The molecular basis of disease

Diagnosing and curing diseases has always been and will continue to be an art. The reason is that man is a complex being with many facets much of which we do not and probably will never understand. Diagnosing and curing diseases has many aspects include biochemical, physiological, psychological, sociological and spiritual ones.

Molecular medicine reduces this variety to the molecular aspect. Living organisms, in general, and humans in particular, are regarded as complex networks of molecular interactions that fuel the processes of life. This "molecular circuitry" has intended modes of operation that correspond to healthy states of the organism and aberrant modes of operation that correspond to diseased states. In molecular medicine, the goal of diagnosing a disease is to identify its molecular basis, i.e. to answer the question what goes wrong in the molecular circuitry. The goal of therapy is to guide the biochemical circuitry back to a healthy state.

As we pointed out, the molecular basis of life is formed by complex biochemical processes that constantly produce and recycle molecules and do so in a highly coordinated and balanced fashion. The underlying basic principles are quite alike throughout all kingdoms of life, even though the processes are much more complex in highly developed animals and the human than in bacteria, for instance. Figure 1.1 gives an abstract view of such an

Bioinformatics - From Genomes to Drugs. Volume I: Basic Technologies. Edited by Thomas Lengauer Copyright © 2002 WILEY-VCH Verlag GmbH, Weinheim ISBN: 3-527-29988-2

METABOLIC PATHW AYS

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Abstract view of part of the metabolic network of the bacterium E. coli. From http://www.genome.ad.jp/kegg/ kegg.html

METABOLIC PATHW AYS

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Abstract view of part of the metabolic network of the bacterium E. coli. From http://www.genome.ad.jp/kegg/ kegg.html underlying biochemical network, the so-called metabolic network of a bacterial cell (the intestinal bacterium E. coli). The figure affords an incomplete and highly simplified account of the actual molecular interactions, but it nicely visualizes the view of a living cell as a biochemical circuit. The figure has the mathematical structure of a graph. Each dot (node) stands of a small organic molecule that is metabolized within the cell. Alcohol, glucose, and ATP are examples for such molecules. Each line (edge) stands for chemical reaction. The two nodes connected by the edge represent the substrate and the product of the reaction. The colors in Figure 1.1 represent the role that the respective reaction plays in metabolism. These roles include the con struction of molecular components that are essential for life - nucleotides (red), amino acids (orange), carbohydrates (blue), lipids (light blue), etc. -or the breakdown of molecules that are not helpful or even harmful to the cell. Other tasks of chemical reactions in a metabolic network pertain to the storage and conversion of energy. (The blue cycle in the center of the Figure is the citric acid cycle.) A third class of reactions facilitates the exchange of information in the cell or between cells. This include the control of when and in what way genes are expressed (gene regulation), but also such tasks as the opening and closing of molecular channels on the cell surface, and the activation or deactivation of cell processes such as replication or apoptosis (induced cell death). The reactions that facilitate communication within the cell or between cells are often collectively referred to as the regulatory network. Figure 1.1 only includes metabolic and no regulatory reactions. Of course the metabolic and the regulatory network of a cell are closely intertwined, and many reactions can have both metabolic and regulatory aspects. In general, much more is known on metabolic than on regulatory networks, even though many relevant diseases involve regulatory rather than metabolic dysfunction.

The metabolic and regulatory network can be considered as composed of partial networks that we call pathways. Pathways can fold in on themselves, in which case we call them cycles. A metabolic pathway is a group of reactions that turns a substrate into a product over several steps (pathway) or recycle a molecule by reproducing in several steps (cycle). The glycolysis pathway (the sequence of blue vertical lines in the center of Figure 1.1), is an example of a pathway that decomposes glucose into pyruvate. The citric acid cycle (the blue cycle directly below the glycolysis pathway in Figure 1.1) is an example of a cycle that produces ATP, the universal molecule for energy transport. Metabolic cycles are essential, in order that the processes of life not accumulate waste or deplete resources. (Nature is much better at recycling than man.)

There are several ways in which Figure 1.1 hides important detail of the actual metabolic pathway. In order to discuss this issue, we have extracted a metabolic cycle from Figure 1.1 (see Figure 1.2). This cycle is a component of cell replication, more precisely; it is one of the motors that drive the synthesis of thymine, a molecular component of DNA. In Figure 1.2, the

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