Figure 1. Glyoxylate cycle and related metabolic pathways in M. tuberculosis.

(a) The beta-oxidation cycle (β-ox) degrades fatty acids to acetyl-CoA (C₂) and propionyl-CoA (C₃). The glyoxylate and methylcitrate cycles are required for anaplerosis and for propionyl-CoA metabolism, respectively, in fatty acid-catabolizing cells. Glyoxylate cycle enzymes are ICL1, ICL2, and MLS; ICL1/ICL2 could also function in the methylcitrate cycle with PRPC and PRPD. Enzymes common to the glyoxylate, methylcitrate, and TCA cycles are ACN, SDH, and FUM. Enzymes common to the glyoxylate and TCA cycles are MDH, MQO, GLTA2, and CITA. Pyruvate is produced from malate by MEZ or from oxaloacetate by sequential action of PCK and PYK; coupled decarboxylation of pyruvate by the pyruvate dehydrogenase complex (PDHC) yields acetyl-CoA. Anaplerosis in carbohydrate-catabolizing cells is by carboxylation of pyruvate or phosphoenolpyruvate (PEP) to oxaloacetate by PCA or PPC, respectively. PPC is absent in M. tuberculosis (dashed line). Gene designations are listed in Supplementary Table 1 online. (b) ICL domain organization. Domains I and III are present in all ICLs. Domain I contains the conserved catalytic motif KKCGH. Domain II is present in fungal and plant ICLs and in mycobacterial ICL2, but absent in mycobacterial ICL1. Domain IV is unique to mycobacterial ICL2. (c) Superimposition of in silico-modeled ICL2 monomer (red) and the X-ray crystal structure of ICL1 monomer (blue). Encircled: ICL catalytic signature motif KKCGH (AA 193-203 in ICL1; AA 213-217 in ICL2). Domain II of ICL2 (AA 269-365) was modeled after the X-ray crystal structure of A. nidulans ICL²⁵. Domain IV (not depicted) had no homology to known sequences.