Glyoxylate cycle

The glyoxylate cycle (glyoxylate shunt) lets bacteria, fungi, plants and nematodes grow on two-carbon compounds such as acetate, ethanol or fatty acids by converting acetyl-CoA into four-carbon dicarboxylic acids without losing carbon as CO2. It shares the citrate synthase, aconitase and malate dehydrogenase reactions with the tricarboxylic acid cycle but replaces the two oxidative decarboxylations with two signature reactions: isocitrate lyase cleaves isocitrate into succinate and glyoxylate, and malate synthase condenses glyoxylate with a second acetyl-CoA to form malate. Malate is oxidized back to oxaloacetate to close the cycle, so each turn takes in two acetyl-CoA and releases one succinate, which is used for gluconeogenesis and biosynthesis. In bacteria all reactions are cytoplasmic and the TCA-cycle enzymes are shared. In eukaryotes the cycle is split between compartments and uses dedicated isozymes: in plant seedlings the enzymes are concentrated in glyoxysomes, a specialized form of peroxisome, whereas in budding yeast citrate synthase is peroxisomal while aconitase, isocitrate lyase and the main malate dehydrogenase are cytosolic and malate synthase is cytosolic on ethanol but peroxisomal on fatty acids, so intermediates cross the peroxisomal membrane. Nematodes and Euglena carry isocitrate lyase and malate synthase as two domains of one bifunctional protein. Mammals lack the signature enzymes.

NEW (YeastPathways project, 2026-10). Scope: the isocitrate lyase plus malate synthase bypass with the three shared reactions that close the cycle (citrate synthase, aconitase, malate dehydrogenase), generalized over bacteria, fungi, plants and nematodes. Succinate export and its further conversion (succinate-fumarate carrier, TCA-cycle succinate dehydrogenase and fumarase, cytosolic malate dehydrogenase and PEP carboxykinase) are downstream links to tca_cycle and gluconeogenesis; acetyl-CoA supply (fatty-acid beta-oxidation, acetyl-CoA synthetase) is upstream. Neither is modelled here. The shared steps carry only the glyoxylate-cycle isozymes as yeast exemplars (peroxisomal CIT2, the cytosolic pool of ACO1, cytosolic MDH2 and peroxisomal MDH3); the mitochondrial isozymes are in tca_cycle. In bacteria such as E. coli the same citrate synthase, aconitase and malate dehydrogenase enzymes serve both cycles. Variant set: malate synthase is either a monofunctional malate synthase A-family enzyme (fungi, plants, enterobacteria; PANTHER PTHR42902) or the C-terminal domain of a bifunctional isocitrate lyase-malate synthase (C. elegans icl-1; the protein falls in the isocitrate lyase family PTHR21631). The malate synthase G family (PTHR42739, E. coli GlcB), which serves the glyoxylate shunt in some bacteria but glycolate utilization in E. coli, is not given an exemplar here; see glycolate_glyoxylate_assimilation for that bacterial route. YeastCyc corrections: DAL7 (malate synthase 2) is excluded because its physiological role is in allantoin catabolism under nitrogen control (PMID:1454530); ACO2 is excluded (homocitrate dehydratase, PMID:23106124); CIT1, CIT3 and MDH1 are mitochondrial TCA-cycle isozymes. Note that CIT2 is dispensable on ethanol or acetate when mitochondrial citrate synthesis can substitute (PMID:23966945), and that MDH2, not peroxisomal MDH3, is the main glyoxylate-cycle malate dehydrogenase on two-carbon substrates (PMID:1986231, PMID:1447211). GO-CAM disagreements: the YeastPathways GLYOXYLATE-BYPASS conversion places every activity, including peroxisomal CIT2, MLS1 and MDH3, in the cytosol, and enables the aconitase and malate synthase reactions by ACO2 and DAL7 respectively. There is no PomBase glyoxylate-cycle model; the PomBase TCA-cycle model 665912ed00000015 types SPBC1683.11c (PomBase icl1) as isocitrate lyase acting with the glyoxylate reductase gor2 in glyoxylate catabolism, whereas UniProt (Q9P6J1) names it a mitochondrial 2-methylisocitrate lyase, so no S. pombe exemplar is given.