A Novel Pyrazolopyrimidine Ligand of Human PGK1 and Stress Sensor DJ1 Modulates the Shelterin Complex and Telomere Length Regulation

Bilsland, Alan; Liu, Yu; Turnbull, A.P.; Sumpton, David; Stevenson, Katrina H.; Cairney, Claire J.; Boyd, Susan M.; Roffey, Jon; Jenkinson, D; Keith, W. Nicol

doi:10.1016/j.neo.2019.07.008

Cited by 6 publications

(13 citation statements)

References 66 publications

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“…Increasing PGK1 abundance in vivo offered strong protection against striatal DA axon dysfunction and was able to reverse cellular phenotypes in primary cultured neurons harboring the PARK20 mutation. These data strongly support the idea that PGK1 activity serves as a critical lever arm in controlling nerve terminal function under hypometabolic conditions and suggests that hypometabolic deficits may underly a wide-spectrum of PD etiology 11,12,14–19 .…”

Section: Introductionsupporting

confidence: 79%

“…An unbiased chemical screen recently led to the identification of an interaction between PGK1 and DJ-1 19 , the product of the PARK7 gene, a genetic driver of familial PD 24,25 . DJ-1 is a chaperone with strong structurally similarity to HSP31 26 but the precise clientele that it supports related to PD is poorly understood 27 .…”

Section: Park7 (Dj-1) Interacts With Pgk1 and Is Necessary For Pgk1 M...mentioning

confidence: 99%

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Phosphoglycerate kinase 1 is a central leverage point in Parkinson's disease driven neuronal metabolic deficits

Kokotos,

Antoniazzi,

Unda

et al. 2023

Preprint

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Phosphoglycerate kinase 1 (PGK1), the first ATP producing glycolytic enzyme, has emerged as a therapeutic target for Parkinson's Disease (PD), since a potential enhancer of its activity was reported to significantly lower PD risk. We Carried out a suppressor screen of hypometabolic synaptic deficits and demonstrated that PGK1 is the rate limiting enzyme in nerve terminal ATP production. Increasing PGK1 expression in mid-brain dopamine neurons protected against hydroxy-dopamine driven striatal dopamine nerve terminal dysfunction in-vivo and modest changes in PGK1 activity dramatically supressed hypometabolic dysfunction in-vitro. Furthermore, PGK1 is cross-regulated by PARK7(DJ-1), a PD associated molecular chaperone, and synaptic deficits driven by PARK20 (Synaptojanin-1) can be reversed by increasing local synaptic PGK1 activity. These data indicate that nerve terminal bioenergetic deficits may underly a a spectrum of PD susceptibilities and the identification of PGK1 as the limiting enzyme in axonal glycolysis provides a mechanistic underpinning for therapeutic protection.

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Section: Introductionsupporting

confidence: 79%

Section: Park7 (Dj-1) Interacts With Pgk1 and Is Necessary For Pgk1 M...mentioning

confidence: 99%

Phosphoglycerate kinase 1 is a central leverage point in Parkinson's disease driven neuronal metabolic deficits

Kokotos,

Antoniazzi,

Unda

et al. 2023

Preprint

View full text Add to dashboard Cite

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“… AfBPs A) for the aurora kinases [30,32, 54] and B) for PKM2 ( 59 , 60 ), [55] TMPK ( 61 ), [56] PGK1 ( 62 ), [57] IRE1α ( 63 ), [58] and PI4KB ( 64 , 65 ) [59,60] …”

Section: Probes Per Kinase Familymentioning

confidence: 99%

Probes for Photoaffinity Labelling of Kinases

et al. 2021

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Protein kinases, one of the largest enzyme superfamilies, regulate many physiological and pathological processes. They are drug targets for multiple human diseases, including various cancer types. Probes for the photoaffinity labelling of kinases are important research tools for the study of members of this enzyme superfamily. In this review, we discuss the design principles of these probes, which are mainly derived from inhibitors targeting the ATP pocket. Overall, insights from crystal structures guide the placement of photoreactive groups and detection tags. This has resulted in a wide variety of probes, of which we provide a comprehensive overview. We also discuss several areas of application of these probes, including the identification of targets and off‐targets of kinase inhibitors, mapping of their binding sites, the development of inhibitor screening assays, the imaging of kinases, and identification of protein binding partners.

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“…Due to their pharmacological properties, pyrazolopyrimidines known as purine analogs have attracted a lot of research. [22,23] They utilized antitrypanosomal, antimetabolites in purine biochemical interactions, sedative and antitrypanosomal, kinase inhibitors, HIV (human immunodeficiency viruses), reverse transcriptase inhibitors, as well as antifungal and antimalarial properties. [24][25][26][27]…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, Antimicrobial and Docking Studies of Benzothiazoles Bearing Pyrazole and Pyrimidine Moieties

Tamam,

Fadda,

El‐Sawy

et al. 2023

ChemistrySelect

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The reaction of enaminonitrile 2 with hydrazine hydrate yielded 5‐amino pyrazole derivative 4. Compound 4 reacted with ethyl acetoacetate, enaminone 8, chalcone 12, enaminonitrile 2, arylidene malononitrile 18, 3‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)‐3‐oxopropanenitrile 21 and phenacyl bromide to give the corresponding pyrazolopyrimidine derivatives 7, 11, 14, 17, 20, 23, and imidazopyrazole 25, respectively. The newly synthesized compounds were characterized by spectral and elemental analyses. The antimicrobial activities of the new compounds were tested against S. aureus, E. coli, and C. albicans. It was found that compound 23 exhibited the highest antimicrobial activity against the tested microorganisms. All tested compounds did not have antifungal activity against A. niger as a fungal strain. Utilizing drug‐likeness (ADME) and molecular docking the effectiveness of compound 23 towards G+ve and G‐ve bacteria has been studied. Accordingly, compound 23 is expected to have a high chance of oral bioavailability due to its compliance with Lipinski′s rule of five. In addition, it plays a critical role in the inhibition of bacterial S. Ribosome, dihydropteroate synthase, transpeptidase, and gyrase B. subunit proteins.

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A Novel Pyrazolopyrimidine Ligand of Human PGK1 and Stress Sensor DJ1 Modulates the Shelterin Complex and Telomere Length Regulation

Cited by 6 publications

References 66 publications

Phosphoglycerate kinase 1 is a central leverage point in Parkinson's disease driven neuronal metabolic deficits

Phosphoglycerate kinase 1 is a central leverage point in Parkinson's disease driven neuronal metabolic deficits

Probes for Photoaffinity Labelling of Kinases

Design, Synthesis, Antimicrobial and Docking Studies of Benzothiazoles Bearing Pyrazole and Pyrimidine Moieties

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