2',3'-Cyclic-nucleotide 3'-phosphodiesterase explained

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2′,3′-Cyclic-nucleotide 3'-phosphodiesterase
Ec Number:	3.1.4.37
Cas Number:	60098-35-3
Go Code:	0004113

2′,3′-Cyclic-nucleotide 3'-phosphodiesterase (EC 3.1.4.37, CNPase, systematic name nucleoside-2′,3′-cyclic-phosphate 2′-nucleotidohydrolase) is an enzyme that in humans is encoded by the CNP gene.^{[1] [2]}

Reaction

CNPase catalyzes the following reaction:

nucleoside 2′,3′-cyclic phosphate + H₂O

\rightleftharpoons nucleoside 2′-phosphate

Function

CNPase is a myelin-associated enzyme that makes up 4% of total CNS myelin protein, and is thought to undergo significant age-associated changes.^[3] It is named for its ability to catalyze the phosphodiester hydrolysis of 2',3'-cyclic nucleotides to 2'-nucleotides, though a cohesive understanding of its specific physiologic functions are still ambiguous.^[4]

Structural studies have revealed that four classes of CNPases belong to one protein superfamily. CNPase's catalytic core consists of three alpha-helices and nine beta-strands. The proposed mechanism of CNPases phosphodiesterase catalytic activity is similar to the second step of the reaction mechanism for RNase A.^[5]

CNPase is expressed exclusively by oligodendrocytes in the CNS, and the appearance of CNPase seems to be one of the earliest events of oligodendrocyte differentiation.^[6] CNPase is thought to play a critical role in the events leading up to myelination.^[7]

CNPase also associates with microtubules in brain tissue and FRTL-5 thyroid cells, and is reported to have microtubule-associated protein-like activity (MAP; see MAP2), being able to catalyze microtubule formation at low molar ratios. Deletion of the C-terminus of CNPase or phosphorylation abolish the catalytic activity of microtubule formation. CNPase can link tubulin to cellular membranes, and might be involved in the regulation cytoplasmic microtubule distribution.^[8]

CNPase has also been demonstrated to inhibit the replication of HIV-1 and other primate lentiviruses by binding the retroviral Gag protein and inhibiting the genesis of nascent viral particles. Whether this is a biological function of CNPase or a coincidental activity remains unclear.^[9]

