Adenine nucleotides metabolism regulator

Chapman, A.G., A.L. Miller, and D.E. Atkinson. 1976. Role of the adenylate deminase reaction in regulation of adenine nucleotide metabolism in Ehrlich ascites tumor cells. Cancer Res. 36 1144-1150. 

Knowles CJ. Microbial metabolic regulation by adenine nucleotide pools. In Microbial Energetics. In Haddock B, Hamilton WA, eds. Cambridge, Cambridge University Press, 1977 241-83. 

Purine and pyrimidine nucleotides are fundamental to life as they are involved in nearly all biochemical processes. Purine and pyrimidine nucleotides are the monomeric units of both DNA and RNA, ATP serves as the universal cellular energy source, adenine nucleotides are components of three key coenzymes (NAC", FAD and Co A), they are used to form activated intermediates, such as UDP-glucose, and they serve as metabolic regulators. 

The nucleotides (1) are the activated precursors of DNA and RNA (2) are the source of derivatives that are activated intermediates in many biosyntheses (3) include ATP, the universal currency of energy in biological systems, and GTP, which powers many movements of macromolecules (4) include the adenine nucleotides, which are components of the major coenzymes NAD", FAD, and CoA and (5) serve as metabolic regulators. 

Since the two isozymes of adenylosuccinate synthetase differ so markedly, changes in the relative amounts of the two could drastically affect the regulation of the reaction they catalyze, and therefore the direction of purine nucleotide metabolism. Determination of this ratio could be a useful indicator of the relative importance of the biosynthetic and the cyclic aspects of the adenine nucleotide interconversion pathway in different tissues or under different metabolic conditions. 

Adenosine has long been known to cause dilatation of coronary blood vessels, and Berne 24, 25) and others 26) have suggested that adenosine produced within the heart might help to regulate coronary blood flow in this way. Thus, factors which reduce myocardial oxygen tension, such as decreased coronary blood flow, hypoxia, or increased myocardial metabolic activity, accelerate adenine nucleotide breakdown and impair resynthesis. The result is formation of adenosine, which interacts with the vascular smooth muscle cells to cause dilatation and consequently increased blood flow, increased oxygen tension, and removal of adenosine. Although Berne proposed that the adenosine is produced in the myocardial cells and reaches the coronary arterioles via the interstitial space, Baer and Drummond 26) have shown that adenylate can be dephosphorylated rapidly by the coronary vasculature itself. 

Figure 3.1 shows the nucleotides formed from the purine adenine - the adenine nucleotides, adenosine monophosphate (AMP), adenosine diphosphate (ADP) and adenosine triphosphate (ATP) - as well as the nucleotide triphosphates formed from the purine guanine and the pyrimidine uracil (see also section 10.3.2 for a discussion of the role of cyclic AMP in metabolic regulation and hormone action). 

The ability of an enzyme to respond to concentrations of metabolites other than its substrate and product adds a new dimension to metabolic regulation. It allows the end product of the metabolic pathway to bring about feedback inhibition on earlier steps (Yates and Pardee, 1956). Such feedback control may be exerted by a metabolite several steps removed in a pathway or by metabolites from a different pathway which share a common intermediate with the first pathway. This regul-ability in strategically located enzymes can have profound effects on cellular metabolism. It allows certain key intermediates in one pathway to act as switches for another pathway for example, citric acid can act as the switch for fatty acid metabolism. Regulation by central intermediates—e.g., adenine and pyridine nucleotides—may in fact determine the resultant direction of metabolism as anabolic or catabolic, depending on the energy reserves or redox state of the cell (see metabolite ratios below). 

Atkinson, D. E., 1971, Adenine nucleotides as imiversal stoichiometric metabolic coupling agents, Adv. Enzyme Regul. 9 207. 

The purine nucleotides GTP and ATP are very important in intermediary metabolism and the regulation of metabolism. Adenine is also a component of cyclic AMP, FAD, NAD, NADP and coenzyme A. Moreover, GTP, ATP and their deoxy derivatives dGTP and dATP are important precursors for the synthesis of RNA and DNA respectively, which are essential for cell growth and division. Purine biosynthesis (Fig. 59.1) needs the amino acids giutamine, giycine and aspartate. Also, tryptophan is needed to supply formate which reacts with tet-rahydrofolate (THF) to produce A "-formyl THF, which donates the formyl group to the purine structure. A molecule of CO2 is also needed. 

Strictly catabolic pathways, in contrast, do not appear to be regulated by end-product inhibition. At least in microorganisms these pathways generate substrates of energy metabolism and the activity of early enzymes of such degradative pathways is often controlled by compounds which reflect the energy state of a cell. These include nucleotides of adenine or other... 

Our own work (3) and that of others (2) with E. coll have shown that the de novo purine biosynthetic pathway is regulated by both a repressor molecule (pur R gene product) and by feedback inhibition. However, Chinese hamster cells are much more sensitive to feedback inhibition by adenine than E, coli and, unlike the situation in E. coli, no repression of PRPP amidotransferase or formyglycinamide biosynthesis could be detected. If repression did occur, it would have to be by a mechanism not normally associated with the purine biosynthetic pathways or at a site late in the purine bios3mthetic pathway. Moreover, the nucleotide pools of cells treated for 2 h with with actinomycin D or cycloheximide showed a substantial increase in nucleotide levels. This Increase in nucleotide concentration is probably sufficient in itself to inhibit de novo purine biosynthesis by feedback inhibition without recourse to a repression mechanism, Snyder and Henderson (10) have also reported an effect of actinomycin D on purine metabolism in Ehrlich ascites cells. In this case, there was no large effect (11% inhibition) on de novo purine biosynthesis, Snyder and Henderson (10) proposed that this decrease was due to a 29% reduction in PRPP levels as a result of increased (1,3-fold increase in ATP and 2,8-fold Increase in GTP) nucleotide pools. These observations are consistent with our data in which a 58% decrease in PRPP level is found over a 2-h period in Chinese hamster cells grown in actinomycin D, The extent of inhibition in Chinese hamster cells is much greater than that reported for Ehrlich ascites cells and may reflect a difference between cells,... 

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