Molecular Cloning of Human Cytosolic Purine 5′-Nucleotidase

Oka, Jun; Matsumoto, Akiyo; Hosokawa, Yu; Inoue, Shintaro

doi:10.1006/bbrc.1994.2752

Cited by 60 publications

(49 citation statements)

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“…18,32,33 The high Km 5NT (also designated as cN-II; accession No. D38524) studied in this patient population 32,[34][35][36] was the first cytoplasmic 5NT cloned. 33 5Ј-3Ј-Nucleotidase (dNT-1; also described as PN-II 37 ; accession No.…”

Section: Discussionmentioning

confidence: 99%

Expression of high Km 5′-nucleotidase in leukemic blasts is an independent prognostic factor in adults with acute myeloid leukemia

Galmarini

Graham

Thomas

et al. 2001

Blood

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Cytarabine (ara-C) requires activation into its triphosphorylated form, ara-CTP, to exert cytotoxic activity. Cytoplasmic 5-nucleotidase (5NT) dephosphorylates ara-CMP, a key intermediate, preventing accumulation of ara-CTP and may reduce cellular sensitivity to the cytotoxic activity of ara-C. To determine whether the level of expression of 5NT is correlated with clinical outcome in patients with acute myeloid leukemia (AML) treated with ara-C, this study analyzed the levels of messenger RNA expression of high Km 5NT by real-time polymerase chain reaction at diagnosis in blast cells of 108 patients with AML. High Km 5NT was expressed at diagnosis in the blast cells of 54% of patients. In univariate analysis, (1) patients whose blast cells contained high levels (values greater than the median value for total population) of high Km 5NT at diagnosis had significantly shorter disease-free survival (DFS) than patients with low levels of high Km 5NT (11 months versus 17.5 months, P ‫؍‬ .02) and (2) high levels of high Km 5NT also predicted significantly shorter overall survival (15.7 months versus 39 months, P ‫؍‬ .01) in young patients (< 57 years; median value for the entire population). In a multivariate analysis taking into account age, karyotype risk, and other factors found to have prognostic significance in univariate analysis, (1) high Km 5NT expression was an independent prognostic factor for DFS and (2) high levels of high Km 5NT also predicted significantly shorter overall survival in young patients. These results demonstrate that the expression of high levels of high Km 5NT in blast cells is correlated with outcome in patients with AML. (Blood. 2001;98: 1922-1926

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Section: Discussionmentioning

confidence: 99%

Expression of high Km 5′-nucleotidase in leukemic blasts is an independent prognostic factor in adults with acute myeloid leukemia

Galmarini

Graham

Thomas

et al. 2001

Blood

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“…Among these the cN-II family is another family of cystolic 5′-nucleotidases 154,155 that appear to have convergently evolved this activity, similar to other families in the HAD superfamily ( Table 1, see above). This family is unified by a unique β hairpin immediately downstream of motif III, which is unlikely to interact with the cap and might have a distinct function in multimerization or interactions with other proteins.…”

Section: The Multi-helical Cap Assemblagementioning

confidence: 97%

Evolutionary Genomics of the HAD Superfamily: Understanding the Structural Adaptations and Catalytic Diversity in a Superfamily of Phosphoesterases and Allied Enzymes

