Disease relevance of TKT

• Purification of recombinant transketolase and separation from the E. coli enzyme has been greatly simplified by means of a non-cleavable hexa-histidine tag [1].
• Since molecular targeted inhibition of transketolase enzyme reactions suppresses tumor growth and metastasis, TKTL1 could be a relevant target for anti-transketolase therapies in gastric cancer [2].
• Expression of the mutated transketolase TKTL1, a molecular marker in gastric cancer [2].
• Upregulation of tyrosine kinase TKT by the Epstein-Barr virus transactivator Zta [3].
• Cells transfected with a fusion gene containing SRE 42 inserted into the promoter of the herpes simplex viral TK gene produced abundant mRNA when grown without sterols [4].

Psychiatry related information on TKT

• Thus, allelic variants of the transketolase gene cannot account for the biochemically distinct forms of the enzyme found in these patients nor be considered as a mechanism for genetic predisposition to the development of Wernicke-Korsakoff syndrome [5].
• We found that the above-mentioned patient and one of the diabetic kindreds with no history of Wernicke's encephalopathy had abnormal transketolase as determined by its Km for TPP [6].
• Studies of transketolase abnormality in Alzheimer's disease [7].
• Erythrocyte transketolase activation by thiamin diphosphate has been studied in elderly patients with moderate or severe chronic dementia, acute alcoholic admissions and chronic alcoholics with evidence of brain damage, mostly of the Wernicke-Korsakoff type [8].
• There were no laboratory or physiological markers for ataxia, including hemoglobin A1a + b, red blood cell transketolase, liver function enzymes, and measures of reaction time and hand-eye coordination [9].

High impact information on TKT

• Chemokine signaling and functional responses: the role of receptor dimerization and TK pathway activation [10].
• The apparent Km for thiamine pyrophosphate was 195 +/- 31 micron for transketolase in extracts of the patients' cells as compared to 16 +/- 2 micron in six control lines (means +/- S.E.M.: P less than 0.001) [11].
• Transketolase in fibroblasts from the patients with the syndrome bound thiamine pyrophosphate less avidly than control lines [11].
• Activation of the coenzyme was studied by measuring thermodynamics and kinetics of deprotonation at the carbon in the 2-position (C2) of thiamine diphosphate in the enzymes pyruvate decarboxylase and transketolase by use of nuclear magnetic resonance spectroscopy, proton/deuterium exchange, coenzyme analogs, and site-specific mutant enzymes [12].
• Our data suggest that an inborn error (i.e., high Km of transketolase for thiamine pyrophosphate) predisposing to thiamine deficiency diseases similar to those reported in Wernicke-Korsakoff syndrome may occur in the general population [13].

Chemical compound and disease context of TKT

• Variants of the enzyme transketolase which possess reduced affinity for its cofactor thiamine pyrophosphate (high apparent Km) have been described in chronic alcoholic patients with Wernicke-Korsakoff syndrome [5].
• Thiamine defiency is closely involved with two neurological disorders, Beriberi and Wernicke-Korsakoff syndromes, and in both of these conditions TK with altered activity are found [14].
• Mass spectra analysis of 13C-labeled carbons revealed that these PC reactions contribute to over 85% of de novo ribose synthesis in RNA from [1,2-(13)C]glucose in cultured Mia pancreatic adenocarcinoma cells, with the fraction synthesized through the TK pathway predominating (85%) [15].
• Melanoma-bearing animals inoculated with HSV TK-expressing Salmonella showed ganciclovir-mediated, dose-dependent suppression of tumor growth and prolonged survival in addition to that seen with bacteria alone [16].
• Exploitation of differences in the substrate specificity of the type I and type II thymidine kinases (EC 2.7.1.21, TK) expressed by the Herpesviridae and Poxviridae (and human cells), respectively, has lead to the development of effective antiherpetic drugs such as acyclovir and gancyclovir [17].

