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Chapter 20 : Nucleoside Deaminases for Cytidine and Adenosine: Comparison with Deaminases Acting on RNA

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Nucleoside Deaminases for Cytidine and Adenosine: Comparison with Deaminases Acting on RNA, Page 1 of 2

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Abstract:

This chapter reviews the structure of cytidine deaminase and implications for evolutionary relationships between members of the cytidine deaminase superfamily. It then summarizes details of the cytidine deaminase (ECCDA) reaction mechanism, with particular reference to the role of conserved residues and aspects of substrate specificity relating to the nucleoside modifying and editing enzymes. The chapter concludes with a discussion of models for RNA editing deaminases derived from sequence homologies and structural studies. APOBEC-1, the sole representative of what will likely be a family of editing cytidine deaminases acting on RNA substrates, shares this signature and, is outlined in detail, it likely has significant tertiary and quaternary homology to the cytidine deaminase, ECCDA. An attempt has been made to rationalize the naming of editing adenosine deaminases, calling them adenosine deaminases acting on RNA (ADARs). Conversion of cytidine to uridine involves two successive steps: hydration of the 3-4 double bond, and subsequent elimination of the leaving ammonia molecule with formation of the keto tautomer of the pyrimidine. A broad, representative sample of APOBEC-1 mutants was examined by biochemical assays for homodimerization, RNA binding, and RNA editing. The X-ray structure has been determined for murine adenosine deaminase, which catalyzes deamination of adenosine to inosine. The secondary and tertiary structure motifs of the two nucleoside deaminases are completely unrelated. The outlines described in the chapter of how C-to-U and A-to-I editing occurs provide coherent hypotheses based on known structures of related enzymes.

Citation: Carter, Jr. C. 1998. Nucleoside Deaminases for Cytidine and Adenosine: Comparison with Deaminases Acting on RNA, p 363-375. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch20

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Nucleic Acids
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RNA
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Cytidine Deaminase
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Pyrimidine Nucleosides
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Figures

Image of Figure 1
Figure 1

The signature of cytidine deaminases, (a) Conserved active-site residues and their catalytic roles as determined from studies of ECCDA. (b) ECCDA active site consisting of the segments shown in panel a. Residues in boldface in panel a are indicated, as are helices A and B.

Citation: Carter, Jr. C. 1998. Nucleoside Deaminases for Cytidine and Adenosine: Comparison with Deaminases Acting on RNA, p 363-375. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch20
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Image of Figure 2
Figure 2

Internal twofold rotation symmetry in the ECCDA monomer lends approximate 222 symmetry to the dimer (a stereo view). The plane separating the monomers is approximately horizontal. The amino-terminal core domain of each monomer is darker gray and contains the active-site residues shown in Fig. 1 . Residues 1-49 of each subunit preceeding the first core domain are half-saturated colors, to emphasize relationships between the four core domains in the dimer. The view illustrates the composite active-site construction, drawing on loops from both subunits.

Citation: Carter, Jr. C. 1998. Nucleoside Deaminases for Cytidine and Adenosine: Comparison with Deaminases Acting on RNA, p 363-375. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch20
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Image of Figure 3
Figure 3

Schematic diagram showing probable evolutionary relationships among cytidine deaminases. The amino-terminal domain of ECCDA has sequence homology to the monomers of the tetrameric CDAs, all of which are likely to have a common ancestor that bound zinc as shown in Fig. 1a .

Citation: Carter, Jr. C. 1998. Nucleoside Deaminases for Cytidine and Adenosine: Comparison with Deaminases Acting on RNA, p 363-375. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch20
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Image of Figure 4
Figure 4

Schematic diagram of the hydrolytic deamination catalyzed by ECCDA. (Adapted from with permission.)

Citation: Carter, Jr. C. 1998. Nucleoside Deaminases for Cytidine and Adenosine: Comparison with Deaminases Acting on RNA, p 363-375. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch20
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Image of Figure 5
Figure 5

Ribose-binding interactions critical for catalysis by ECCDA. E91 and N89 form hydrogen bonds to the 3′ OH group of the nucleoside inhibitor, zebularine hydrate (ZebOH). The darkly shaded loop providing these residues corresponds exactly to the GAP-1 peptide in the apolipoprotein mRNA editing deaminase subunit ( ).

