Minimal metabolic functionality

Keywords Elementary mode analysis Engineering Genetic knockout analysis Metabohc minimal metabolic functionality Rational strain design... 

Minimal Metabolic Functionality (MMF) technique focuses on finding a minimum set of multiple deleted reactions to reprogram metabolic pathways of a rationally designed strain to overproduce target product(s). Figure 2.2 shows the three steps... 

Pharmacokinetics Widely distributed. Protein binding ticarcillin 45%-60%, clavulanate 9%-30%. Minimally metabolized in the liver. Primarily excreted unchanged in urine. Removed by hemodialysis. Half-life 1-1.2 hr (increased in impaired renal function). 

Zanamivir is delivered directly to the respiratory tract via inhalation. Ten to twenty percent of the active compound reaches the lungs, and the remainder is deposited in the oropharynx. The concentration of the drug in the respiratory tract is estimated to be more than 1000 times the 50% inhibitory concentration for neuraminidase, and the pulmonary half-life is 2.8 hours. Five to fifteen percent of the total dose (10 mg twice daily for 5 days for treatment and 10 mg once daily for prevention) is absorbed and excreted in the urine with minimal metabolism. Potential adverse effects include cough, bronchospasm (occasionally severe), reversible decrease in pulmonary function, and transient nasal and throat discomfort. 

While no firm underlying mechanisms have been demonstrated, some authors have suggested that irreversible oxidation of the cobalt atom in vitamin B12 by nitrous oxide can lead to inactivation of enzymes dependent on this vitamin, with resultant metabolic aberrations. Such examples have included methionine synthetase and thymidylate synthetase, which are essential in the synthetic pathways leading to the production of myelin and thymidine, respectively. Should these enzymes be impaired during the sensitive periods of in utero development, the potential for malformations may unfortunately be realized. To date, no studies have been able to demonstrate conclusively that low-level exposure to nitrous oxide is associated with a meaningful disruption of crucial metabolic functions to produce the above-described toxicity however, measures including improved waste gas-scavenging systems should be taken to minimize exposure of personnel. 

Carnitine acyltransferases in mitochondria, peroxisomes and the endc lasmic reticulum are different gene products and serve different metabolic functions in the cell. Here we summarize briefly evidence that carnitine octanoyltransferase (COT) from the peroxisomes and carnitine palmitoyltransferase II (CPT-II) from the mitochondria (both matrix facing enzymes) differ kinetically and demonstrate that they differ in their sensitivity to conformationally constrained inhibitors that mimic the reaction intermediate. Medium chain inhibitors are 15 times more effective on COT than on CPT-II and long chain inhibitors, such as hemipalmitoylcamitinium, 80 times more effective on the mitochondrial enzyme. Thus, it may be possible to develop inhibitors to inhibit mitochondrial P-oxidation with minimal effects on peroxisomtd P-oxidation and other acyl-CoA dependent reactions. 

Noncompartmental analysis is limited in that it is not descriptive or predictive concentrations must be interpolated from data. The appeal of noncompartmental analysis is that the shape of the blood concentration-versus-time curve is not assumed to be represented by an exponential function and, therefore, estimates of metabolic and pharmacokinetic parameters are not biased by this assumption. In order to minimize errors in parameter estimates that are introduced by interpolation, a large number of data points that adequately define the concentration-versus-tie curve are needed. 

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