Inhibition of thymidine kinase activity in liver and hepatomas by TTP and d-CTP

Bresnick, Edward; Thompson, U.B.; Morris, Harold P.; Liebelt, A G

doi:10.1016/0006-291x(64)90340-7

Cited by 82 publications

(12 citation statements)

References 12 publications

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“…Foetal, neonatal and adult cardiac thymidine kinase is not inhibited by dCTP; adult but not foetal human hepatic and splenic thymidine kinases, and adult but not foetal rat hepatic thymidine kinase are, however, inhibited by this nucleotide (Taylor et al, 1972;Bresnick et al, 1964). Our observation that dTMP did not inhibit cardiac thymidine kinase is in contrast with the finding of Taylor et al (1972) that dTMP did inhibit human hepatic and splenic thymidine kinases.…”

Section: Effect Of Nucleotides On Thymidine Kinase Actiuitycontrasting

confidence: 81%

Thymidine kinase activity in cardiac muscle during embryonic and postnatal development

Gillette

Claycomb

1974

Biochemical Journal

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Cytoplasmic thymidine kinase from cardiac muscle of the rat has been characterized.It has a pH optimum of 9.0 and a Km value for thymidine of 1.6/UM. The sedimentation coefficient ofthis enzyme in sucrose gradients is 4.5 S, which represents a molecular weight of approx. 69000. Thymidine kinase prepared from cardiac muscle of foetal, neonatal and adult rats is inhibited by dTTP and dTDP; there is neither inhibition nor stimulation by dTMP, dCTP, dATP, dGTP or cyclic AMP. The activity of thymidine kinase in differentiating cardiac muscle of foetal and neonatal rats declines progressively with development, reaching adult values of almost zero by the fifteenth to seventeenth day of postnatal development. This represents a 70-fold decrease in enzyme activity from 3 days before birth to 17 days after birth. The loss of thymidine kinase activity in differentiating cardiac muscle correlates temporally with the cessation of DNA biosynthesis and the loss of cytoplasmic DNA polymerase activity in this tissue.

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Section: Effect Of Nucleotides On Thymidine Kinase Actiuitycontrasting

confidence: 81%

Thymidine kinase activity in cardiac muscle during embryonic and postnatal development

Gillette

Claycomb

1974

Biochemical Journal

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“…Specifically, in vitro studies found dTTP is a feedback inhibitor of human thymidine kinase 1 (35, 36) and is a regulator of ribonucleotide reductase (37). It remains unclear whether these inhibitory mechanisms can occur in quiescent cells, such as in cardiac myocytes.…”

Section: Discussionmentioning

confidence: 99%

Transgenic cardiac-targeted overexpression of human thymidylate kinase

Kohler

Hosseini

Cucoranu

et al. 2010

Laboratory Investigation

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Thymidylate kinase (TMPK) is a nucleoside monophosphate kinase that catalyzes phosphorylation of thymidine monophosphate (TMP) to thymidine diphosphate (TDP). TMPK also mediates phosphorylation of monophosphates of thymidine nucleoside analog (NA) prodrugs on the pathway to their active triphosphate antiviral or anti-tumor moieties. Novel transgenic mice (TG) expressing human (h) TMPK were genetically engineered using the α-myosin heavy chain promoter to drive its cardiac-targeted over-expression. In “2 by 2” protocols, TMPK TGs and wild type (WT) littermates were treated with the NA zidovudine (a deoxythymidine analog, AZT) or vehicle for 35 days. Alternatively, TGs and WTs were treated with a deoxycytidine NA (racivir, RCV) or vehicle. Changes in mitochondrial DNA (mtDNA) abundance and mitochondrial ultrastructure were defined quantitatively by real-time PCR and transmission electron microscopy, respectively. Cardiac performance was determined echocardiographically. Results showed TMPK TGs treated with either AZT or RCV exhibited decreased cardiac mtDNA abundance. Cardiac ultrastructural changes were seen only with AZT. AZT-treated TGs exhibited increased left ventricle (LV) mass. In contrast, LV mass in RCV treated TGs and WTs remained unchanged. In all cohorts, LV end-diastolic dimension (LVEDD) remained unchanged. This novel cardiac-targeted overexpression of hTMPK helps define the role of TMPK in mitochondrial toxicity of antiretrovirals.

