ICDH-1 is most structurally similar to the R132H mutant human ICDH found in glioblastomas. Similar to human R132H ICDH, Mtb ICDH-1 also catalyzes the formation of α-hydroxyglutarate. Regulation The IDH step of the citric acid cycle is often (but not always) an irreversible reaction due to its large negative change in free energy. It must therefore be carefully regulated to avoid depletion of isocitrate (and therefore an accumulation of alpha-ketoglutarate). The reaction is stimulated by the simple mechanisms of substrate availability (isocitrate, NAD+ or NADP+, Mg2+ / Mn2+ ), product inhibition by NADH (or NADPH outside the citric acid cycle) and alpha-ketoglutarate, and competitive feedback inhibition by ATP. A conserved ncRNA upstream of the icd gene which codes for NADP+-dependent isocitrate dehydrogenase (IDH) has been reported in bacterial genomes, due to its characteristics this ncRNA resembles previous regulatory motifs called riboswitches, icd-II ncRNA motif has been proposed as a strong candidate riboswitch. Catalytic mechanisms Isocitrate dehydrogenase catalyzes the chemical reactions: Isocitrate + NAD+ 2-oxoglutarate + CO2 + NADH + H+ Isocitrate + NADP+ 2-oxoglutarate + CO2 + NADPH + H+ The overall free energy for this reaction is -8.4 kJ/mol. Steps Within the citric acid cycle, isocitrate, produced from the isomerization of citrate, undergoes both oxidation and decarboxylation. The enzyme isocitrate dehydrogenase (IDH) holds isocitrate within its active site using the surrounding amino acids, including arginine, tyrosine, asparagine, serine, threonine, and aspartic acid. In the provided figure, the first box shows the overall isocitrate dehydrogenase reaction. The necessary reactants for this enzyme mechanism are isocitrate, NAD+/NADP+, and Mn2+ or Mg2+. The products of the reaction are alpha-ketoglutarate, carbon dioxide, and NADH + H+/NADPH + H+. Water molecules help to deprotonate the oxygen atoms of isocitrate. The second box in the figure illustrates step 1 of the reaction, which is the oxidation of the alpha-carbon (C2 here, also called alpha-C). In this process, the alcohol group of the alpha-carbon is deprotonated and the resulting lone pair of electrons forms a ketone group on that carbon. NAD+/NADP+ acts as an electron-accepting cofactor and collects the resulting hydride from C2. The oxidation of the alpha carbon introduces a molecular arrangement where electrons (in the next step) will flow from the nearby carboxyl group and push the electrons of the double bonded oxygen up onto the oxygen atom itself, which collects a proton from a nearby lysine. The third box illustrates step 2, which