Biological context of TKT

• Cloning of human transketolase cDNAs and comparison of the nucleotide sequence of the coding region in Wernicke-Korsakoff and non-Wernicke-Korsakoff individuals [5].
• Since the syndrome has been shown to be directly related to thiamine deficiency, it has been hypothesized that such transketolase variants may represent a genetic predisposition to the development of this syndrome [5].
• To test this hypothesis, human transketolase cDNA clones were isolated, and their nucleotide and predicted amino acid sequence were determined [5].
• Comparison with known transketolases (TK) demonstrated a TKR-specific deletion mutating one thiamine binding site [14].
• Since it has been postulated that the vertebrate genome arose by two cycles of tetraploidization from a cephalochordate genome, this could represent an example of the modulation of the function of a preexisting transketolase gene by gene duplication [14].

Anatomical context of TKT

• TKT protein expression was reduced in fibroblasts compared to keratocytes (n=2) [18].
• Transketolase from human leukocytes. Isolation, properties and induction of polyclonal antibodies [19].
• The occurrence of multiple enzyme forms in fresh human white cells has also been established by the analysis of transketolase in isolated populations of either lymphocytes or polymorphonuclear leukocytes, from individual healthy subjects [19].
• We isolated mRNA from biliary epithelial cell (BEC)-enriched cell fractions, amplified the TK transcripts using degenerative primers, and identified specific TKs by restriction enzyme digest analysis and then performed in situ hybridization [20].
• We detected a strong upregulation of the mutated transketolase transcript (TKTL1) in a considerable number of patients with gastric cancer (GC) or cancer of the gastroesophageal junction (GEJ) [2].

Associations of TKT with chemical compounds

• Recent studies suggest that corneal cells express high levels of so-called corneal crystallins, such as aldehyde dehydrogenase (ALDH) and transketolase (TKT) that contribute to maintaining cellular transparency [18].
• Here, we demonstrate that this protein is transketolase (TKT; EC 2.2.1.1), an enzyme in the nonoxidative branch of the pentose-phosphate pathway, based on peptide and cDNA isolation and sequence analysis of mouse cornea protein and RNA samples, respectively [21].
• Transketolase belongs to the family of thiamin diphosphate dependent enzymes [1].
• The enzyme was finally detached from CM-cellulose by specific elution with a D-xylulose-5-phosphate/D-ribose-5-phosphate mixture and the isolated product exhibited a specific activity of about 10 units/mg protein at 37 degrees C. Transketolase preparations are contamination-free, except for a slight residual activity of phosphohexose isomerase [19].
• We propose that TKTL1 upregulation is a common phenomenon in GC and cancer of the GEJ leading to an enhanced, oxygen-independent glucose usage which might contribute to a more aggressive tumor growth [2].

Other interactions of TKT

• RT-PCR, western blotting and immunolabeling were used to detect mRNA and protein expression of ALDH isozymes and TKT [18].
• TKT maps to 3p14 and distal to FRA3B, localizing TKT to 3p14.3 [22].
• Moreover, correlation of expression levels of Zta and TKT transcripts in nasopharyngeal carcinoma biopsy specimens was clearly demonstrated by quantitative PCR (Q-PCR), which provides the first evidence for an effect of Zta on cellular gene expression in vivo [3].
• An analysis of the nucleotide sequence upstream from pgk showed the presence of a gene encoding glyceraldehyde-3-phosphate dehydrogenase and the 3' end of an open reading frame encoding a protein which is 50% identical to transketolase encoded by cbbT of X. flavus [23].
• Erythrocyte transketolase activity was assayed and %TPP effect was calculated to define the vitamin B1 status among 63 young boys and girls from the Oasis with normal or G6PD-deficiency [24].

Analytical, diagnostic and therapeutic context of TKT

• The abnormality in transketolase persisted through serial passages in tissue culture in cells grown in medium containing excess thiamine and no ethanol, indicating that the aberrations were genetic rather than dietary [11].
• RD114-pseudotyped retroviral vectors kill cancer cells by syncytium formation and enhance the cytotoxic effect of the TK/GCV gene therapy strategy [25].
• Vitamin B(1) status assessed by direct measurement of thiamin pyrophosphate in erythrocytes or whole blood by HPLC: comparison with erythrocyte transketolase activation assay [26].
• TK mutants with complete gene deletions were distinguished by Southern blot analysis [27].
• Mobility shift assays were used to examine protein binding to the human TK gene CCAAT boxes [28].

References