Disease relevance of ADK

• Recent evidence indicates that expression of ADK undergoes rapid coordinated changes during brain development and following brain injury, such as after epileptic seizures and stroke [1].
• We conclude that pathologic overexpression of ADK as in epilepsy may also render the brain more susceptible to injury from ischemia [2].
• A multivariate logistic analysis confirmed that size and histological type are the 2 most important predictors of ADK, both in solitary and in multiple adenomas [3].
• After stratification by histology, T-CEA positivity was prognostic of better survival in squamous cell carcinoma (SCC) (p=0.024) but not in adenocarcinomas (ADK) (p=0.87) [4].
• Cell lines used were the adenocarcinoma (ADK), A-549, and the squamous-cell carcinoma (SCC), LX-1 [5].

Psychiatry related information on ADK

• We have identified compound, 1o, which has potent whole cell AK inhibitory potency, analgesic activity and minimal reduction of locomotor activity [6].

High impact information on ADK

• Similarly, in mammalian cells the cyclic adenosine 3',5'-monophosphate-dependent protein kinase (PKA) and phosphatase 2B [calcineurin (CaN)] are complexed by an A kinase anchoring protein, AKAP79 [7].
• The adenosine kinase-deficient mutant was still as sensitive as its parent to growth inhibition caused by adenosine deaminase was inhibited [8].
• Mutants deficient in adenosine kinase or adenine phosphoribosyltransferase activities were selected from the WI-L2 line of human lymphoblasts [8].
• In ischemic tissues adenosine accumulates due to inhibition of adenosine kinase, and in inflamed tissues adenosine is formed from adenine nucleotides that are released from many cells including platelets, mast cells, nerves, and endothelium [9].
• The comparative order of PHA-induced increase in cellular enzyme activities examined was: thymidine kinase > uridine kinase > deoxycytidine kinase > adenosine kinase > 5'-nucleotidase [10].

Chemical compound and disease context of ADK

• In particular, topotecan and cis-platin were more active in squamous cell carcinoma than in adenocarcinoma cell lines (p=0.006 and 0.001 respectively at 0.1 microM concentration), while paclitaxel was more active in ADK than in SCC cell lines (p=0.004 at 0.01 microM concentration) [11].
• The antiproliferative effect of paclitaxel, docetaxel, gemcitabine, topotecan, SN-38 and cis-platin was studied on 5 non-small cell lung cancer (NSCLC) cell lines, 3 of which were adenocarcinoma (ADK) and 2 squamous cell carcinoma (SCC) [11].
• CONCLUSION: In view of the present results, obtained in the female Sprague-Dawley rat, it can be envisaged that the long-term inhibition of mammary ADK promotion by a brief, preventive treatment with melatonin could also reduce the risk of breast cancer induced in women by unidentified environmental factors [12].
• In adult brain, ADK is primarily expressed in a subpopulation of astrocytes and striking upregulation of ADK in these cells has been associated with astrogliosis after kainic acid-induced status epilepticus (KASE) in the kainic acid mouse model of temporal lobe epilepsy [13].
• In experiment 2, 3/4 NX rats were divided into four groups (C, control, n = 4; D, 80% restriction diet, n = 4; AD, temocapril + RD, n = 9; and ADK, temocapril + RD + AST-120, n = 9) for the examination of renal function, blood pressure, hematocrit (Ht), serum albumin, and proteinuria every month [14].

Biological context of ADK

• Adenosine kinase catalyzes the phosphorylation of adenosine to AMP and hence is a potentially important regulator of extracellular adenosine concentrations [15].
• Full-length cDNA clones encoding catalytically active adenosine kinase were obtained from lymphocyte, placental, and liver cDNA libraries [15].
• The AK gene in CH is comprised of 11 exons ranging in length from 36 to 765 nt, with the majority <100 nt [16].
• The endpoints of these deletions lie in the large introns within the AK gene [16].
• The BLAST searches of the subsequently released draft human genome sequence have revealed that the AK gene structure in human is identical to that in CH [16].

Anatomical context of ADK

• We have also determined the nature of the genetic alterations in two of the class A AK(-) mutants of CHO cells, which are obtained at a very high spontaneous frequency (10(-3)-10(-4)) in this cell line [16].
• Gene structure for adenosine kinase in Chinese hamster and human: high-frequency mutants of CHO cells involve deletions of several introns and exons [16].
• Assignment of the gene for human adenosine kinase to chromosome 10 using a somatic cell hybrid clone panel [17].
• In adult brain ambient levels of adenosine are controlled by adenosine kinase (ADK), the major adenosine-metabolizing enzyme, expressed most strongly in astrocytes [18].
• At early postnatal stages ADK immunoreactivity was prominent in neurons, notably in cerebral cortex and hippocampus [18].

Associations of ADK with chemical compounds

• 3. DNA fragmentation evoked by 2-CADO was inhibited by NBMPR and by 5'-iodotubercidin, an adenosine kinase inhibitor, but not by xanthine amine congener, an A(1) and A(2) receptor antagonist, or by selective AdoR antagonists [19].
• Pretreatment of the mutants with the ADK inhibitor 5-iodotubercidin led to lesions similar to those in WT mice [2].
• RESULTS: The results clearly showed almost identical preventive and curative effects of melatonin on the growth of DMBA-induced mammary ADK [12].
• However, seizures in kainic acid-injected mutants displayed increased intra-ictal spike frequency compared with wild-type mice, indicating that, once epilepsy is established, increased levels of ADK aggravate seizure severity [13].
• The 3/4 NX rats were divided into three groups (C, control, n = 7; AD, captopril (an ACEI) +80% restriction diet (RD), n = 8; and ADK, ACEI + RD + AST-120, n = 8) and survival was observed for 72 weeks [14].

Regulatory relationships of ADK

• Single-channel studies showed that NBMPR and adenosine kinase inhibitors activated CFTR Cl- channels [20].

Other interactions of ADK

• Inhibitors of adenosine kinase and 5'-nucleotidase increased and decreased, respectively, whole-cell currents, whereas inhibition of adenosine deaminase had no effect [20].
• Stimulation of CFTR by A(2B)AR uses protein kinase (PK) A signaling elements that are localized within the apical/subapical compartment, including G proteins, adenylyl cyclase, PKA-II, A-kinase anchoring proteins, and phosphodiesterases [21].
• Instead, 2-CADO, but not adenosine, is taken up into RA-FLSs via human equilibrative nucleoside transporter-1, where it is phosphorylated by adenosine kinase [19].
• In addition GSR, NP, EST-D, and ADK have been assigned to pter-1q12; PEP-S and PGM2 to 1q12-1q21, and PEP-B to 1q32-1qter [22].
• Conversely, chronic overexpression of ADK causes seizures in epilepsy and promotes cell death in epilepsy and stroke [1].

Analytical, diagnostic and therapeutic context of ADK

• We determined the structure of human adenosine kinase by X-ray crystallography using MAD phasing techniques and refined the structure to 1.5 A resolution [23].
• Since ontogeny of the adenosine system is largely unknown, we investigated ADK expression and cellular localization during postnatal development of the mouse brain, using immunofluorescence staining with cell-type specific markers [18].
• In recent years, novel treatment strategies have been developed that make use of the intracerebral transplantation of cells that are ADK deficient and, thus, release adenosine [1].
• A combination of protein kinase A type II (RII) overlay screening, database searches and PCR was used to identify a centrosomal A-kinase anchoring protein [24].
• The inhibition of cell stiffening was associated with an increase in intracellular cAMP as measured by enzyme-linked immunoassay (EIA) and an increase in the activity of the cAMP-dependent kinase (A-kinase) [25].

References