Disease relevance of Adk

• These results confirmed that xyl-A toxicity was mediated through its phosphorylated form and indicated that resistance may result from increased adenosine deaminase levels and/or adenosine kinase deficiency [1].
• METHODS: Perfused C57/B16 mouse hearts were subjected to 20 min ischemia 40 min reperfusion in the absence or presence of adenosine deaminase inhibition (50 microM erythro-2-(2-hydroxy-3-nonyl)adenine; EHNA) adenosine kinase inhibition (10 microM iodotubercidin; IODO), or 10 microM adenosine [2].
• Adenosine kinase deficiency in tritiated deoxyadenosine-resistant mouse S49 lymphoma cell lines [3].
• Adenosine transport by a variant of C1300 murine neuroblastoma cells deficient in adenosine kinase [4].
• Both sublines of L1210 and P388 leukemia resistant to neplanocin A were cross-resistant in vitro to bredinin and 9-beta-D-arabinofuranosyladenine, which have been reported to be activated by adenosine kinase [5].
• After pharmacological induction of an otherwise epileptogenesis-precipitating acute brain injury, transgenic mice with reduced forebrain ADK were resistant to subsequent epileptogenesis [6].

High impact information on Adk

• We have transferred the mouse Ak alpha and Ak beta genes, which encode the class II I-Ak molecule, into mouse L-cell fibroblasts and hamster B cells [7].
• Cell lines expressing these genes were analyzed by quantitative immunofluorescence using 16 mAbs reactive to Ak beta or Ad beta [8].
• Transfection of M12.C3 B lymphoma cells with most mutant Ak beta* genes results in the expression of Ak beta* Ad alpha molecules on the cell surface [9].
• To identify which polymorphic residues determine the allospecific antibody binding sites on A beta polypeptides, mutant Ak beta genes were constructed encoding single or multiple amino acids of the d allele at 14 polymorphic positions in the beta 1 domain [8].
• In this report we describe the DNA sequence analysis of the Ak beta gene of four cell lines that express serologically altered Ak beta polypeptides in association with wild-type Ak alpha polypeptides [10].

Chemical compound and disease context of Adk

• The uptake of adenosine by an adenosine kinase deficient variant of C1300 murine neuroblastoma cells has been studied in the absence and in the presence of erythro-9-(2-hydroxy-3-nonyl)adenine, a potent adenine deaminase inhibitor [4].
• The 3',5'-cyclic phosphate derivative (cMTIMP) of methylthioinosine (MTI) was shown to produce feedback inhibition of the de novo purine pathway in an Ehrlich ascites tumor subline resistant to MTI because of lack of adenosine kinase activity for the nucleoside analog [11].
• Mouse leukemia L1210 cell lines that were selected for resistance to deoxyguanosine (dGuo-R) or lacked adenosine kinase activity (ED2) were used to evaluate the nature of the nucleoside kinase that was required to phosphorylate nucleoside analogs to their respective active nucleotide form [12].

Biological context of Adk

• Thus, phosphorylation of 2'-deoxyformycin A appears to be required for biological activity and is probably catalyzed by AK rather than dCK [13].
• Cytological localization of adenosine kinase, nucleoside phosphorylase-1, and esterase-10 genes on mouse chromosome 14 [14].
• Homozygous Adk(-/-) mutants developed normally during embryogenesis [15].
• In an effort to study the role of AK in Ado homeostasis in the central nervous system, two isoforms of the enzyme were cloned from a mouse brain cDNA library [16].
• Adenosine kinase as a new selective marker in somatic cell genetics: isolation of adenosine kinase--deficient mouse cell lines and human--mouse hybrid cell lines containing adenosine kinase [17].

Anatomical context of Adk

• Evidence is presented for the assignment of the gene for adenosine kinase to Mus musculus chromosome 14 by synteny testing and karyotypic analysis of mouse X Chinese hamster somatic cell hybrid clones [18].
• Mouse mutant cell lines deficient in adenosine kinase have been derived [17].
• Overexpression of adenosine kinase in epileptic hippocampus contributes to epileptogenesis [19].
• Immunohistochemical analysis of brain sections of control mice revealed intense staining for adenosine kinase, mainly in astrocytes, which were more or less evenly distributed throughout the brain, as well as in some neurons, particularly in olfactory bulb, striatum, and brainstem [19].
• To establish a link between adenosine kinase expression and seizure activity, we analyzed the expression of adenosine kinase in the brain of control mice and in a kainic acid-induced mouse model of mesial temporal lobe epilepsy [19].

Associations of Adk with chemical compounds

• The Adk gene was localized to bands A2 to B, Np-1 to bands B to C1, and Es-10 to bands D2 to E2 [14].
• ADA-deficient cultures were also rescued by the adenosine kinase inhibitor 5'-amino-5'-deoxyadenosine (5'A5'dAdo), indicating that the metabolite responsible for the inhibition of thymocyte development is not adenosine or deoxyadenosine, but a phosphorylated derivative of an ADA substrate [20].
• Physiologically, adenosine is efficiently metabolized to AMP by adenosine kinase (ADK), an enzyme highly expressed in liver [15].
• ADK not only ensures normal adenine nucleotide levels but also is essential for maintaining S-adenosylmethionine-dependent transmethylation processes, where adenosine, an obligatory product, has to be constantly removed [15].
• Accordingly, seizures and interictal spikes were suppressed by the injection of a low dose of the adenosine kinase inhibitor 5-iodotubercidin [19].

Regulatory relationships of Adk

• Adenosine kinase inhibition promotes survival of fetal adenosine deaminase-deficient thymocytes by blocking dATP accumulation [20].

Other interactions of Adk

• In fetal thymocytes of 16 gestational days, ADA activity was lower, and PNP, AK and deoxyCRK activities were higher than those in the adult thymocytes [21].
• Fibroblasts were engineered to release adenosine by inactivating the adenosine-metabolizing enzymes adenosine kinase and adenosine deaminase [22].
• The genes coding for adenosine kinase (ADK; ATP:adenosine 5'-phosphotransferase, EC 2.7.1.20) and esterase-10 (ES-10; carboxylesterase, carboxylic-ester hydrolase, EC 3.1.1.1) are both located on chromosome 14 in the mouse [23].
• Caspase activation could be blocked by 5'-amino-5'-deoxyadenosine, which inhibits the phosphorylation of adenosine by adenosine kinase [24].
• Adenosine-dependent activation of tyrosine hydroxylase is defective in adenosine kinase-deficient PC12 cells [25].

Analytical, diagnostic and therapeutic context of Adk

• Inclusion of the adenosine deaminase inhibitor coformycin (10 microM) and the adenosine kinase inhibitor 5'-iodotubercidin (0.1 microM) in the microdialysis perfusion buffer increased extracellular adenosine concentration in tumors to as high as 13 microM [26].
• 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 [27].
• The development of resistance to 3'-dANO was studied in cell cultures and found to be accompanied by changes in the enzyme activities of the reductase, the adenosine kinase, and the adenosine deaminase [28].
• Sequence analysis of the Ak alpha gene showed that a single base transition (C----T) resulted in a stop codon at amino acid residue 222 [29].
• To evaluate the potential functional role of the alpha- and beta-chain N-linked oligosaccharides we used site-directed mutagenesis to construct class II Ak alpha and Ak beta genes that encode polypeptides with altered N-linked oligosaccharide acceptor sites in the N-terminal domain of both polypeptides [30].

References