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“…As is the case with uridine kinase (90), thymidine kinase appears t o be present in fetal and adult liver in different forms (22,87), and its activity is subject t o product inhibition by dTTP and dCTP (22).…”

Section: )mentioning

confidence: 99%

A Review: Biological and Clinical Aspects of Pyrimidine Metabolism

1974

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Interest in pyrimidine nucleotide biosynthesis has stemmed largely from the importance of these molecules as components of nucleic acids. Regulation of pyrimidine biosynthesis has been most extensively investigated in micro-organisms in which cell division is effectively controlled by regulation of the activity of the enzymes of the d e n o v o pathway (77, 11 0). The relation between pyrimidine biosynthesis and cellular proliferation in mammals has become clearer with the accumulation of a considerable body of evidence which indicates that there is a close correlation between the activity of enzymes involved in pyrimidine biosynthesis and the rate of cellular proliferation.The d e n o v o pyrimidine biosynthetic pathway and the urea cycle b o t h utilize carbamyl phosphate, and important nitrogen carrier. The biosynthesis of pyrimidine and purine nucleotides are connected by a common intermediate, phosphoribosyl pyrophosphate (PRPP). In addition, pyrimidine nucleotides act as sugar and phospholipid carriers and are important in lipopolysaccharide biosynthesis. The importance of these interrelations is most forcibly emphasized b y certain clinical phenomena which will be discussed later. This paper will attempt t o review the broad biologic aspects of pyrimidine nucleotide biosynthesis. A detailed consideration of d e n o v o pyrimidine biosynthesis in eucaryotic cells is available in the recent review by Jones (81). Pyrimidine biosynthesis in procaryotes has been reviewed in depth by O'Donovan and Neuhard (1 10). PATHWAYS O F PYRIMIDINE NUCLEOTIDE BIOSYNTHESISIn cells from multicellular organisms, pyrimidine nucleotide biosynthesis can proceed b y two mechanisms. D e n o v o biosynthesis of uridylic acid proceeds from simple components such as carbon dioxide, a source of nitrogen (either ammonia or the amide nitrogen of glutamine), ATP, aspartate. and ribose in the form of phosphoribosyl p y r~p h o s~h a t e . A reutilization ("salvage") mechanism is also available t o cells.-.whereby preformed pyrimidine bases o r nucleosides can be converted t o the nucleotide by the addition of ribose phosphate or phosphate. DE NOVO MECHANISMD e n o v o biosynthesis of uridylic acid required six enzymatic steps (Fig. 1). In procaryotes one enzyme supplies the carbamyl phosphate required for both pyrimidine nucleotide and arginine biosynthesis. Consequently, aspartate transcarbamylase is the first enzyme unique to the d e n o v o pyrimidine pathway and an important locus for control of the pathway (77).In contrast, in ureotelic vertebrates, there are t w o carbamyl phosphate synthetases. The first, carbamyl phosphate synthetase I, is located in the inner membrane of the mitochondrion of the liver and also appears t o be present in small quantities in kidney and small intestine (82). The second, carbamyl phosphate syntlietase 11, has a more ubiquitous distribution and was first demonstrated t o be present in Ehrlich ascites cells (58,59) and in hematopoietic mouse spleen (75,143). This enzyme was originally difficult t o dete...

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Inhibition of thymidine kinase activity in liver and hepatomas by TTP and d-CTP

Cited by 82 publications

References 12 publications

Thymidine kinase activity in cardiac muscle during embryonic and postnatal development

Thymidine kinase activity in cardiac muscle during embryonic and postnatal development

Transgenic cardiac-targeted overexpression of human thymidylate kinase

A Review: Biological and Clinical Aspects of Pyrimidine Metabolism

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