Further reading

• Drummond GI, Iyer NT, Keith J . 1962 . Hydrolysis of ribonucleoside 2',3'-cyclic phosphates by a diesterase from brain . J. Biol. Chem. . 237 . 11 . 3535–3539 . 10.1016/S0021-9258(19)70852-7 . free .
• Helfman DM, Kuo JF . A homogeneous cyclic CMP phosphodiesterase hydrolyzes both pyrimidine and purine cyclic 2':3'- and 3':5'-nucleotides . The Journal of Biological Chemistry . 257 . 2 . 1044–7 . Jan 1982 . 10.1016/S0021-9258(19)68305-5 . 6274851 . free .
• Helfman DM, Shoji M, Kuo JF . Purification to homogeneity and general properties of a novel phosphodiesterase hydrolyzing cyclic CMP and cyclic AMP . The Journal of Biological Chemistry . 256 . 12 . 6327–34 . Jun 1981 . 10.1016/S0021-9258(19)69166-0 . 6263914 . free .
• Kurihara T, Nishizawa Y, Takahashi Y, Odani S . Chemical, immunological and catalytic properties of 2':3'-cyclic nucleotide 3'-phosphodiesterase purified from brain white matter . The Biochemical Journal . 195 . 1 . 153–7 . Apr 1981 . 6272743 . 1162865 . 10.1042/bj1950153 .
• Nishizawa Y, Kurihara T, Takahashi Y . Spectrophotometric assay, solubilization and purification of brain 2':3'-cyclic nucleotide 3'-phosphodiesterase . The Biochemical Journal . 191 . 1 . 71–82 . Oct 1980 . 6258586 . 1162183 . 10.1042/bj1910071 .
• Thompson RJ . 2',3'-cyclic nucleotide-3'-phosphohydrolase and signal transduction in central nervous system myelin . Biochemical Society Transactions . 20 . 3 . 621–6 . Aug 1992 . 1385234 . 10.1042/bst0200621 .
• Leroy MJ, Dumler I, Lugnier C, Shushakova ND, Ferré F . A new peptide (1150Da) selectively activates the calcium-calmodulin sensitive isoform of cyclic nucleotide phosphodiesterase from human myometrium . Biochemical and Biophysical Research Communications . 184 . 2 . 700–5 . Apr 1992 . 1315529 . 10.1016/0006-291X(92)90646-3 . 1 .
• Douglas AJ, Fox MF, Abbott CM, Hinks LJ, Sharpe G, Povey S, Thompson RJ . Structure and chromosomal localization of the human 2',3'-cyclic nucleotide 3'-phosphodiesterase gene . Annals of Human Genetics . 56 . Pt 3 . 243–54 . Jul 1992 . 1360194 . 10.1111/j.1469-1809.1992.tb01149.x . 34627658 . 1 .
• Staugaitis SM, Bernier L, Smith PR, Colman DR . Expression of the oligodendrocyte marker 2'3'-cyclic nucleotide 3'-phosphodiesterase in non-glial cells . Journal of Neuroscience Research . 25 . 4 . 556–60 . Apr 1990 . 2161933 . 10.1002/jnr.490250413 . 29416130 .
• Agrawal HC, Sprinkle TJ, Agrawal D . 2',3'-cyclic nucleotide-3'-phosphodiesterase in the central nervous system is fatty-acylated by thioester linkage . The Journal of Biological Chemistry . 265 . 20 . 11849–53 . Jul 1990 . 10.1016/S0021-9258(19)38476-5 . 2164018 . free .
• Kurihara T, Takahashi Y, Nishiyama A, Kumanishi T . cDNA cloning and amino acid sequence of human brain 2',3'-cyclic-nucleotide 3'-phosphodiesterase . Biochemical and Biophysical Research Communications . 152 . 2 . 837–42 . Apr 1988 . 2835044 . 10.1016/S0006-291X(88)80114-1 .
• Sprinkle TJ, McMorris FA, Yoshino J, DeVries GH . Differential expression of 2':3'-cyclic nucleotide 3'-phosphodiesterase in cultured central, peripheral, and extraneural cells . Neurochemical Research . 10 . 7 . 919–31 . Jul 1985 . 2995854 . 10.1007/BF00964629 . 34362955 .
• Sheedlo HJ, Doran JE, Sprinkle TJ . An investigation of 2':3'-cyclic nucleotide 3'-phosphodiesterase (EC 3.1.4.37, CNP) in peripheral blood elements and CNS myelin . Life Sciences . 34 . 18 . 1731–7 . Apr 1984 . 6328143 . 10.1016/0024-3205(84)90572-1 .
• Monoh K, Kurihara T, Takahashi Y, Ichikawa T, Kumanishi T, Hayashi S, Minoshima S, Shimizu N . Structure, expression and chromosomal localization of the gene encoding human 2',3'-cyclic-nucleotide 3'-phosphodiesterase . Gene . 129 . 2 . 297–301 . Jul 1993 . 8392017 . 10.1016/0378-1119(93)90283-9 . 1 .
• Löbbert RW, Winterpacht A, Seipel B, Zabel BU . Molecular cloning and chromosomal assignment of the human homologue of the rat cGMP-inhibited phosphodiesterase 1 (PDE3A)--a gene involved in fat metabolism located at 11p 15.1 . Genomics . 37 . 2 . 211–8 . Oct 1996 . 8921398 . 10.1006/geno.1996.0544 .
• Stricker R, Kalbacher H, Reiser G . The epitope recognized by a monoclonal antibody in the myelin-associated protein CNP . Biochemical and Biophysical Research Communications . 237 . 2 . 266–70 . Aug 1997 . 9268698 . 10.1006/bbrc.1997.7125 .
• O'Neill RC, Braun PE . Selective synthesis of 2',3'-cyclic nucleotide 3'-phosphodiesterase isoform 2 and identification of specifically phosphorylated serine residues . Journal of Neurochemistry . 74 . 2 . 540–6 . Feb 2000 . 10646504 . 10.1046/j.1471-4159.2000.740540.x . 25697047 . free .
• Zauli G, Milani D, Mirandola P, Mazzoni M, Secchiero P, Miscia S, Capitani S . HIV-1 Tat protein down-regulates CREB transcription factor expression in PC12 neuronal cells through a phosphatidylinositol 3-kinase/AKT/cyclic nucleoside phosphodiesterase pathway . FASEB Journal . 15 . 2 . 483–91 . Feb 2001 . 11156964 . 10.1096/fj.00-0354com . free . 26315564 . 1 .
• Bifulco M, Laezza C, Stingo S, Wolff J . 2',3'-Cyclic nucleotide 3'-phosphodiesterase: a membrane-bound, microtubule-associated protein and membrane anchor for tubulin . Proceedings of the National Academy of Sciences of the United States of America . 99 . 4 . 1807–12 . Feb 2002 . 11842207 . 122275 . 10.1073/pnas.042678799 . 2002PNAS...99.1807B . free .
• Davidoff MS, Middendorff R, Köfüncü E, Müller D, Jezek D, Holstein AF . Leydig cells of the human testis possess astrocyte and oligodendrocyte marker molecules . Acta Histochemica . 104 . 1 . 39–49 . 2002 . 11993850 . 10.1078/0065-1281-00630 . 1 .
• Basrur V, Yang F, Kushimoto T, Higashimoto Y, Yasumoto K, Valencia J, Muller J, Vieira WD, Watabe H, Shabanowitz J, Hearing VJ, Hunt DF, Appella E . Proteomic analysis of early melanosomes: identification of novel melanosomal proteins . Journal of Proteome Research . 2 . 1 . 69–79 . 2003 . 12643545 . 10.1021/pr025562r . 1 .
• Kozlov G, Lee J, Elias D, Gravel M, Gutierrez P, Ekiel I, Braun PE, Gehring K . Structural evidence that brain cyclic nucleotide phosphodiesterase is a member of the 2H phosphodiesterase superfamily . The Journal of Biological Chemistry . 278 . 46 . 46021–8 . Nov 2003 . 12947117 . 10.1074/jbc.M305176200 . 1 . free .

