Summary
Much research in comparative physiology is now performed using ‘omics’ tools and many results are interpreted in terms of the effects of changes in gene expression on energy metabolism. However, ‘metabolism’ is a complex phenomenon that spans multiple levels of biological organization. In addition rates and directions of flux change dynamically under various physiological circumstances. Within cells, message level cannot be equated with protein level because multiple mechanisms are at play in the ‘regulatory hierarchy’ from gene to mRNA to enzyme protein. This results in many documented instances wherein change in mRNA levels and change in enzyme levels are unrelated. It is also known from metabolic control analysis that the influence of single steps in pathways on flux is often small. Flux is a system property and its control tends to be distributed among multiple steps. Consequently, change in enzyme levels cannot be equated with change in flux. Approaches developed by Hans Westerhoff and colleagues, called ‘hierarchical regulation analysis’, allow quantitative determination of the extent to which ‘hierarchical regulation’, involving change in enzyme level, and ‘metabolic regulation’, involving the modulation of the activity of preexisting enzyme, regulate flux. We outline these approaches and provide examples to show their applicability to problems of interest to comparative physiologists.
FOOTNOTES
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Funding
Research funding was provided by the US National Science Foundation [IOB 0517694 to R.K.S.] and the Natural Sciences and Engineering Research Council of Canada [to C.D.M.].
Glossary
- Allosteric
- Referring to regulation of the conformation or activity of a protein, mediated by reversible, concentration-dependent binding of a low-molecular-weight metabolite to a specific site.
- Direction of flux
- Used in reference to scenarios involving reversal of carbon flow through linear pathways (e.g. glycolysis versus gluconeogenesis) or alteration of rates of flow at branchpoints (e.g. regulation at the pyruvate branchpoint leads to various rates of conversion to lactate, acetylcoenzyme A, alanine, oxaloacetate, etc.).
- Flux
- In the simplest situation, the steady-state rate of conversion of an initial pathway substrate to the final end-product, e.g. the rate of glucose conversion to lactate or ethanol.
- Fluxome
- All the quantified fluxes of metabolites.
- Genome
- All the DNA and the information it encodes in a cell or organism.
- LON protease
- ATP-dependent serine protease localized in mitochondria.
- Metabolome
- All the low-molecular-weight molecules involved in metabolic transformations catalyzed by enzymes in the proteome.
- Omes
- Term coined to describe all biological entities named or renamed using words that end in ‘ome’.
- Omic tool
- Technique or approach employed to study a specific ome, e.g. DNA microarrays used to study the transcriptome, and proteomic tools used to study the proteome.
- Proteasome
- Large protein complex that degrades proteins tagged with ubiquitin.
- Proteome
- All proteins translated from the transcriptome.
- Transcriptome
- All the messenger RNA transcribed from the genome.
- Ubiquitination
- Enzyme-catalyzed reaction that tags proteins with ubiquitin, marking them for degradation.
- © 2012.
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