Irreversible inactivation of purple acid phosphatase by hydrogen peroxide and ascorbate

Beck, Jennifer L.; Durack, M.; Hamilton, Susan; Jersey, John de

doi:10.1016/s0162-0134(99)00022-7

Cited by 14 publications

(19 citation statements)

References 28 publications

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“…The results are consistent with the generation of hydroxyl radicals by the enzyme, and subsequent inactivation as a result of reaction of the hydroxyl radicals with active-site residues. 9 The presence of the inactive form of TRAP in the circulation (see earlier) could be indirect evidence that a strong oxidative environment occurs during bone resorption in vivo and may also suggest a simple mechanism of feedback regulation of TRAP enzyme activity by product inhibition.…”

Section: Other Possible Functions Of Trap Enzymesmentioning

confidence: 96%

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Structure, function, and regulation of tartrate-resistant acid phosphatase

Oddie

Schenk

Angel

et al. 2000

Bone

200

198

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Section: Other Possible Functions Of Trap Enzymesmentioning

confidence: 96%

“…44 TRAP may become irreversibly inactivated by oxidation in the presence of ascorbate. 9 The recent availability of monoclonal antibodies against TRAP 20,41,43,44,51,57 has permitted the identification of an inactivated "yellowish" form of the enzyme as the major form in the circulation. 44 …”

Section: Introduction: Biochemistry Of Tartrate-resistant Acid Phosphmentioning

confidence: 99%

Structure, function, and regulation of tartrate-resistant acid phosphatase

Oddie

Schenk

Angel

et al. 2000

Bone

200

198

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“…1 This therefore makes human PAP (hPAP) a very attractive target for the development of anti-osteoporotic drugs. [48][49][50][51][52][53][54][55]156 1. known to inhibit PAP activity. However, most of these compounds are too toxic to be used in vivo, as they are non-specific inhibitors and thus their potential as therapeutics is limited.…”

Section: Paps' Biological Functionsmentioning

confidence: 99%

“…Table 4: PTyr analogues (X) substituted in Fmoc-Glu-X-Ala-amide (5)(6)(7)(8)(9)(10) Efforts into developing PAP inhibitors have also focused on using the approach of mimicking the PAPs' substrate phosphoesters, by replacing the hydrolysable O-P bond in phosphoric esters with non-cleavable C-P bond in phosphonates. 48,51,[53][54]156 However, the replacement of the ester oxygen with a methylene group can potentially lead to loss of interaction between the compound and an acid or metal ion in PAP's active site. Nonetheless, this approach has led to several antiosteoporotic drug leads.…”

Section: Paps' Biological Functionsmentioning

confidence: 99%

“…156 Interestingly, each of the enantiomer has comparable IC 50 values against both PAPs between each other, and what is more fascinating is that the racemic 25f is more potent than the individual enantiomers (see Based on the high inhibitory properties of 25, McGeary and co-workers have put in efforts towards improving the potency of compounds 25, and therefore designed yet another series of PAP inhibitors 26 (Figure 9), where the ether bond in 25 was replaced with a secondary amide bond in 26. 54 This modification was chosen as the amide bond in compound 26 is expected to improve the water solubility of the inhibitors and also be easier to synthesise than 25. 54 Scheme 1 shows the four-step synthetic method to synthesise 25 from 1-naphthaldehyde (27), and Scheme 2 shows the three-step synthetic method to synthesise 26 from the same starting material 1-naphthaldehyde (27).…”

Section: Inhibitormentioning

confidence: 99%

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

Pahmi¹

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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 ...

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Biological and Biomedical Aspects of Metal Phenolates

Ming

2014

Patai's Chemistry of Functional Groups

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The phenol functionality is involved in diverse biological processes and functions, serving as a proton donor and as a metal‐binding ligand. It is commonly found in many biochemicals (such as siderophores and the amino acids tyrosine and tryptophan), pharmaceuticals (including antibiotics, metal‐chelating agents, and diagnostic agents), and natural products (such as polyphenols, flavonoids, and salicylic acid). In association with other functional groups, the phenol moiety forms various types of metal‐binding sites of diverse structures and functions, for example, for iron binding and transport, in enzymes for oxygenation of substrates, and for biotransformation of aromatic compounds. Many environmentally hazardous aromatic compounds such as bisphenol A, PCB, and DDT can be degraded by tyrosinate(phenolate)‐containing metalloenzymes from microorganisms, which provides a clue for bioremediation of these toxic substances. Moreover, the phenol‐containing wet‐adhesive byssal proteins from some clams and mussels has stimulated further development of adhesive materials for medical and other applications; and the study of binding of transferrin with nanoparticles affords better understanding of protein–mineral interfacial interactions. In addition to these naturally occurring metal‐phenolate centers, there are many metal complexes of phenol and derivatives that exhibit various catalytic activities and serve as structural and/or functional model systems for tyrosinate‐containing metalloproteins.

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Irreversible inactivation of purple acid phosphatase by hydrogen peroxide and ascorbate

Cited by 14 publications

References 28 publications

Structure, function, and regulation of tartrate-resistant acid phosphatase

Structure, function, and regulation of tartrate-resistant acid phosphatase

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

Biological and Biomedical Aspects of Metal Phenolates

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