Notes and References

1. Sprinkle TJ, Lanclos KD, Lapp DF . Assignment of the human 2′,3′-cyclic nucleotide 3′-phosphohydrolase gene to chromosome 17 . Genomics . 13 . 3 . 877–80 . Jul 1992 . 1322358 . 10.1016/0888-7543(92)90174-Q .
2. Web site: Entrez Gene: CNP 2′,3′-cyclic nucleotide 3′-phosphodiesterase.
3. Hinman JD, Chen CD, Oh SY, Hollander W, Abraham CR . Age-dependent accumulation of ubiquitinated 2',3'-cyclic nucleotide 3'-phosphodiesterase in myelin lipid rafts . Glia . 56 . 1 . 118–33 . Jan 2008 . 17963267 . 10.1002/glia.20595 . 8729201 .
4. Kursula P . Structural properties of proteins specific to the myelin sheath . Amino Acids . 34 . 2 . 175–85 . Feb 2008 . 17177074 . 10.1007/s00726-006-0479-7 . 20270722 .
5. Sakamoto Y, Tanaka N, Ichimiya T, Kurihara T, Nakamura KT . Crystal structure of the catalytic fragment of human brain 2',3'-cyclic-nucleotide 3'-phosphodiesterase . Journal of Molecular Biology . 346 . 3 . 789–800 . Feb 2005 . 15713463 . 10.1016/j.jmb.2004.12.024 .
6. Kasama-Yoshida H, Tohyama Y, Kurihara T, Sakuma M, Kojima H, Tamai Y . A comparative study of 2',3'-cyclic-nucleotide 3'-phosphodiesterase in vertebrates: cDNA cloning and amino acid sequences for chicken and bullfrog enzymes . Journal of Neurochemistry . 69 . 4 . 1335–42 . Oct 1997 . 9326261 . 10.1046/j.1471-4159.1997.69041335.x . free .
7. Gravel M, Peterson J, Yong VW, Kottis V, Trapp B, Braun PE . Overexpression of 2',3'-cyclic nucleotide 3'-phosphodiesterase in transgenic mice alters oligodendrocyte development and produces aberrant myelination . Molecular and Cellular Neurosciences . 7 . 6 . 453–66 . Jun 1996 . 8875429 . 10.1006/mcne.1996.0033 . 35687881 .
8. Bifulco M, Laezza C, Stingo S, Wolff J . 2',3'-Cyclic nucleotide 3'-phosphodiesterase: a membrane-bound, microtubule-associated protein and membrane anchor for tubulin . Proceedings of the National Academy of Sciences of the United States of America . 99 . 4 . 1807–12 . Feb 2002 . 11842207 . 122275 . 10.1073/pnas.042678799 . 2002PNAS...99.1807B . free .
9. . Inhibition of HIV-1 particle assembly by 2′,3′-cyclic-nucleotide 3′-phosphodiesterase . Cell Host & Microbe . 12 . 4 . 585–97 . Oct 2012 . 23084924 . 3498451 . 10.1016/j.chom.2012.08.012 .