Adenosine monophosphate synthesis

Levy, S.G., Wasson. D.B.. Carson, D.A., and Cottam, H.B., Synthesis of 2-chloro-2, 5 -dideoxy-5 -difluoromethylphosphinyladenosine. A nonhydrolyzable isosteric, isopolar analog of 2-chlorodeoxy-adenosine monophosphate. Synthesis, 843, 1996. 

In the mid-1970s it was recognized that chronic, but not acute, administration of antidepressants to animals caused desensitization of NE-stimulated cyclic adenosine monophosphate synthesis. In fact, for most antidepressants, downregulation of /3-adrenergic receptors accompanies this desensitization. ... 

CycHc adenosine monophosphate (cAMP), produced from ATP, is involved in a large number of ceUular reactions including glycogenolysis, Hpolysis, active transport of amino acids, and synthesis of protein (40). Inorganic phosphate ions are involved in controlling the pH of blood (41). The principal anion of interceUular fluid is HP (Pig. 3) (41). 

Adenosine is not active orally, but adrninistered as an iv bolus dmg adenosine rapidly eliminates supraventricular tachycardias within 1—2 min after dosing. The dmg slows conduction through the AV node. Adenosine is rapidly removed from the circulation by uptake into red blood ceUs and vascular endothehal ceUs. Thus the plasma half-life is less than 10 s. Adenosine is rapidly metabolized to inosine or adenosine monophosphate and becomes part of the body pool for synthesis of adenosine-triphosphate. 

Not all analogues become active against cancer cells through incorporation into nucleic acid. Some analogues block the synthesis of normal purine and pyrimidine nucleotides for example, 8-azaguanine blocks guanosine monophosphate (GMP) synthesis and 6-mercaptopurine inhibits adenosine monophosphate (AMP) syn-thesis. 

But now, a strategy, used for the synthesis of derivative (622) (lit. synthesis (622) see in Ref. 555), which is the most efficient analog of the commercial drug rolipram with a broad spectrum of action (in particular, anti-inflammatory, antidepressant, neuroprotective, and immunodepressing effects), is presented in Scheme 3.286. (The principle action of rolipram is based on selective inhibition of adenosine monophosphate (AMP)-specific phosphodiesterase.) Derivative (622) is almost 10 times more efficient than rolipram, but the biological activity of (622) was determined only for the racemate (555). 

Figure 8-1. Hormonal regulation of fat metabolism. A Control of fatty acid synthesis by reversible phosphorylation of acetyl CoA carboxylase. B Regulation of tri-acylglycerol degradation by reversible phosphorylation of hormone-sensitive lipase. cAMP, cyclic adenosine monophosphate HS, hormone-sensitive.

Figure 8-6. Hormonal regulation of cholesterol synthesis by reversible phosphorylation of HMG CoA reductase. Availability of mevalonic acid as the fundamental building block of the sterol ring system controls flux through the pathway that follows. cAMP, cyclic adenosine monophosphate HMG CoA, hydroxymethylglutary I CoA.

In Fig. 1 various targets of some important cytostatic agents are depicted. Their main mechanisms of action can be briefly summarized as follows. Pentostatin blocks purine nucleotides by inhibiting adenosine deaminase. 6-Mercaptopurine and 6-thioguanine inhibit purine ring biosynthesis and they inhibit nucleotide interconversions. Methotrexate by inhibiting dihydrofolate reduction blocks thymidine monophosphate and purine synthesis. 5-Fluorouracil also blocks thymidine monophosphate synthesis. Dactinomycin, daunorubicin, doxorubicin and mitoxantrone intercalate with DNA and inhibit RNA synthesis. L-asparaginase deaminates... 

Plasma calcium concentration is the principal factor regulating PTH synthesis and release. The increase in PTH synthesis and secretion induced by hypocalcemia is believed to be mediated through activation of parathyroid gland adenylyl cyclase and a subsequent increase in intracellular cyclic adenosine monophosphate (cAMP). 

