Sandbox 30008

Function

Nucleoside triphosphatase or nucleoside triphosphate diphosphohydrolase (NTPase) is responsible for degradation of nucleotides to their monophosphate form. NTPase is found in mammals and in pathogenic microbes. In mammals NTPase hs a crucial role in regulation of purinergic signalling by hydrolysis of extracellular nucleotides. The function of NTPase in pathogens is still unknown^[1].

Relevance

The modulation of NTPase activity sems a good therapeutic method for regulating the concentration of ATP. High ATP concentration has been shown to be involved in various disorders in the CNS including brain injury, ischemia, neuro-inflammation, epilepsy, neuropathic pain and migraine^[2].

Structural highlights

The 3D structure of the complex between NTPase 2 and the ATP analog AMPPNP shows the NTPase structure composed of two domains. Domain I contains the N-terminal and C-terminal and domain II the core residues. The structure contains 7 Cys-Cys bonds one of which located between domain I and II and reaching the diametrically positioned monomer was found by mutational analysis to be responsible for activation. The ATP analog - AMPPNP - is located in a cleft and forms interactions with domain I and domain II^[3].

NTPase 2 tetramer complex with AMPPNP and Mg++ ion (green) (PDB code 4a5a)

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3D structures of nucleoside triphosphatase3D structures of nucleoside triphosphatase

Updated on 12-May-2020

ReferencesReferences

↑ Krug U, Totzauer R, Zebisch M, Strater N. The ATP/ADP Substrate Specificity Switch between Toxoplasma gondii NTPDase1 and NTPDase3 is Caused by an Altered Mode of Binding of the Substrate Base. Chembiochem. 2013 Oct 2. doi: 10.1002/cbic.201300441. PMID:24115522 doi:http://dx.doi.org/10.1002/cbic.201300441
↑ Roszek K, Czarnecka J. Is Ecto-nucleoside Triphosphate Diphosphohydrolase (NTPDase)-based Therapy of Central Nervous System Disorders Possible? Mini Rev Med Chem. 2015;15(1):5-20. doi: 10.2174/1389557515666150219114416. PMID:25694082 doi:http://dx.doi.org/10.2174/1389557515666150219114416
↑ Krug U, Zebisch M, Krauss M, Strater N. Structural insight into the activation mechanism of Toxoplasma gondii nucleoside triphosphate diphosphohydrolases by disulfide reduction. J Biol Chem. 2011 Nov 30. PMID:22130673 doi:10.1074/jbc.M111.294348

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Joel L. Sussman

[1] Krug U, Totzauer R, Zebisch M, Strater N. The ATP/ADP Substrate Specificity Switch between Toxoplasma gondii NTPDase1 and NTPDase3 is Caused by an Altered Mode of Binding of the Substrate Base. Chembiochem. 2013 Oct 2. doi: 10.1002/cbic.201300441. PMID:24115522 doi:http://dx.doi.org/10.1002/cbic.201300441

[2] Roszek K, Czarnecka J. Is Ecto-nucleoside Triphosphate Diphosphohydrolase (NTPDase)-based Therapy of Central Nervous System Disorders Possible? Mini Rev Med Chem. 2015;15(1):5-20. doi: 10.2174/1389557515666150219114416. PMID:25694082 doi:http://dx.doi.org/10.2174/1389557515666150219114416

[3] Krug U, Zebisch M, Krauss M, Strater N. Structural insight into the activation mechanism of Toxoplasma gondii nucleoside triphosphate diphosphohydrolases by disulfide reduction. J Biol Chem. 2011 Nov 30. PMID:22130673 doi:10.1074/jbc.M111.294348

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