Structure−Activity Relationship of Uridine 5‘<b>-</b>Diphosphoglucose Analogues as Agonists of the Human P2Y<sub>14</sub> Receptor

Ko, Hyojin; Fricks, Ingrid; Иванов, А. А.; Harden, T. Kendall; Jacobson, Kenneth A.

doi:10.1021/jm061222w

Cited by 59 publications

(73 citation statements)

References 40 publications

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“…Nevertheless, when a new compound is considered for clinical development, it is generally recommended to initiate therapy at a low dose to minimize potential adverse effects. A high-potency UDPGlc, MRS 2690, displays approximately 7-fold higher potency than UDP-Glc (60), and became commercially available in recent years. This new compound may allow a reduction in the dose of UDP-Glc needed while maintaining the desired effects.…”

Section: Discussionmentioning

confidence: 99%

The nucleotide sugar UDP-glucose mobilizes long-term repopulating primitive hematopoietic cells

Kook¹,

Cho²,

Lee³

et al. 2013

J. Clin. Invest.

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Hematopoietic stem progenitor cells (HSPCs) are present in very small numbers in the circulating blood in steady-state conditions. In response to stress or injury, HSPCs are primed to migrate out of their niche to peripheral blood. Mobilized HSPCs are now commonly used as stem cell sources due to faster engraftment and reduced risk of posttransplant infection. In this study, we demonstrated that a nucleotide sugar, UDP-glucose, which is released into extracellular fluids in response to stress, mediates HSPC mobilization. UDP-glucosemobilized cells possessed the capacity to achieve long-term repopulation in lethally irradiated animals and the ability to differentiate into multi-lineage blood cells. Compared with G-CSF-mobilized cells, UDP-glucose-mobilized cells preferentially supported long-term repopulation and exhibited lymphoid-biased differentiation, suggesting that UDP-glucose triggers the mobilization of functionally distinct subsets of HSPCs. Furthermore, co-administration of UDP-glucose and G-CSF led to greater HSPC mobilization than G-CSF alone. Administration of the antioxidant agent NAC significantly reduced UDP-glucose-induced mobilization, coinciding with a reduction in RANKL and osteoclastogenesis. These findings provide direct evidence demonstrating a potential role for UDP-glucose in HSPC mobilization and may provide an attractive strategy to improve the yield of stem cells in poor-mobilizing allogeneic or autologous donors.

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Section: Discussionmentioning

confidence: 99%

The nucleotide sugar UDP-glucose mobilizes long-term repopulating primitive hematopoietic cells

Kook¹,

Cho²,

Lee³

et al. 2013

J. Clin. Invest.

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“…For example, 2-thio-UDP-glucose (MRS2690) exhibits 30-fold greater potency for the P2Y 14 R than does UDPglucose (Ko et al, 2007. Several analogs of UDP also have been developed that exhibit high potency at the P2Y 14 R (Das et al, 2010).…”

Section: Mechanisms Of Release and Metabolism Of Nucleotide Sugarsmentioning

confidence: 99%

UDP-Sugars as Extracellular Signaling Molecules: Cellular and Physiologic Consequences of P2Y₁₄ Receptor Activation

Lazarowski

Harden

2015

Mol Pharmacol

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UDP-sugars, which are indispensable for protein glycosylation reactions in cellular secretory pathways, also act as important extracellular signaling molecules. We discuss here the broadly expressed P2Y 14 receptor, a G-protein-coupled receptor targeted by UDP sugars, and the increasingly diverse set of physiologic responses discovered recently functioning downstream of this receptor in many epithelia as well as in immune, inflammatory, and other cells.

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“…Effects of P2Y14 agonists on osteoclast formation UDP-glucose and related sugar nucleotides including UDPgalactose, UDP-glucuronic acid and UDP-N-acetylglucosamine are all potent agonists of the P2Y14 receptor (Chambers et al, 2000;Ko et al, 2007). We investigated the effects of P2Y14 agonists on osteoclast formation.…”

Section: P38 Map Kinase Pathway Is Involved In Rankl-induced P2y14 Exmentioning

confidence: 99%

Selective Induction of P2Y14 Receptor by RANKL Promotes Osteoclast Formation

Lee

Park

Lee

2013

Molecules and Cells

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The purinergic receptor P2Y, G protein coupled, 14 (P2Y14) receptor for UDP-glucose and other UDP-sugars has been implicated in the regulation of the stem cell compartment as well as neuroimmune function. However, the role of P2Y14 in osteoclast formation is completely unknown. We found that RANKL selectively induced P2Y14 among seven mammalian P2Y receptors when analysed at both the mRNA and protein level, but inhibitors of the mitogenactivated protein (MAP) kinase pathway suppressed induction of P2Y14 proteins. Extracellular addition of UDP-sugars such as UDP-glucose, UDP-galactose, UDP-glucuronic acid, and UDP-N-acetyl glucosamine promoted RANKLinduced osteoclastogenesis, while P2Y14 downregulation by RNA interference inhibited osteoclast formation. Taken together, these results suggest that P2Y14 may act as the receptor for UDP-sugars in osteoclast precusors and may regulate RANKL-induced osteoclastogenesis.

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Structure−Activity Relationship of Uridine 5‘-Diphosphoglucose Analogues as Agonists of the Human P2Y₁₄ Receptor

Cited by 59 publications

References 40 publications

The nucleotide sugar UDP-glucose mobilizes long-term repopulating primitive hematopoietic cells

The nucleotide sugar UDP-glucose mobilizes long-term repopulating primitive hematopoietic cells

UDP-Sugars as Extracellular Signaling Molecules: Cellular and Physiologic Consequences of P2Y₁₄ Receptor Activation

Selective Induction of P2Y14 Receptor by RANKL Promotes Osteoclast Formation

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Structure−Activity Relationship of Uridine 5‘-Diphosphoglucose Analogues as Agonists of the Human P2Y14 Receptor

Cited by 59 publications

References 40 publications

The nucleotide sugar UDP-glucose mobilizes long-term repopulating primitive hematopoietic cells

The nucleotide sugar UDP-glucose mobilizes long-term repopulating primitive hematopoietic cells

UDP-Sugars as Extracellular Signaling Molecules: Cellular and Physiologic Consequences of P2Y14 Receptor Activation

Selective Induction of P2Y14 Receptor by RANKL Promotes Osteoclast Formation

Contact Info

Product

Resources

About

Structure−Activity Relationship of Uridine 5‘-Diphosphoglucose Analogues as Agonists of the Human P2Y₁₄ Receptor

UDP-Sugars as Extracellular Signaling Molecules: Cellular and Physiologic Consequences of P2Y₁₄ Receptor Activation