Novel Substrates for Kinases Involved in the Biosynthesis of Inositol Pyrophosphates and Their Enhancement of ATPase Activity of a Kinase.

Autor: Mohanrao R; School of Chemistry, Indian Institute of Science Education and Research Thiruvananthapuram, Kerala 695551, India., Manorama R; Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, India., Ganguli S; Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, India.; Manipal Academy of Higher Education, Manipal 576104, India., Madhusudhanan MC; School of Chemistry, Indian Institute of Science Education and Research Thiruvananthapuram, Kerala 695551, India., Bhandari R; Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, India., Sureshan KM; School of Chemistry, Indian Institute of Science Education and Research Thiruvananthapuram, Kerala 695551, India.
Jazyk: angličtina
Zdroj: Molecules (Basel, Switzerland) [Molecules] 2021 Jun 11; Vol. 26 (12). Date of Electronic Publication: 2021 Jun 11.
DOI: 10.3390/molecules26123601
Abstrakt: IP6K and PPIP5K are two kinases involved in the synthesis of inositol pyrophosphates. Synthetic analogs or mimics are necessary to understand the substrate specificity of these enzymes and to find molecules that can alter inositol pyrophosphate synthesis. In this context, we synthesized four scyllo -inositol polyphosphates- scyllo -IP 5 , scyllo -IP 6 , scyllo -IP 7 and Bz- scyllo -IP 5 -from myo -inositol and studied their activity as substrates for mouse IP6K1 and the catalytic domain of VIP1, the budding yeast variant of PPIP5K. We incubated these scyllo -inositol polyphosphates with these kinases and ATP as the phosphate donor. We tracked enzyme activity by measuring the amount of radiolabeled scyllo -inositol pyrophosphate product formed and the amount of ATP consumed. All scyllo -inositol polyphosphates are substrates for both the kinases but they are weaker than the corresponding myo -inositol phosphate. Our study reveals the importance of axial-hydroxyl/phosphate for IP6K1 substrate recognition. We found that all these derivatives enhance the ATPase activity of VIP1. We found very weak ligand-induced ATPase activity for IP6K1. Benzoyl- scyllo -IP 5 was the most potent ligand to induce IP6K1 ATPase activity despite being a weak substrate. This compound could have potential as a competitive inhibitor.
Databáze: MEDLINE
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