Metabolism is a network

WARWICK DUNN: Metabolism is central to all life on planet Earth. It fuels many different biochemical processes in each cell in our bodies. It is the integration of the physical and chemical processes employing small biochemicals, otherwise known as metabolites, involved in the maintenance and reproduction of life. Metabolism helps us to break down food by catabolic processes, by microorganisms in our gut and in our cells. It is the sum of the biochemical processes that are required to produce and use energy and to synthesise cellular components like proteins and DNA. Metabolism is also a major source of cellular information that integrates intracellular and environmental signals to coordinate processes such as nutrient utilisation, hormone signalling, or cell differentiation.

Metabolism can be separated into catabolic and anabolic processes. Catabolism involves the breakdown of organic substrates, typically upon oxidation processes, to provide chemical energy in the form of adenosine triphosphate or otherwise known as ATP. ATP is like a rechargeable battery that’s continuously broken down and recharged by removal and addition of phosphate chemical groups. The breaking of covalent bonds to remove a phosphate group releases energy that fuels our cells and provides heat in our bodies. Catabolic reactions also generate metabolic intermediates that may be used in subsequent anabolic reactions. Glycolysis is an example of a catabolic metabolic pathway. Anabolism results in the synthesis of cellular components from metabolic precursors and requires energy, compared to catabolism which produces energy.

So in anabolic reactions, ATP is consumed. An example of an anabolic process is the synthesis of glucose from carbon dioxide in plants. Some metabolic pathways are involved in both catabolic and anabolic processes, for example the Krebs or TCA cycle. Central or primary metabolism includes energy and core component production and is highly conserved across the microbe, plant, and animal kingdoms. Secondary metabolism includes specialised areas of metabolism, for example the production of antibiotics in the microbe Streptomyces or the production of metabolites which act as defence mechanisms in plants. Metabolism is often thought of in terms of pathways in which reactions are grouped together and related biochemical conversions.

A metabolite, the starting substrate or precursor, is catalysed to another metabolite via an enzyme, often in the presence of a co-factor. For example, glucose is converted to glucose-6 phosphate via hexokinase and the conversion of ATP to ADP. The subsequent reactions result in the production of pyruvate, which is further metabolised and can enter the Krebs or TCA cycle. The synthesis of metabolites does not occur in isolation of each other. Instead, large sets of metabolites are synthesised simultaneously and the accumulation of each metabolite depends on its rate of degradation and synthesis. Multiple metabolic pathways can share metabolites. And the synthesis of one metabolite can require the integrated operation of more than one metabolic pathway.

By considering this, we can define that a network or map representation is a more accurate description of metabolism rather than discrete pathways. This network, a regulatory sequence with inputs and outputs, is highly conserved across species. Nutrients are taken in and used to produce monomers and macromolecules to synthesise biomass and proliferate. Within the metabolic network, the majority of metabolites have a few connections, whereas a few metabolites have many connections. These could be called metabolic hubs. As with other networks, such as the London Underground or the World Wide Web, the metabolic network is complex. And a bottleneck in one location may have a wider effect on different areas of the network.

However, the metabolic pathways can also coordinate with each other to maximise processes occurring across the entire network. For example, in low glucose conditions ATP production is increased via the up-regulation of fatty acid beta-oxidation. Glycolysis and gluconeogenesis are very similar metabolic pathways, which operate in reverse of each other and are coordinated to ensure only one pathway is in operation at any one time. Glycolysis converts glucose to pyruvate in high glucose conditions, whereas gluconeogenesis converts pyruvate and other metabolic intermediates to glucose in low glucose conditions.

The first representation of the metabolic network was produced in 1955 by Donald Nicholson. Approximately 20 pathways were mapped in this metabolic network. This work was extended during the 1960s and included the majority of the pathways that we now know as the metabolic network. However, the pathways contained approximately 400 metabolites, a number that is far exceeded in the metabolic databases available today. The work to produce the metabolic network can be categorised into two different areas. The Pre-Isotopic Era, in which cell-free extracts were used to discover enzymatic activity. For example, the work performed by Eduard Buchner, who discovered the enzyme complex he termed “zymase” extracted from yeast cells which metabolise glucose to carbon dioxide and ethanol.

The second era, the Isotope Era, in which an unnatural label in the form of an isotope was tracked as it was transferred from one metabolite to another in a metabolic pathway or pathways, providing insight into the route of the isotope, and therefore the connectivity between metabolites, through the complex metabolic network. With metabolomics, we are now entering a new era. We have the information documented in the network and are using it to build databases of all the metabolites represented in metabolism or specific metabolomes, like human blood or human urine. However, we are now finding many analytes in our data that do not correspond to metabolites in these pathways.

As we extend our knowledge of metabolism through this new and powerful technique of metabolomics, we will further extend the metabolic network and our knowledge of this.