Burroughs¹,

Allen²,

Dunaway‐Mariano³

et al. 2006

Journal of Molecular Biology

387

520

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The HAD (haloacid dehalogenase) superfamily includes phosphoesterases, ATPases, phosphonatases, dehalogenases, and sugar phosphomutases acting on a remarkably diverse set of substrates. The availability of numerous crystal structures of representatives belonging to diverse branches of the HAD superfamily provides us with a unique opportunity to reconstruct their evolutionary history and uncover the principal determinants that led to their diversification of structure and function. To this end we present a comprehensive analysis of the HAD superfamily that identifies their unique structural features and provides a detailed classification of the entire superfamily. We show that at the highest level the HAD superfamily is unified with several other superfamilies, namely the DHH, receiver (CheY-like), von Willebrand A, TOPRIM, classical histone deacetylases and PIN/FLAP nuclease domains, all of which contain a specific form of the Rossmannoid fold. These Rossmannoid folds are distinguished from others by the presence of equivalently placed acidic catalytic residues, including one at the end of the first core β-strand of the central sheet. The HAD domain is distinguished from these related Rossmannoid folds by two key structural signatures, a "squiggle" (a single helical turn) and a "flap" (a beta hairpin motif) located immediately downstream of the first β-strand of their core Rossmanoid fold. The squiggle and the flap motifs are predicted to provide the necessary mobility to these enzymes for them to alternate between the "open" and "closed" conformations. In addition, most members of the HAD superfamily contains inserts, termed caps, occurring at either of two positions in the core Rossmannoid fold. We show that the cap modules have been independently inserted into these two stereotypic positions on multiple occasions in evolution and display extensive evolutionary diversification independent of the core catalytic domain. The first group of caps, the C1 caps, is directly inserted into the flap motif and regulates access of reactants to the active site. The second group, the C2 caps, forms a roof over the active site, and access to their internal cavities might be in part regulated by the movement of the flap. The diversification of the cap module was a major factor in the exploration of a vast substrate space in the course of the evolution of this superfamily. We show that the HAD superfamily contains 33 major families distributed across the three superkingdoms of life. Analysis of the phyletic patterns suggests that at least five distinct HAD proteins are traceable to the last universal common ancestor (LUCA) of all extant organisms. While these prototypes diverged prior to the emergence Abbreviations used: HAD, haloacid dehalogenase; PNKP, polynucleotide kinase phosphatase; KDO 8-P, deoxy-Dmannose-octulosonate 8-phosphate; CTD, carboxyl-terminal domain; PNKP, polynucleotide kinase phosphatase; LUCA, last universal common ancestor.E-mail address of the corresponding author: aravind@ncbi.nlm.nih.gov of the LUCA, t...

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“…1). Interestingly, there is no homology to the previously published human and bovine sequences of cN-II (27,28) or with that for e-N (9, 29). We therefore reached the surprising conclusion that cN-I is a novel protein, unrelated to cN-II or e-N.…”

Section: Resultsmentioning

confidence: 85%

The Mechanism of Adenosine Formation in Cells

Sala-Newby¹,

Składanowski²,

Newby³

1999

Journal of Biological Chemistry

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Adenosine increases blood flow and decreases excitatory nerve firing. In the heart, it reduces rate and force of contraction and preconditions the heart against injury by prolonged ischemia. Based on indirect kinetic arguments, an AMP-selective cytosolic 5-nucleotidase designated cN-I has been implicated in adenosine formation during ATP breakdown. The molecular identity of cN-I is unknown, although an IMP/GMP-selective cytosolic 5-nucleotidase (cN-II) and an ecto-5-nucleotidase (e-N) have been cloned. We utilized the high abundance of cN-I in pigeon heart to purify a 40-kDa subunit for partial protein sequencing and subsequent cDNA cloning. We obtained a full-length clone encoding a novel 40-kDa peptide, unrelated to cN-II or e-N, that was most abundant in heart, brain, and breast muscle. Immunolocalization in heart showed a striated cytoplasmic location, suggesting association with contractile elements. Transient expression in COS-7 cells, generated a 5-nucleotidase that catalyzed adenosine formation from AMP, which was increased during ATP catabolism. In conclusion, the cloning and expression of cN-I provides definitive evidence of its ability to produce adenosine during ATP breakdown.

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Molecular Cloning of Human Cytosolic Purine 5′-Nucleotidase

Cited by 60 publications

References 0 publications

Expression of high Km 5′-nucleotidase in leukemic blasts is an independent prognostic factor in adults with acute myeloid leukemia

Expression of high Km 5′-nucleotidase in leukemic blasts is an independent prognostic factor in adults with acute myeloid leukemia

Evolutionary Genomics of the HAD Superfamily: Understanding the Structural Adaptations and Catalytic Diversity in a Superfamily of Phosphoesterases and Allied Enzymes

The Mechanism of Adenosine Formation in Cells

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