Enzymes are catalysts designed to function in the metabolic networks of biological systems. This review shows
mechanisms underlying chemical contribution to the biological system performance and adaptations in permanently
changing environment. The catalyst is exemplified by the 2-oxoglutarate dehydrogenase complex irreversibly degrading a
branch point metabolite 2-oxoglutarate at the crossroad of carbon, nitrogen and fat metabolism. According to the key
metabolic position and multienzyme structure, the complex exhibits rich regulation, demonstrating main principles governing
the catalysis within metabolic network. First, the catalyst kinetics is changed through the enzyme-ligand interactions
affecting the catalyst structure. The ligands include both small molecules and proteins, affecting catalysis by binding
either to active (coenzymes, substrates, products or inhibitors) or allosteric sites. Allostery enables enzymatic sensitivity
to general cellular signals, transmitted, in particular, by second messengers (Ca2+), adenine nucleotide phosphorylation
status or redox potential. Regulation of catalysis by heterologous protein-protein interactions helps organization of metabolic
pathways. Secondly, different regulators may interact through the protein structure effecting synergistic or antagonistic
relationships through combined conformational stabilization or competitive binding. The latter is supported by
common structural elements, e.g. adenine moiety, present in a number of biologically essential molecules. Thirdly, cellular
systems may control the enzymatic catalysis by posttranslational modifications which may either effect or disable catalysis.
The inactivation may protect catalyst itself and/or surrounding medium under conditions of metabolic impairment.
Thus, enzymology enables our predictive capacity regarding both the enzyme impact on general metabolism and response
to the metabolic changes within cellular network. This paves the way to the knowledge-based design of pharmacological
tools to perform metabolic regulation required for solving medical and bioengineering problems.
Keywords: lipoic acid, multienzyme complex, neurodegeneration, 2-oxoglutarate dehydrogenase, phosphorylation potential,
redox regulation, thiamine deficiency, tricarboxylic acid cycle
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