Citation: Carter, Jr. C. 1998. Nucleoside Deaminases for Cytidine and Adenosine: Comparison with Deaminases Acting on RNA, p 363-375. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch20
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Image of Figure 6
Figure 6

Comparison of initial and final ground states on the ECCDA reaction pathway. The darkly-shaded nucleoside is 3-deazacytidine, a stable substrate analog. The lightly shaded nucleoside is the product, uridine. As the reaction proceeds, the 4-NH, group is pulled into a binding site to the left, while the pyrimidine is pulled toward the zinc by the attacking nucleophile. After the first tetrahedral transition state ( Fig. 4 ), the carboxylate sidechain of Glu 104 rotates (curved arrow), transferring a proton from the nucleophilic hydroxyl group to the leaving ammonia. (Adapted with permission from .)

Citation: Carter, Jr. C. 1998. Nucleoside Deaminases for Cytidine and Adenosine: Comparison with Deaminases Acting on RNA, p 363-375. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch20
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Image of Figure 7
Figure 7

Sequence alignment of a consensus APOBEC-1 sequence with that of ECCDA. The two large, mid-gray blocks correspond to the two core domains in ECCDA, and the lightest gray box between them is the linker. Residue identities are shown in reverse contrast. Deletions (GAP-0, -1, and -2) and an insertion (SITWF) are shown in dark gray and in reverse contrast. (Adapted from , with permission.)

Citation: Carter, Jr. C. 1998. Nucleoside Deaminases for Cytidine and Adenosine: Comparison with Deaminases Acting on RNA, p 363-375. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch20
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Image of Figure 8
Figure 8

Comparison of the active-site access in ECCDA (a) and the APOBEC-1 homology model (b). CPK models at the center are the two bound transition-state analog molecules, ZebOH. The dark gray β-α-β crossover at the top is formed by residues 272-284, which undergo the largest rearrangement upon removal of GAP-2. The medium gray extended loop in the center of panel a is the GAP-1 loop. GAP-2 can be identified from the third β-strand from the top in either ECCDA subunit. The dimers are considerably elongated along this view, which foreshortens the large cavity that results from structural remodeling in APOBEC-1. (Adapted from , with permission.)

Citation: Carter, Jr. C. 1998. Nucleoside Deaminases for Cytidine and Adenosine: Comparison with Deaminases Acting on RNA, p 363-375. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch20
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Image of Figure 9
Figure 9

Evidence that GAP-1 and GAP-2 peptides actually represent the mass of an RNA substrate, (a) Phenylalanines cross-linked to substrate RNA occur where the spheres (residues 107 and 124) are located in ECCDA. The GAP-1 peptide (residues 79-101) is a thick, dark gray coil. Residue 78′ in the APOBEC-1 model actually precedes residue 79 of GAP-1 in ECCDA. Residue 35 shows the location of the “putative nuclear localization signal,” containing the sequence RRR in APOBEC-1, which could also therefore be involved in RNA binding, (b) Two GAP-1 and two GAP-2 peptides are assembled with the two active-site pyrimidine ligands to form a mimic of the RNA substrate. The GAP-1 peptides are in identical locations to those in ECCDA. GAP-2 peptides have essentially been interchanged with the relocated helical segments 272-284. (c) Model of the RNA substrate with two exposed bases representing the targeted C6666 and the downstream U. (Adapted from , with permission.)

Citation: Carter, Jr. C. 1998. Nucleoside Deaminases for Cytidine and Adenosine: Comparison with Deaminases Acting on RNA, p 363-375. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch20
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Image of Figure 10
Figure 10

Comparison of the ECCDA zinc-binding motif (a) with structural fragments of the hhal (b) and taql (c) DNA methyltransferases. The latter family has been proposed as a model for the ADAR family of adenosine deaminases ( ). The spheres show, in each case, the FIAE sequences in ECCDA and in alignments described for the corresponding HAE peptides by these authors. Dark gray rod representations are, respectively, the ZebOH ligand for ECCDA and the S-adenosylmethionine substrates of the two methylases.

Citation: Carter, Jr. C. 1998. Nucleoside Deaminases for Cytidine and Adenosine: Comparison with Deaminases Acting on RNA, p 363-375. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch20
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Image of Figure 11
Figure 11

Schematic of the hhal methylase, complexed to a DNA duplex substrate (medium gray), showing how the extruded base is drawn into proximity to the SAM methyl donor ( ). The location of the α-β-α fagments shown in Fig. 9 are indicated in dark gray, and the location of putative catalytic residues HAE are emphasized in white.

Citation: Carter, Jr. C. 1998. Nucleoside Deaminases for Cytidine and Adenosine: Comparison with Deaminases Acting on RNA, p 363-375. In Grosjean H, Benne R (ed), Modification and Editing of RNA. ASM Press, Washington, DC. doi: 10.1128/9781555818296.ch20
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