Aconitase catalytic cycle

Figure 3 The catalytic cycle of aconitase. The circle symbolizes the [3Feb-4S] structure that carries the reactive Fea. Note that the right-hand side of the scheme is the mirror image of the left-hand side with respect to the CaCpCT fragment.

When induced in macrophages, iNOS produces large amounts of NO which represents a major cytotoxic principle of those cells. Due to its affinity to protein-bound iron, NO can inhibit a number of key enzymes that contain iron in their catalytic centers. These include ribonucleotide reductase (rate-limiting in DNA replication), iron-sulfur cluster-dependent enzymes (complex I and II) involved in mitochondrial electron transport and cis-aconitase in the citric acid cycle. In addition, higher concentrations of NO,... 

Although the equilibrium mixture at pH 7.4 and 25 °C contains less than 10% isocitrate, in the cell the reaction is pulled to the right because isocitrate is rapidly consumed in the next step of the cycle, lowering its steady-state concentration. Aconitase contains an iron-sulfur center (Fig. 16-10), which acts both in the binding of the substrate at the active site and in the catalytic addition or removal of H20. 

Fluorocitrate is an inhibitor of the citric acid cycle enzyme, aconitase. Fluorocitrate is produced by catalytic combination of fluoroacetyl-CoA (see fluoroacetate) with oxaloacetate by the enzyme citrate synthase. 

Various relationships between enzymes of the Krebs cycle and mitochondria are possible. For instance, all enzymes could be enclosed within mitochondrial structures or the enzymes could take part in the structural build-up of the cell. There is no evidence demonstrating that all enzymes of the Krebs cycle are part of the mitochondria. The existence of enzymes with multiple catalytic properties (isocitric dehydrogenase, aconitase, and malic dehydrogenase) and the failure to separate the multiple steps of an overall reaction (pyruvic and a-ketoglutarate oxidation) are sometimes taken as evidence for the participation of the enzyme in the building-up of the mitochondrial structure, but these arguments do not take into account the limitations of the actual biochemical methods, and, therefore, conclusions based upon them are premature. 

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