From: Marino-Ramirez, Leonardo (NIH/NLM/NCBI) [E]
Sent: Tuesday, November 07, 2006 1:49 PM
To: NLM/NCBI List ncbi-seminar
Cc: Mauricio Rodriguez
Subject: Special Seminar to be presented on Nov. 9 (Thursday) at 10
am.,Bldg. 38A, 5th floor conference room

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PYRIMIDINE NUCLEOTIDE DE NOVO BIOSYNTHESIS AS A MODEL OF METABOLIC
CONTROL 


Mauricio Rodriguez Rodriguez, PhD
Air Force Research Laboratory
Cellular Dynamics & Engineering Program
Wright State University
Physics Department


This presentation highlights a thorough investigation and description of
metabolic control dynamics in vivo and in silico using as a model de
novo pyrimidine biosynthesis. Metabolic networks have been studied
intensely for decades, which has helped to develop a detailed
understanding of the way cells carry out their biosynthetic and
catabolic functions. Biochemical reactions have been defined; pathway
structures have been proposed; networks of genetic control have been
examined; and mechanisms of enzymatic activity and regulation have been
elucidated. In parallel with these types of traditional biochemical
analysis, there has been increasing interest in engineering cellular
metabolism for commercial and medical applications. Several different
mathematical approaches and control theories have been developed to
model biochemical pathways by combining stoichiometric and/or kinetic
information with probabilistic analysis. The advent of genomic-derived
data has contributed to an enhanced interest in the comparative logic of
metabolic networks through mathematical modeling efforts. However, most
of the research performed to date has relied almost exclusively on
theoretical analyses and non-dynamic physiological states. The studies
described in this presentation provide a unique effort toward combining
mathematical analysis with dynamic transition experimental data. Most
importantly these studies emphasize the significance of providing a
quantitative framework for understanding metabolic control. The pathway
of de novo biosynthesis of pyrimidines in Escherichia coli provides an
ideal model for the study of metabolic control, as there is extensive
documentation available on each gene and enzyme involved as well as on
their corresponding mechanisms of regulation. Biochemical flux through
the pathway was analyzed under dynamic conditions using
middle-exponential growth and steady state cultures. The fluctuations of
the biochemical pathway intermediates and end products transitions were
quantified in response to physiological perturbation. Different growth
rates allowed the comparison of rapid versus long-term equilibrium
shifts in metabolic adaptation. Finally, monitoring enzymatic activity
levels during metabolic transitions provided insight into the
interaction of genetic and biochemical mechanisms of regulation. Thus,
it was possible to construct a robust mathematical model that faithfully
represented, with a remarkable predictability, the nature of the
metabolic response to specific environmental perturbations. These
studies constitute a significant contribution to quantitative
biochemistry as well as in the field of metabolic control, which can be
extended to other cellular processes as well as different organisms.