Purple acid phosphatase inhibitors as leads for osteoporosis chemotherapeutics

Hussein, Waleed M.; Feder, Daniel; Schenk, Gerhard; Guddat, L.W.; McGeary, Ross P.

doi:10.1016/j.ejmech.2018.08.004

Cited by 15 publications

(4 citation statements)

References 73 publications

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“…PAPs were first isolated from mammalian species and play a role in bone metabolism ( Feder et al , 2019a ). Serum concentrations of PAPs are significantly increased in patients suffering from osteoporosis, and hence several inhibitors have been developed as therapeutic agents to treat this condition ( Hussein et al , 2018 ; Feder et al , 2019b ). Since their discovery in mammals, many PAP isoforms have also been purified from plant tissues ( del Pozo et al , 1999 ; Miller et al , 2001 ; Bozzo et al , 2004 ), and the physiological functions of a number of them have been characterized, most of which are related to P nutrition ( Tran et al , 2010b ; Wang et al , 2011 ; Robinson et al , 2012 ; Lu et al , 2016 ; Li et al , 2017 ; Mehra et al , 2017 ; Wu et al , 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Purple acid phosphatase 10c encodes a major acid phosphatase that regulates plant growth under phosphate-deficient conditions in rice

Deng

et al. 2020

Journal of Experimental Botany

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Abstract Whilst constitutive overexpression of particular acid phosphatases (APases) can increase utilization of extracellular organic phosphate, negative effects are frequently observed in these transgenic plants under conditions of inorganic phosphate (Pi) sufficiency. In this study, we identified rice purple acid phosphatase 10c (OsPAP10c) as being a novel and major APase that exhibits activities associated both with the root surface and with secretion. Two constructs were used to generate the OsPAP10c-overexpression plants by driving its coding sequence with either a ubiquitin promoter (UP) or the OsPAP10c-native promoter (NP). Compared with the UP transgenic plants, lower expression levels and APase activities were observed in the NP plants. However, the UP and NP plants both showed a similar ability to degrade extracellular ATP and both promoted root growth. The growth performance and yield of the NP transgenic plants were better than the wild-type and UP plants in both hydroponic and field experiments irrespective of the level of Pi supply. Overexpression of APase by its native promoter therefore provides a potential way to improve crop production that might avoid increased APase activity in untargeted tissues and its inhibition of the growth of transgenic plants.

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Section: Introductionmentioning

confidence: 99%

Purple acid phosphatase 10c encodes a major acid phosphatase that regulates plant growth under phosphate-deficient conditions in rice

Deng

et al. 2020

Journal of Experimental Botany

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“…The residues for which the abbreviations have not been defined (LXZ, NGA and GL0) are similar to NAG, NAG and GAL, respectively, but with one or more inverted chiral centers. Bottom: glycosylation-tree extension at AsnC81 in PDB entry 6g46 (Hussein et al, 2018). Three residues could be added at this position, which was enabled partly because of improved refinement in PDB-REDO (R free decreased from 23.1% to 21.5%).…”

Section: Discussionmentioning

confidence: 99%

Building and rebuilding N-glycans in protein structure models

Beusekom

Wezel

Hekkelman

et al. 2019

Acta Cryst Sect D Struct Biol

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N-Glycosylation is one of the most common post-translational modifications and is implicated in, for example, protein folding and interaction with ligands and receptors. N-Glycosylation trees are complex structures of linked carbohydrate residues attached to asparagine residues. While carbohydrates are typically modeled in protein structures, they are often incomplete or have the wrong chemistry. Here, new tools are presented to automatically rebuild existing glycosylation trees, to extend them where possible, and to add new glycosylation trees if they are missing from the model. The method has been incorporated in the PDB-REDO pipeline and has been applied to build or rebuild 16 452 carbohydrate residues in 11 651 glycosylation trees in 4498 structure models, and is also available from the PDB-REDO web server. With better modeling of N-glycosylation, the biological function of this important modification can be better and more easily understood.

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“…[84] The various fragments bound to at least one of four distinct locations (S1-S4, with S1 partially occupied by phosphate; Figure 1) within the active site of pig PAP (described below), all in the vicinity of the repression loop and the long groove under this loop, an area we targeted previously and obtained good inhibitors. [42,43,45] Crystal structure of the pig PAP-CC063346 complex. Phosphate is bound to the metal center (located in S1) in two, slightly different bidentate orientations (Figure 2), differing in their mode of interaction with the His92 imidazole nitrogen atom (H-bond in the primary occupant and a salt bridge in the secondary occupant).…”

Section: In Crystallo Screen To Identify Fragments That Bind To the Active Site Of Pig Papmentioning

confidence: 99%

“…[38] These observations have identified PAP as a promising target for the design of specific inhibitors as leads for the development of novel chemotherapeutics to treat osteoporosis and related bone ailments. [39][40][41][42][43][44][45] Moreover, since PAP is a marker for several other human diseases, potent PAP inhibitors may also find clinical applications in the treatment of other conditions associated with elevated levels of PAP in the bloodstream, e. g. AIDS encephalopathy, [46] Gaucher's disease, [47] hairy cell leukemia, [48] Alzheimer's disease, [49,50] osteoclastoma, [51] breast cancer, [31,35,[52][53][54] chronic obstructive pulmonary disease (COPD), asthma, [55] rheumatoid arthritis [32,56] and bone metastases. [53] Mammalian PAPs characterized to date are highly conserved across different species, exhibiting over 85 % amino acid sequence identity.…”

Section: Introductionmentioning

confidence: 99%

Rational Design of Potent Inhibitors of a Metallohydrolase Using a Fragment‐Based Approach

et al. 2021

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Metallohydrolases form a large group of enzymes that have fundamental importance in a broad range of biological functions. Among them, the purple acid phosphatases (PAPs) have gained attention due to their crucial role in the acquisition and use of phosphate by plants and also as a promising target for novel treatments of bone-related disorders and cancer. To date, no crystal structure of a mammalian PAP with drug-like molecules bound near the active site is available. Herein, we used a fragment-based design approach using structures of a mammalian PAP in complex with the Maybridge TM fragment CC063346, the amino acid L-glutamine and the buffer molecule HEPES, as well as various solvent molecules to guide the design of highly potent and efficient mammalian PAP inhibitors. These inhibitors have improved aqueous solubility when compared to the clinically most promising PAP inhibitors available to date. Furthermore, drug-like fragments bound in newly discovered binding sites mapped out additional scaffolds for further inhibitor discovery, as well as scaffolds for the design of inhibitors with novel modes of action.

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Purple acid phosphatase inhibitors as leads for osteoporosis chemotherapeutics

Cited by 15 publications

References 73 publications

Purple acid phosphatase 10c encodes a major acid phosphatase that regulates plant growth under phosphate-deficient conditions in rice

Purple acid phosphatase 10c encodes a major acid phosphatase that regulates plant growth under phosphate-deficient conditions in rice

Building and rebuilding N-glycans in protein structure models

Rational Design of Potent Inhibitors of a Metallohydrolase Using a Fragment‐Based Approach

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