.I tw as also employed in the visualizing of different levels of ALP in osteosarcoma cells and tissue,t hus demonstrating its interest for the diagnosis of this type of cancer.

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Alkaline phosphatase isozymes in cultured human cancer cells

Cited by 41 publications

References 50 publications

Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) Degradation by Alkaline Phosphatase

Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) Degradation by Alkaline Phosphatase

In silico design, synthesis, and biological evaluation of radioiodinated quinazolinone derivatives for alkaline phosphatase–mediated cancer diagnosis and therapy

In Situ Localization of Enzyme Activity in Live Cells by a Molecular Probe Releasing a Precipitating Fluorochrome

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