Computer Simulation of Metabolism
Simulation of The Pathway of DMSP Biosynthesis in Enteromorpha intestinalis
A.D. Hanson, D.A. Gage, K.D. Nolte, W.A. Hicks, T. Leustek, A.J. Cooper, A. Nadolska-Orczyk, S. Islam, P.J. Rich, D. Rhodes
Acknowledgment: This work was supported by a grant from the Office of Naval Research (ONR)
An example of the utility of the above computer simulation models is shown in the following figure, drawn from results described by Gage et al (1997) concerning the 35S labeling kinetics of the osmolyte
3-dimethylsulfoniopropionate (DMSP) from exogenously supplied [35S]-methionine in the marine alga Enteromorpha intestinalis. Computer models were used to quantitatively interpret the uptake kinetics of a dose of
[35S]-methionine (5.0 nmol.gfw-1, 10,000 nCi.nmol-1), the labeling kinetics of the endogenous free methionine pool, protein-bound methionine, DMSP, and its putative precursors, DMSHB (4-dimethylsulfonio-2-hydroxybutyrate) and MTHB (4-methylthio-2-hydroxybutyrate).
The modeling results support the conclusion (Gage et al, 1997) that DMSP is synthesized in Enteromorpha intestinalis by the following route:
provided that it is envisaged that both MTHB (4-methylthio-2-hydroxybutyrate) and DMSHB (4-dimethylsulfonio-2-hydroxybutyrate) are compartmentalized between metabolically active and inactive pools [note that in the labeling experiment considered here,
the isotopic labeling of MTOB (4-methylthio-2-oxobutyrate) was not measured]. As can be seen in the simulations shown below, the complex labeling kinetics of MTHB and DMSHB suggest the occurrence of rapidly labeling "metabolic" pools in slow equilibrium with metabolically inactive or "storage" pools of these intermediates. The fluxes via the "metabolic" pools of the intermediates MTHB and DMSHB are quantitatively consistent with roles of these pools as intermediates in the DMSP synthesis pathway.
Values of starting pool sizes (P2, P3, A2, B2, C2, C6, D2, D6, and E2) are given in units of nmol.gfw-1, values of starting specific acitvities (P1, A1, B1, C1, C5, D1, D5, and E1) are given in units of
nCi.nmol-1, and rates (A8, A3, A4, B3, B4, C3, C4, D3, D4 and E3) are given in units of nmol.min.-1gfw-1. Graphs show simulated (lines), and observed (squares) amounts of
radioactivity (nCi.gfw-1) in each intermediate or the end-product, DMSP, at each time. For considering the uptake kinetics of [35S]-methionine from the medium, it was envisaged that approx. 8.6% of the
supplied precursor was as [35S]-methionine sulfoxide which was not taken up by the algae and remained in the medium (P3 = 0.43 nmol.gfw-1). As the pool of exogenous
[35S]-methionine (starting pool size P2 = 4.57 nmol.gfw-1) was consumed, the rate of uptake of methionine was envisaged to decline proportionately (rate of uptake A8 = P2 * k). The best-fitting value of k was found to be close to 0.287.
For each intermediate considered, a mean absolute deviation between observed and simulated labeling kinetics for the time-course is computed for each program run. This represents a measure of "goodness-of-fit" between observed and simulated values [the lower the mean deviation, the better the fit]. Values of pool sizes and fluxes were progressively adjusted until a close match between simulated and observed values was obtained [i.e. until the grand mean deviation value was minimized].
Download a version of the Visual Basic program illustrated above. To run this program you must have Visual Basic 5.0 (or greater) installed on your computer.
An interactive version of this specific model is also available as a Java applet. This applet should function with both Netscape Navigator and Internet Explorer 3.0 or above. Simulated values are shown in graphical format. This model currently does not provide numerical estimates of "goodness-of-fit".
Gage, D.A., Rhodes, D., Nolte, K.D., Hicks, W.A., Leustek, T., Cooper, A.J.L. and Hanson, A.D. 1997. A new route for synthesis of dimethylsulphoniopropionate in marine algae. Nature 387: 891-894.