Diastereomeric Specificity of 2',3'-Cyclic Nucleotide 3-Phosphodiesterase

Heaton, Paul A.; Eckstein, Fritz

doi:10.1093/nar/24.5.850

Cited by 19 publications

(15 citation statements)

References 18 publications

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“…The cyclic nucleotides were found to be effective in the low micromolar concentration range. The effects of 2Ј,3Ј-cAMP on PT development were observed even at 0.5 M, and maximal efficiency was seen at 5 M. 2Ј,3Ј-Cyclic NADP is also a substrate for 2Ј,3Ј-cyclic nucleotide 3Ј-phosphohydrolase (20). 2Ј,3Ј-cNADP was able to shorten the lag phase before Ca 2ϩ efflux and to increase the rate of Ca 2ϩ release from both kinds of mitochondria, rat brain and liver mitochondria, when they were loaded with threshold Ca 2ϩ concentrations.…”

Section: Discussionmentioning

confidence: 94%

Ca²⁺-dependent permeability transition regulation in rat brain mitochondria by 2′,3′-cyclic nucleotides and 2′,3′-cyclic nucleotide 3′-phosphodiesterase

Azarashvili¹,

Krestinina²,

Galvita³

et al. 2009

American Journal of Physiology-Cell Physiology

109

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Azarashvili T, Krestinina O, Galvita A, Grachev D, Baburina Y, Stricker R, Evtodienko Y, Reiser G. Ca 2ϩ -dependent permeability transition regulation in rat brain mitochondria by 2Ј,3Ј-cyclic nucleotides and 2Ј,3Ј-cyclic nucleotide 3Ј-phosphodiesterase. Am J Physiol Cell Physiol 296: C1428 -C1439, 2009. First published April 8, 2009 doi:10.1152/ajpcell.00006.2009.-Recent evidence indicates that 2Ј,3Ј-cyclic nucleotide 3Ј-phosphodiesterase (CNP), a marker enzyme of myelin and oligodendrocytes, is also present in neural and nonneural mitochondria. However, its role in mitochondria is still completely unclear. We found CNP in rat brain mitochondria and studied the effects of CNP substrates, 2Ј,3Ј-cyclic nucleotides, on functional parameters of rat brain mitochondria. 2Ј,3Ј-cAMP and 2Ј,3Ј-cNADP stimulated Ca 2ϩ overload-induced Ca 2ϩ release from mitochondrial matrix. This Ca 2ϩ release under threshold Ca 2ϩ load correlated with membrane potential dissipation and mitochondrial swelling. The effects of 2Ј,3Ј-cyclic nucleotides were suppressed by cyclosporin A, a potent inhibitor of permeability transition (PT). PT development is a key stage in initiation of apoptotic mitochondriainduced cell death. 2Ј,3Ј-cAMP effects were observed on the functions of rat brain mitochondria only when PT was developed. This demonstrates involvement of 2Ј,3Ј-cAMP in PT regulation in rat brain mitochondria. We also discovered that, under PT development, the specific enzymatic activity of CNP was reduced. Thus we hypothesize that suppression of CNP activity under threshold Ca 2ϩ load leads to elevation of 2Ј,3Ј-cAMP levels that, in turn, promote PT development in rat brain mitochondria. Similar effects of 2Ј,3Ј-cyclic nucleotides were observed in rat liver mitochondria. Involvement of CNP in PT regulation was confirmed in experiments using mitochondria from CNP-knockdown oligodendrocytes (OLN93 cells). CNP reduction in these mitochondria correlated with lowering the threshold for Ca 2ϩ overload-induced Ca 2ϩ release. Thus our results reveal a new function for CNP and 2Ј,3Ј-cAMP in mitochondria, being a regulator/promotor of mitochondrial PT. oligodendrocyte mitochondria; 2Ј,3Ј-cyclic nucleotide 3Ј-phosphodiesterase; permeability transition; calcium transport THE ENZYME 2Ј,3Ј-CYCLIC NUCLEOTIDE 3Ј-phosphodiesterase (CNP, EC 3.1.4.37) accounts for ϳ2-5% of the total protein in the central nervous system myelin and 0.5-1% of peripheral nervous system myelin (36). CNP catalyzes the hydrolysis of 2Ј,3Ј-cyclic nucleotides to form the corresponding 2Ј-monophosphates (3). CNP was shown to be an integral protein of myelin of oligodendrocytes in the central nervous system and of peripheral myelin in Schwann cells (36,39). The majority of studies investigating the role of CNP were focused exclusively on the expression of CNP in oligodendrocytes and Schwann cells and the involvement of CNP in myelinogenesis. However, there is increasing evidence showing that this enzyme is present in a variety of other cell types. CNP-like enzyme activity was found ...

