China
Africa
Explore chapters and articles related to this topic
Genetics of gastric cancer
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
Identified by Ohta et al. in 1996,FHIT is a human gene located in 3p14.2, a region that is commonly deleted in multiple different tumor types, including gastric cancer. 3p14.2 was originally identified as an area of interest in cancer formation when Cohen et al. (1979) observed a constitutional reciprocal t(3;8) translocation associated with familial bilateral multifocal clear cell renal carcinoma. It was later shown that the site of the chromosomal break is 3p14.2 and that this 200–300 kb region is frequently homozygously deleted in many types of cancer (Wang and Perkins, 1984). This region of deletion contains the fragile site locus FRA3B as well as FHIT. FHIT (‘fragile histidine triad’) is a member of the histidine triad gene family and encodes a protein similar to the aphl gene in S. pombe. The gene consists of 10 exons distributed over at least 500 kb with three 5′ untranslated exons centromeric to the 3p14.2 translocation associated with clear cell renal carcinoma and the remaining exons telomeric to the translocation breakpoint. Exon 5 is within the homozygously deleted fragile site (Gemma et al., 1997). FHIT encodes a protein that is a 147-amino acid AP3A hydrolase. The preferred substrates for FHIT, AP3A (diadenosine 5′,5″P(1),P(3)-triphosphate) and AP4A, appear to have various intracellular functions including the regulation of DNA replication and signaling stress responses (Barnes et al., 1996).
Regulatory mechanisms of exopolysaccharide synthesis and biofilm formation in Streptococcus mutans
Published in Journal of Oral Microbiology, 2023
Ting Zheng, Meiling Jing, Tao Gong, Jiangchuan Yan, Xiaowan Wang, Mai Xu, Xuedong Zhou, Jumei Zeng, Yuqing Li
Ap4A is a dinucleotide metabolite that consists of two adenosines joined in the 5′−5′ linkage by four phosphates [26,27]. During translation, aminoacyl-tRNA synthetases (AARS) catalyze the transfer of the AMP moiety from the aminoacyl adenylate to the ATP to form Ap4A in the absence of tRNA [28]. Ap4A is symmetrically decomposed into two molecules of ADP or asymmetrically into AMP and ATP by the Ap4A hydrolase YqeK, which was identified and characterized in S. mutans [29]. Zheng et al. showed that the in-frame deletion of the yqeK gene in S. mutans causes an increase in the intracellular Ap4A levels, while biofilm formation and water-insoluble exopolysaccharides production are decreased [30]. The knockout of the yqeK gene leads to the downregulation of important virulence genes related to biofilms, such as gtfB, gtfC, and gtfD [30]. Although the mechanisms involved in the role of Ap4A need to be further investigated, these results suggest that it affects biofilm formation in S. mutans by affecting the expression of gtfs and the activity of Gtfs.
Functional genetic evaluation of DNA house-cleaning enzymes in the malaria parasite: dUTPase and Ap4AH are essential in Plasmodium berghei but ITPase and NDH are dispensable
Published in Expert Opinion on Therapeutic Targets, 2019
Hirdesh Kumar, Jessica Kehrer, Mirko Singer, Miriam Reinig, Jorge M. Santos, Gunnar R. Mair, Friedrich Frischknecht
The P. falciparum ortholog of Ap4AH (bis(5ʹ-nucleosyl)-tetraphosphatase) hydrolyzes diadenosine 5′,5″-P1,P4-tetraphosphate, which is a by-product catalyzed by tRNA synthetase and ligases, to GTP and GMP [45]. At low concentrations, Ap4A activates microphthalmia transcription factor (MITF) dependent gene expression in mast cells [64] and also regulates ATP sensitive K+ channels in cardiac myocytes which otherwise get inhibited at higher concentration [65]. High level of Ap4A is linked with DNA damage, stress responses, and apoptosis. Enzymes hydrolyzing Ap4A prevent these effects [66]. E. coli NDX-4, an enzyme that hydrolyzes Ap4A to ATP has also been reported to hydrolyze toxic 8-oxo-dGTP [67]. Our failed attempts to delete and maintain an ap4ah(-) parasite and recent structural and functional studies of the P. falciparum homolog Ap4A suggest that Ap4AH is a potentially druggable enzyme [52].