Clinical and Biological Aspects of Acid Phosphatase

Moss, D. W.; Raymond, Frank D.; Wile, D.; Rej, Robert

doi:10.3109/10408369509084690

Cited by 44 publications

(25 citation statements)

References 219 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Tartrate-sensitive lysosomal acid phosphatase (LAS) protein levels in the host were measured because accumulation of this protein reflects upregulation of endosome/phagosome maturation. 17 Rab7 was measured since this protein regulates endosome/lysosome maturation, and is associated with organellar membranes of lysosomes, endosomes, phagosomes and autophagosomes via prenylation of the C-terminal double cysteines. 15 The activation of Rab7 acts to block the binding of an antibody generated against the prenylation site of Rab7 in an Inhibition ELISA.…”

Section: Research Papermentioning

confidence: 99%

Symbiophagy as a cellular mechanism for coral bleaching

Downs¹,

Kramarsky‐Winter²,

Martinez³

et al. 2009

Autophagy

115

128

View full text Add to dashboard Cite

Section: Research Papermentioning

confidence: 99%

Symbiophagy as a cellular mechanism for coral bleaching

Downs¹,

Kramarsky‐Winter²,

Martinez³

et al. 2009

Autophagy

115

128

View full text Add to dashboard Cite

“…The enzyme is secreted into the resorptive space and there is evidence that it is required for normal bone resorption. Serum levels are elevated in patients with metabolic bone diseases such as osteoporosis and cancers with bone metastases [4]. A transgenic mouse in which the enzyme is overexpressed [5] exhibits increased bone turnover and thus resorption (osteoporosis), while the transgenic mouse knock-out [6] exhibits the opposite phenotype (osteopetrosis).…”

mentioning

confidence: 99%

Phosphotyrosyl peptides and analogues as substrates and inhibitors of purple acid phosphatases

Valizadeh

Schenk

Nash

et al. 2004

Archives of Biochemistry and Biophysics

View full text Add to dashboard Cite

Purple acid phosphatases are metal-containing hydrolases. While their precise biological role(s) is unknown, the mammalian enzyme has been linked in a variety of biological circumstances (e.g., osteoporosis) with increased bone resorption. Inhibition of the human enzyme is a possible strategy for the treatment of bone-resorptive diseases such as osteoporosis. Previously, we determined the crystal structure of pig purple acid phosphatase to 1.55 A and we showed that it is a good model for the human enzyme. Here, a study of the pH dependence of its kinetic parameters showed that the pig enzyme is most efficient at pH values similar to those encountered in the osteoclast resorptive space. Based on the observation that phosphotyrosine-containing peptides are good substrates for pig purple acid phosphatase, peptides containing a range of phosphotyrosine mimetics were synthesized. Kinetic analysis showed that they act as potent inhibitors of mammalian and plant purple acid phosphatases, with the best inhibitors exhibiting low micromolar inhibition constants at pH 3-5. These compounds are thus the most potent organic inhibitors yet reported for the purple acid phosphatases.

show abstract

“…[1][2][3] The safety issues of bisphosphonates include the risk of excessive inhibition of bone remodelling from its prolonged use, which increases the accumulation of bone microdamage, thus delaying the healing of fractures and reducing bone strength. [33][34][35] Bisphosphonates that are taken…”

Section: Current Osteoporosis Treatmentsmentioning

confidence: 99%

“…[30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] Evidence in the literature that suggests PAP's role in bone resorption include (1) transgenic mice with osteoclasts that over-expressed the PAP gene developed mild osteoporosis, 33 (2) transgenic PAP-knockout mice developed osteopetrosis (opposite of osteoporosis), 33,45 (3) osteoporosis patients are found to have elevated PAP serum levels, 46 and (4) osteoclastic bone resorption was hindered in in vitro bone resorptive assays by either a PAP specific antibody, or if molybdate, a potent PAP inhibitor, was used in the assays. [37][38] The strong correlation between PAP and the development of osteoporosis based on the evidence in the literature as stated above suggests that inhibiting PAP could halt or delay osteoporosis development.…”

