Biology Reference
In-Depth Information
As the urea cycle operates only to eliminate excess nitrogen. High concentration level of ammonia in
the cell results in hyperammonemia which is a typical fatal event, coma and death ever been reported.
Laboratory studies can reveal elevated arginine levels, mild hyperammonemia, and a mild increase in
urine orotic acid. The diagnosis now can be confirmed by enzymatic analysis in the model. On high-
protein diets or under starvation state, proteins are degraded and amino acid carbon skeletons are used
to provide energy, thus increasing the quantity of nitrogen. But the amino nitrogen must be excreted.
To facilitate this process, enzymes of the urea cycle are controlled at the gene level to enhance the
concentrations of enzymes. As the urea cycle takes place both in mitochondria and cytoplasma, the
effects involved also come from the membrane transportation. Some mitochondrial membrane diseases,
e.g. ornithine transporter deficiency, surely effect the transportation of ornithine into matrix and results
in high concentration of ornithine accumulation in plasma, which gets a feedback to the transition of
arginine into urea and finally hyperammonnemia. From the model we know the treatment for defects of
the enzymes in the urea cycle could be either limiting the input of ammonia (limiting protein intake) or
replacing the missing intermediates from the cycle (supplementing with arginine or citrulline). Patients
with OTC deficiency benefit from citrulline supplementation because citrulline can accept ammonia to
form arginine.
DISCUSSION
The case study shows that the Petri net allows easy incorporation of qualitative insights into a pure
mathematical model and adaptive identification and optimization of key parameters to fit system behaviors
observed in gene regulated metabolic networks. The advantages of applying hybrid Petri nets (HPN)
to model and simulate are: (i) The HPN model has a user-friendly graphical interface that allows an
easy design, simulation and visualization. (ii) With the discrete and continuous events, HPN can easily
handle gene regulatory and metabolic reactions. (iii) The inhibitor arc is useful for mechanistic studies
to learn how enzymes interact with their substrates, to know the role of inhibitors in enzyme regulation
and gene expression. Moreover, powered with mathematical equations, simulation is executable and
dynamic results are visible.
As in the cell, there are usually hundreds of interconnected metabolic pathways and gene regulatory
networks and control of these presents more complex features. It is feasible to extend the Petri net model
in a plug-in way. A large complex network model can be handled with the same set of structural and
behavioral properties. When HPN models are applied to such a large network, the hierarchical concept
makes it possible to develop a generalized variant of HPN at a global level. On the other hand, the subnet
of the Petri net model provides us the basic model of which we already know its inner behavior and
functions. Then we can construct a system by plugging together sub-models in order to understand the
higher-level system and to predict its behavior.
With rapid development of PN, many important extensions to the above general Petri nets classification
appear. In the past few years, a number of Petri net tools have been used to model and simulate metabolic
pathways and gene regulatory networks, e.g. UltraSAN, Design/CPN and VON++. More tools can
be found at
http://www.daimi.aau.dk/PetriNets/tools/quick.html
. However, different tools have their
characteristics and cannot embed various functions. Almost all Petri net tools were intended to model
manufacture, distribution, and communication systems rather than biological systems. It requires the
collaboration of biologists and Petri net researchers to construct a specific Petri net tool that contains all
necessary features. Fortunately, Matsuno et al. [2001] adapted the VON++ to the GON program, and
have made a significant progress.
