Bioconversion kinetics

At steady state, changes in the concentrations of drug and metabolite with distance involving diffusional and concurrent bioconversion kinetics are given by... 

Enantioselective enzymatic esterifications represent a further type of biotransformation that has been used for the synthesis of optically active organosilicon compounds. The first example of this particular type of bioconversion (kinetic racemate resolution) is illustrated in Scheme 22. Starting from the racemic l-silacyclohexan-2-ol rac-43, the optically active 5-phenylpentanoate (S)-94 was prepared by enantioselective esterification with 5-phenylpentanoic acid using 2-methylheptane as solvent and crude Candida cylin-dracea lipase (CCL E.C. 3.1.1.3) as biocatalyst7. The enantiomeric purity of (S)-94 was ca 65% ee (bioconversion not optimized). 

A series of 2 -(0-acyl) derivatives of 9-(2-hydroxyethoxymethyl)gua-nine (acyclovir) was synthesized by Shao and coworkers.63 64 The bioconversion kinetics of the prodrugs appeared to depend on both the polar and the steric properties of the acyl substituents. Rat nasal perfusion studies using the in situ perfusion technique showed no measurable loss of acyclovir from the perfusate. Also, the extent of nasal absorption appeared to depend on the lipophilicity of the prodrugs. All the prodrugs showed enhanced absorption. Branching of the acyl... 

Previously, we have shown that functional secretion of OPH molecules into the periplasmic space induced about 2.8-fold higher specific whole cell OPH activity [10]. From the detail reaction kinetic studies in this work, we showed that this periplasmic space-secretion strategy provided much improved bioconversion capability and efficiency ( 1.8-fold) for Paraoxon as a model organophosphate compound. From these results, we confirmed that Tat-driven periplasmic secretion of OPH can be successfully employed to develop a whole cell biocatalysis system with notable enhanced bioconversion efficiency and capability for environmental toxic organophosphates. 

The kinetics of soybean lipoxygenase-1 in a biphasic medium is different from the kinetics in an aqueous system [Fig. 5(a),(b)]. The kinetic curve in the two-phase system has a sigmoid shape, which is due to surface active properties of LA and HP [25]. When initial LA concentration is small in the organic phase (0-5 mM) its transfer is poor and bioconversion in the aqueous phase is slow. 

This system displays a two-enzyme kinetic model in which bioconversion is controlled by the interaction between the two reactions and the mass transfer. This situation offers a more realistic model for the conditions occurring in vivo, in which some pathways of intermediary metabolism consist of linear sequences of reactions. These pathways take place in highly organized compartments. 

Figure 30 Appearance kinetics of PNU-82,899 and the monoester metabolite into the receiver sink. Diester diffused into the Caco-2 cell, resulting in rapid bioconversion of the diester to the monoester. Membrane surface metabolism was not detected. The initial donor concentration was 145 pM, and donor and receiver solutions were at pH 7.4. ( ) Monoester. AC /Af = 0.44 pM/min efflux P = 2.68 X 10 5 cm/sec. (O) Diester. ACf/Af = 0.034 pM/min efflux P = 0.21 X 10-5 cm/sec.

BIOCHEMICAL SELF-ASSEMBLY ACTIN ASSEMBLY KINETICS HEMOGLOBIN S POLYMERIZATION MICROTUBULE ASSEMBLY KINETICS BIOCONJUGATE BIOCONVERSION BIOLEACHING... 

The second approach to prolonged therapeutic action is based on the controlled rate of conversion of the promoiety into the active compound in vivo. This approach requires particularly detailed study of the kinetics of prodrug-drug conversion. A classic example is bioconversion of azathioprine to 6-mercaptopurine. Azathioprine is used commonly in kidney transplantation, rheumatoid arthritis, and the treatment of various skin disorders. After administration, azathioprine undergoes slow... 

The above procedure allows the thermal kinetic behavior of both enzymes involved in the nitrile bioconversion to be characterized fully and helps obtain the complete kinetic equation. 

In this section the basic kinetic model for enzyme-catalyzed bioconversions is presented. Understanding this model is the foundation for deriving more complex models. In their theory of enzyme catalysis, Michaelis and Menten 113 postulated the existence of an enzyme substrate complex (ES), which is built up in a reversible... 

CS is absorbed very rapidly from the respiratory tract, and the half-lives of CS and its principal bioconversion products are reported to be extremely short. The disappearance of CS follows first-order kinetics over the dose range examined. CS spontaneously hydrolyzes to malononitrile, and the latter is transformed to cyanide in animal tissues. Metabolically, CS undergoes conversion to 2-chlorobenzyl mal-ononitrile (CSHj), 2-chlorobenzaldehyde (oCB), 2-chlorohippuric acid, and thio-cyanate. " CS and its metabolites can be detected in the blood after inhalation exposure, but only after large inhalation doses. Following inhalation exposure of rodent and non-rodent species to CS aerosol, CS and two of its metabolites... 

Hydrolysis and fermentation models were developed using two hydrolysis datasets and two SSF datasets and by using modified Michaelis-Menten and Monod-type kinetics. Validation experiments made to represent typical kitchen waste correlated well with both models. The models were generated in Matlab Simulink and represent a simple method for implementing ODE system solvers and parameter estimation tools. These types of visual dynamic models may be useful for applying kinetic or linear-based metabolic engineering of bioconversion processes in the future. 

There are numerous compilations of pKg values" in the physical chemistry literature, including several for pharmaceutically relevant organic weak acids and bases [1-8]. These are complemented by further compilations of pharmaceutically relevant physicochemical data such as partition coefficients, solubilities, and reaction rate constants [6]. At the same time, other pharmaceutically interesting phenomena have not yet received the attention they deserve, such as the detailed substrate specificity and kinetics of endogenous enzyme systems (e.g., esterases and phosphatases), which are relevant to the rational design of prodrugs and the predictability of their bioconversion to active drug [13]. 

N. Pras, Bioconversion Spectrum and Related Kinetic Aspects of Entrapped Cells of Mucuna pruriens L. Ph.D. Thesis, University of Groningen, Groningen, The Netherlands, 1988. 

The production of DOD from oleic acid is unique in that it involves an addition of two hydroxy groups at two positions and a rearrangement of the double bond of the substrate molecule. The reaction at the A9,10 position resembles hydration, and the reaction at the C-7 position seems like a hydroxylation. Subsequent investigation of reactions catalyzed by PR3 led to the isolation of another new compound, 10-hy-droxy-8-octadecenoic acid (HOD) (34). From the structure similarity between HOD and DOD, it is likely that HOD is an intermediate in the formation of DOD from oleic acid by strain PR3. Kinetic studies (34) showed that the conversion from HOD to DOD is not a rate-limiting step. The bioconversion pathway for flie production of DOD from oleic acid is postulated as follows (Fig. 3) a hydratase in strain PR3 attacks oleic acid at the C-10 position, introduces a hydroxy group, and at the same time shifts the double bond from C-9 to C-8. The resulting product (HOD) is then oxidized by a hydroxylase at the C-7 position to produce DOD. 

Mosier, N. S., Hall, R, Ladisch, C.M., Ladisch, M.R. Reaction Kinetics, Molecular Action, and Mechanisms of Cellulolytic Proteins. Vol. 65, p. 23 MUhlemann, H.M., Bungay, HR. Research Perspectives for Bioconversion of Scrap Paper. Vol. 65, p. 193... 

Xiu ZL, Zeng AP, An LJ. (2000). Mathematical modehng of kinetics and research on multi-phcity of glycerol bioconversion to 1,3-propanediol. J Dalian Univ Technol, 40, 428-433. 

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