Section: Molecular Weight Of Ppap Is 35000 µMol/mg Conclusion and Fmentioning

confidence: 99%

“…There has been evidence that suggests a strong link between PAP and the development of osteoporosis [30][31][32] in the literature, due to mammalian PAP's postulated role in bone resorption. 16,30,[33][34][35][36][37][38][39][40][41][42][43][44][45] Therefore, this work aims to develop new PAP inhibitors for the development of anti-osteoporotic chemotherapeutics using the approaches discussed in Section 1.5.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Design, synthesis and testing of purple acid phosphatase inhibitors for the development of anti-osteoporotic drugs

Pahmi¹

View full text Add to dashboard Cite

Purple acid phosphatases (PAPs) are binuclear metallohydrolases that have been isolated from various mammals, plants, fungi and bacteria. They catalyse phosphoric ester hydrolysis under acidic to neutral conditions by utilising two closely spaced heterovalent metal ions in their active sites. In mammals, PAP activity is associated with bone resorption, which can lead to bone diseases such as osteoporosis. For instance, osteoporosis patients are observed to have elevated PAP serum levels.Furthermore, research has shown that transgenic mice that over-expressed the PAP gene developed mild osteoporosis. These observations therefore make human PAP an attractive target to develop anti-osteoporotic drugs.This project employed the strategy of using a substrate analogue, where the lead compound (as shown below) with K i value of 8 µM against pig PAP was chosen as the basis in this rational drug design. Therefore acyl derivatives of α-aminoarylmethylphosphonic acids (as shown below) were designed as potential new potent PAP inhibitors. Docking studies suggested that the derivatives would have high binding affinity due to the phosphonate moiety (substrate mimic) binding to the binuclear metal centre, which are as intended. Furthermore, the long acyl chains make favourable interactions with the long hydrophobic groove adjacent to the dimetal centre, and depending on the size and substitutions on the aromatic ring, the ring might occupy the space in any of the small pockets in the vicinity of the active site; all of which contribute to the predicted high binding affinities of the derivatives to the enzyme.The lead compound: (naphthalene-1-yl(tetradecanamido)methyl)phosphonic acidR 2 = Me(CH 2 ) m -, Me(CH 2 ) n OCH 2 -; m = 8, 10, 12, 14, 16; n = 7, 15, 17. Acyl derivatives of α-(amino(aryl)methyl)phosphonic acids IIIThe derivatives were synthesised in three or four steps method in good yields and then tested as pig PAP inhibitors. The kinetic studies in this project were performed using newly extracted and purified pig PAP. The extraction and purification of pig PAP from the allantoic fluid of a pregnant pig was successfully carried out using fast protein liquid chromatography (FPLC) by adapting a well-established protocol. Kinetic analysis showed that the derivatives have high inhibition potencies against pig PAP with K i values in the low micromolar to nanomolar range. The most potent pig PAP inhibitor within this series was the octadecyl-derivative of α-(phenyl(amido)methyl)phosphonic acid with K i value of 168 nM. This is the most potent pig PAP inhibitor to date.Screening tests on a hundred other compounds were also performed to identify new possible alternative PAP inhibitors. Most of the compounds have metal-binding moieties as they were developed as inhibitors of a metallo-β-lactamase, which is also a binuclear metallohydrolase.Therefore it was thought that they might have inhibition properties against PAPs. However, they were found to have little or no inhibition against pig PAP. Nonetheless, these results ...

show abstract

Clinical and Biological Aspects of Acid Phosphatase

Cited by 44 publications

References 219 publications

Symbiophagy as a cellular mechanism for coral bleaching

Symbiophagy as a cellular mechanism for coral bleaching

Phosphotyrosyl peptides and analogues as substrates and inhibitors of purple acid phosphatases

Design, synthesis and testing of purple acid phosphatase inhibitors for the development of anti-osteoporotic drugs

Contact Info

Product

Resources

About