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Section: Discussionmentioning

confidence: 94%

Ca²⁺-dependent permeability transition regulation in rat brain mitochondria by 2′,3′-cyclic nucleotides and 2′,3′-cyclic nucleotide 3′-phosphodiesterase

Azarashvili¹,

Krestinina²,

Galvita³

et al. 2009

American Journal of Physiology-Cell Physiology

109

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“…Prior to that, CNPase had already been shown to have substrate stereoselectivity, using nucleoside 2′,3′-cyclic monophosphorothioate analogs [65] .…”

Section: Activitymentioning

confidence: 99%

The myelin membrane-associated enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase: on a highway to structure and function

Raasakka

Kursula

2014

Neurosci. Bull.

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The membrane-anchored myelin enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) was discovered in the early 1960s and has since then troubled scientists with its peculiar catalytic activity and high expression levels in the central nervous system. Despite decades of research, the actual physiological relevance of CNPase has only recently begun to unravel. In addition to a role in myelination, CNPase is also involved in local adenosine production in traumatic brain injury and possibly has a regulatory function in mitochondrial membrane permeabilization. Although research focusing on the CNPase phosphodiesterase activity has been helpful, several open questions concerning the protein function in vivo remain unanswered. This review is focused on past research on CNPase, especially in the fields of structural biology and enzymology, and outlines the current understanding regarding the biochemical and physiological signifi cance of CNPase, providing ideas and directions for future research.Keywords: 2′,3′-cyclic nucleotide 3′-phosphodiesterase; calmodulin; central nervous system; cytoskeleton; myelin proteins; RNA ·Review· IntroductionMyelin is a specialized multilamellar structure, which is wrapped around neuronal axons by oligodendrocytes in the central nervous system (CNS) and by Schwann cells in the peripheral nervous system (PNS). The membrane sheets of myelin are densely packed, resulting in the extrusion of cytosolic elements and in the formation of a lipid-rich, insulating sheath that enables the acceleration of nerve impulses. A mature myelin sheath can be morphologically divided into compact and non-compact myelin, of which the latter has a higher cytosolic content and further contains several subcompartments, such as the abaxonal and adaxonal layers, as well as the paranodal loops [1,2] .Myelin contains a set of unique proteins that generally display strict localization to either compact or non-compact myelin, which is thought to be at least partially driven by size exclusion [3,4] . The myelin environment being low in aqueous content and harboring negatively charged, tightly packed membrane interfaces, myelin proteins typically exhibit attributes such as strong hydrophobicity, peripheral membrane association, transmembrane domains, and a high positive net charge, as well as intrinsic disorder [5] .Several myelin proteins have delicately regulated expression levels and functions. Past research using cell culture and animal models have outlined the importance of various proteins in demyelination -a situation where myelin undergoes morphological changes and loss [6] .Demyelination causes neurological disorders, including multiple sclerosis (MS), Charcot-Marie-Tooth disease, and leukodystrophies, such as Pelizaeus-Merzbacher disease [7][8][9][10] .2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase)is one of the most abundant proteins in CNS myelin and a possible auto-antigen in MS [4,11] . The high expression levels of CNPase, together with its rather unusual enzymatic after the initial di...