The selection of transformed chloroplasts usually involves the use of an antibiotic resistance marker. Spectinomycin is used most routinely because of the high specificity it displays as a prokaryotic translational inhibitor as well as the relatively low side effects it exerts on plants. The bacterial aminoglycoside 3 -adenyltransferase gene (ciadA) confers resistance to both streptomycin and spectinomycin. The aadA protein catalyzes the covalent transfer of an adenosine monophosphate (AMP) residue from adenosine triphosphate (ATP) to spectinomycin, thereby converting the antibiotic into an inactive form that no longer inhibits protein synthesis for prokaryotic 70S ribosomes that are present in the chloroplast. 

Activation of Gs or Gi proteins results in stimulation or inhibition, respectively, of adenylyl cyclase which catalyses the formation of cyclic adenosine monophosphate (cAMP) from ATP The cAMP binds to protein kinase A (PKA), which mediates the diverse cellular effects of cAMP by phosphorylating substrate enzymes, thereby increasing their activity. Among the responses mediated by cAMP are increases in contraction of cardiac and skeletal muscle and glycogenolysis in the liver by adrenaline (epinephrine). Because a single activated receptor can cause the conversion of up to 100 inactive Gs proteins to the active form, and each of these results in the synthesis of several hundred cAMP molecules, there is a very considerable signal amplification. For example, adrenaline concentrations as low as 10-10 M can stimulate the release of glucose sufficient to increase... 

Early events — release of histamine, synthesis of cyclic adenosine monophosphate (cyclic AMP), stimulation of RNA polymerase, and increased excitability of the myometrium. 

The ATP molecule contains pyrophosphate linkages (bonds formed when two phosphate units are combined together) that release energy when needed. ATP can be hydrolyzed in two ways the removal of terminal phosphate to form adenosine diphosphate (ADP) and inorganic phosphate, or the removal of a terminal diphosphate to yield adenosine monophosphate (AMP) and pyrophosphate. The latter is usually cleaved further to yield two phosphates. This results in biosynthesis reactions, which do not occur alone, that can be driven in the direction of synthesis when the phosphate bonds are hydrolyzed. 

Isolated keratinocytes subjected to cyclic strain exhibit a significant increase in cell proliferation, DNA synthesis, and protein synthesis compared to stationary or constantly loaded cells, which appear to involve changes in cyclic AMP. Takei et al. (1997) reported a strain-induced reduction in the levels of cyclic adenosine monophosphate, protein kinase A (PKA), and prostaglandin E2 (PGE2) as compared to stationary controls. Takei et al. (1997) also studied the effects of cyclic strain on protein kinase C (PKC) activation and translocation in cultured keratinocytes. 

M19. Mitra, S. P., and Carraway, R. E., Synergistic effects of neurotensin and beta-adrenergic agonist on 3,5-cyclic adenosine monophosphate accumulation and DNA synthesis in prostate cancer PC3 cells. Biochem. Pharmacol. 57, 1391-1397 (1999). 

Dietary purines are largely catabolized in the gut, rather than used by the body for the synthesis of nucleic acids. The end-product of purine catabolism in humans is uric add. The diet accounts f[ir less than half of the uric add appearing in the bloodstream, Most of the plasma uric add, or urate, originates from catabolism of the purines synthesized by the body (endogenous purines). The major purines are adenine and guanine. They occur mainly as nucleotides, such as adenosine triphosphate (ATP) and guanosine triphosphate (GTP), and as parts of nucleic acids. For example, the adenine in (UvfA occurs as adenosine monophosphate, and the adenine in DNA occurs as deoxyadenosine monophosphate. 

FEGURE. 11 Conversion of ino< irte monophosphate to adenosine monophosphate and guanos-ine monophosphate. Aspartate donates an amino group in the synthesis of AMP. Cltitaminc donates an amino group in the Synthesis of GMP, Folate is not used in these steps of purine metabolism. 

Firstly, Cd causes renal damage with effects principally on renal tubular cells, i.e. the site of la,25-dihy-droxyvifamin D synfhesis resulfing in an infrinsic vitamin D deficiency. This will impair the gastrointestinal absorption of calcium, reduce the calcium incorporation in bone and ultimately result in the development of osteomalacia. It is well known that la,25-dihydroxyvi-tamin D is the biologically active metabolite of vitamin D. As there is a sequential relationship between the synthesis of la,25-dihydroxyvitamin D in the kidney and cyclic-adenosine monophosphate, adenylcyclase, parathyroid hormone, a direct interference of Cd with any of these steps cannot be excluded. 

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