Resynthesis

MetaHoelement complexes may be useful for the post-irradiation treatment of radiation injury, based on the observation that several of these compounds accelerate recovery of, among other things, lympho/hemopoiesis. Preirradiation Mn2(0)(DIPS)g increases the survival of y-irradiated mice (103). Treatment of mice that have been exposed to an LD q q dose of y-rays plus Mn2(0)(DIPS)g either 1 or 3 h after irradiation also increases survival, which supports the hypothesis that this compound is an effective radiorecovery agent (105). Again, this increase in survival may result from the resynthesis of radiation-depleted Mn-dependent enzymes that facHitate the recovery of immunocompetence and tissue repair, as reported for Cu(II)2(DIPS)4. 

Thermodynamic considerations demand that the energy necessary for biosynthesis of any substance exceed the energy available from its catabolism. Otherwise, organisms could achieve the status of perpetual motion machines A few molecules of substrate whose catabolism yielded more ATP than required for its resynthesis would allow the cell to cycle this substance and harvest an endless supply of energy. 

In conclusion, there appears to be some supporting evidence, other than these tracer studies, that the synthesis of HMX and RDX molecules can be accomplished thru a build-up from single methylene-containing spedes or other small molecules, and that this route can also take place via a total degradation and resynthesis from molecules such as Hexamine. However, die development of an economical process for the large scale production of these expl nitramines, in particular HMX, via a method precluding the use of Hexamine, is vet to be accomplished... 

The net result of ATP degradation and resynthesis will be the formation of creatine (Cr) and inorganic phosphate (Pj) and a decrease in phosphocreatine (PCr). 

An insufficient rate of ATP resynthesis for optimal energy supply for actomyosin crossbridge formation and cycling, or for the additional ATPase reactions, Na" -K pumping and Ca reuptake and/or release by the SR. 

The middle panel shows the fall in PCr concentration in the muscle and the simultaneous increase in Pj released daring ATP degradation and resynthesis via the creatine kinase reaction ... 

Creatine supplementation has been shown to increase the rate of PCr resynthesis in the recovery period after ischemic exercise (Greenhaff et al., 1993a). This could be attributed to an acceleration of oxidative phosphorylation by increased free creatine content available to the mitochondrial fraction of the creatine kinase enzyme, as previously suggested (Bessman and Fonyo, 1966). 

Figure 8. A. Glycogen content in the vastus lateralis muscle after a mixed diet (a) and during 5 days of total starvation ( ) in one subject and eight days of carbohydrate-poor diet (o) followed by a carbohydrate-rich diet ( ) in a second subject. B. Muscle glycogen content before and after exercise. Before exercise the diet was mixed (a) and in the following days was either total starvation ( ) or carbohydrate-poor (o) and finally followed by 1-2 days of a carbohydrate-rich diet ( ). Note the slow rate of glycogen resynthesis when the diet is carbohydrate-poor compared to the rate when the diet is carbohydrate-rich. Redrawn from Hultman and Bergstrom (1967).

Greenhaff, P.L., Bodin, K., Harris, R.C., Hultman, E., Jones, D.A., McIntyre, D.B., Sbderlund, K., Turner, D.L. (1993a). The influence of oral creatine supplementation on muscle PCr resynthesis following muscle contraction in man. J. Physiol. 467, 75 (Abstract). 

Hultman, E., Bergstrdm. J., McLennan-Andersson, N. (1967). Breakdown and resynthesis of phosphorylcreatine and adenosine triphosphate in connection with muscular work. Scand. J. Clin. Lab. Invest. 16, 56-66. 

Once candidate hits have been identified, it is important to confirm the identity of the compounds, either by resupply (ifpossible) or resynthesis. It is not uncommon for compounds in large library collections to decompose, to be impure, or to be mislabeled (despite the guarantees often provided by commercial suppliers). 

It should be noted that the process whereby PI(4,5)P2 is cleaved by PLC and subsequently resynthesized is meta-bolically expensive. Thus, for each mole of PI(4,5)P2 hydrolyzed and resynthesized, 3 moles of ATP and 1 mole of CTP are consumed. ATP is consumed at the DAG kinase, PI4-kinase and PIP-kinase steps, whereas CTP is utilized by CDP-DAG synthase. Consequently, it is likely that, under physiological conditions, PI(4,5)P2 breakdown is kept to a minimum. Since PI(4,5)P2 represents only a minor fraction of the total inositol lipid pool, its resynthesis would be a prerequisite for both acute and sustained signaling. Despite the obvious physiological importance, mechanisms that regulate the resynthesis of PI(4,5)P2 have not been well-defined. However, some evidence has... 

The decreased level of free inositol leads to a reduction in the rate of Ptdlns resynthesis and to the subsequent accumulation of cytidine mo-nophosphorylphosphatidate (CMP-PA), the cosubstrate for the resynthesis, and of the other lipid metabolites, phosphatidic acid (PA) and DAG... 

C. carpio 5 initial reduction by 50% of serum cholinesterase activity which gradually increased to 130% of control values during exposure for 2 weeks, suggesting that paraquat may influence resynthesis of acetylcholinesterase 28... 

Kassis JA, Gorski J (1983) On the mechanism of estrogen receptor replenishment recycling, resynthesis and/or processing. Mol Cell Biochem 52 27... 

When CYP2E1 was inhibited by intraperitoneal injection of DCE, levels of exhaled -hexane increased approximately 25-fold within 4 hours and returned to pre-dose levels at approximately 24 hours, closely paralleling the inhibition and resynthesis time-course for CYP2E1. No increase in lipid peroxidation was observed, indicating that the increase in exhaled -hexane was the result of inhibition of metabolism. It is probable that many P-450 isoforms are capable of hydroxylating -hexanc (both in vivo and under laboratory conditions) it is not possible at this time to specify which forms are definitely involved in -hexane metabolism in vivo. 

---