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“…In these analogues, one of the cyclic phosphate oxygen atoms is replaced by a sulfur. Previously, it has been shown that the Sp epimer of 2',3'-cAMPS is a functional substrate for CNPase, while the Rp epimer is not 36 . We used both wild-type CNPase and selected mutants to determine crystal structures of CNPase in the presence of the two phosphorothioate epimers.…”

Section: Phosphorothioate Complexesmentioning

confidence: 99%

“…CNPase has stereospecificity towards 2',3'-cAMPS analogues, with only the Sp epimer being a good substrate 36 . Our crystal structures with both the Sp and Rp epimers indicate subtle differences in the cyclic ligand conformation; while the Sp epimer is very similar to 2',3'-cAMP, the Rp epimer complex structure is missing the nucleophilic water molecule.…”

Section: Further Insights From Active-site Ligand Complexesmentioning

confidence: 99%

Self-Assembly Characteristics of a Crystalline–Amorphous Diblock Copolymer in Nanoscale Thin Films

Kim

Ahn

et al. 2013

Macromolecules

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Abstract2H phosphoesterases catalyze reactions on nucleotide substrates and contain two conserved histidine residues in the active site. Very limited information is currently available on the details of the active site and substrate/product binding during the catalytic cycle of these enzymes. We performed a comprehensive X-ray crystallographic study of mouse 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), a membrane-associated enzyme present at high levels in the tetrapod myelin sheath. We determined crystal structures of the CNPase phosphodiesterase domain complexed with substrate, product, and phosphorothioate analogues. The data provide detailed information on the CNPase reaction mechanism, including substrate binding mode and coordination of the nucleophilic water molecule. Linked to the reaction, an open/close motion of the β5-α7 loop is observed. The role of the N terminus of helix α7 -unique for CNPase in the 2H family -during the reaction indicates that 2H phosphoesterases differ in their respective reaction mechanisms, despite the conserved catalytic residues. Furthermore, based on small-angle X-ray scattering, we present a model for the full-length enzyme, indicating the two domains of CNPase form an elongated molecule. Finally, based on our structural data and a comprehensive bioinformatics study, we discuss the conservation of CNPase in various organisms.

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Diastereomeric Specificity of 2',3'-Cyclic Nucleotide 3-Phosphodiesterase

Cited by 19 publications

References 18 publications

Ca²⁺-dependent permeability transition regulation in rat brain mitochondria by 2′,3′-cyclic nucleotides and 2′,3′-cyclic nucleotide 3′-phosphodiesterase

Ca²⁺-dependent permeability transition regulation in rat brain mitochondria by 2′,3′-cyclic nucleotides and 2′,3′-cyclic nucleotide 3′-phosphodiesterase

The myelin membrane-associated enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase: on a highway to structure and function

Self-Assembly Characteristics of a Crystalline–Amorphous Diblock Copolymer in Nanoscale Thin Films

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Diastereomeric Specificity of 2',3'-Cyclic Nucleotide 3-Phosphodiesterase

Cited by 19 publications

References 18 publications

Ca2+-dependent permeability transition regulation in rat brain mitochondria by 2′,3′-cyclic nucleotides and 2′,3′-cyclic nucleotide 3′-phosphodiesterase

Ca2+-dependent permeability transition regulation in rat brain mitochondria by 2′,3′-cyclic nucleotides and 2′,3′-cyclic nucleotide 3′-phosphodiesterase

The myelin membrane-associated enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase: on a highway to structure and function

Self-Assembly Characteristics of a Crystalline–Amorphous Diblock Copolymer in Nanoscale Thin Films

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Ca²⁺-dependent permeability transition regulation in rat brain mitochondria by 2′,3′-cyclic nucleotides and 2′,3′-cyclic nucleotide 3′-phosphodiesterase

Ca²⁺-dependent permeability transition regulation in rat brain mitochondria by 2′,3′-cyclic nucleotides and 2′,3′-cyclic nucleotide 3′-phosphodiesterase