Then, at the end of the cycle, the original acetate atoms are shuffled around to recreate the oxaloacetate. The citric acid cycle provides the electrons that fuel the process of oxidative phosphorylation--our major source of ATP and energy. These electrons then fuel the production of a proton gradient by two proton pumps: cytochrome bc1 and cytochrome c oxidase.
All of this action occurs in our mitochondria--the citric acid cycle enzymes are inside the mitochondria, and the protein pumps are in the mitochondrial membrane.
Citrate synthase. The cycle gets started with the enzyme citrate synthase, shown here from PDB entry 1cts. The pyruvate dehydrogenase complex has previously connected an acetyl group to the carrier coenzyme A, which holds it in an activated form. Citrate synthase pops off the acetyl group and adds it to oxaloacetate, forming citric acid. The enzyme opens and closes around these molecules during the reaction--to explore the structures, take a look at the Molecule of the Month on citrate synthase.
The citrate formed in the first step is a bit too stable, so the second step moves an oxygen atom to create a more reactive isocitrate molecule.
Aconitase, shown here from PDB entry 7acn , performs this isomerization reaction, with the assistance of an iron-sulfur cluster. To explore this reaction, take a look at the Molecule of the Month on aconitase.
Isocitrate dehydrogenase. The real work begins in the third step of the cycle. Isocitrate dehydrogenase, shown here from PDB entry 3blw , removes one of the carbon atoms, forming carbon dioxide, and transfers electrons to NADH. To explore this molecule in more detail, take a look at the Molecule of the Month on isocitrate dehydrogenase.
The next step is performed by a huge multienzyme complex, similar to the pyruvate dehydrogenase complex. A lot of things happen in this complex. Another carbon atom is released as carbon dioxide, electrons are transferred to NADH, and the remaining part of the molecule in connected to coenzyme A.
The complex is composed of three separate enzymes, all connected by flexible tethers. The illustration shown here includes only a few of the tethered molecules--in the actual complex, the central core is surrounded by 24 enzymes. This illustration was created using several PDB entries: 1e2o , 1bbl , 1pmr , 2eq7 , and 2jgd. Succinyl-CoA synthetase from mitochondria top and bacteria bottom. The fifth step is the only step in the cycle where ATP is made directly.
The bond between succinate and coenzyme A is particularly unstable, and provides the energy needed to build a molecule of ATP.
In mitochondria, the enzyme shown on the top from PDB entry 2fp4 actually creates GTP in the reaction, which is readily converted to ATP by the enzyme nucleoside diphosphate kinase. A similar form of succinyl coA synthetase is found in the cytoplasm, which uses ATP and is thought to be mostly involved in the opposite reaction, creating succinyl-CoA for use in biosynthetic tasks.
Succinate dehydrogenase, with the membrane shown schematically in gray. The sixth step is performed by a protein complex that is bound in the membrane of the mitochondrion.
It links its citric acid cycle task directly to the electron transport chain. ATP provides for example energy for muscle contractions and can therefore be referred to as "energy currency" of the cells. Before the fuel molecules can be inserted in the Krebs Cycle, they must first all be converted into acetyl-CoA. Looking at the path of a nutrient, such as glucose, the oxidation of the molecule takes place in the glycolysis.
The product of the glycolysis is pyruvate. In a further reaction, which is catalyzed by the enzyme complex pyruvate dehydrogenase, acetyl-CoA is formed out of pyruvate, which can be introduced into the citric acid cycle or Krebs Cycle. In an eight-step reaction sequence, the acetyl group of acetyl-CoA is oxidised into two molecules of CO 2 see Figure.
Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 23 —9. Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Blood 7 — Glycolytic reprogramming by TLRs in dendritic cells. Nat Immunol 15 4 —5. Expression of the nitric oxide synthase gene in mouse macrophages activated for tumor cell killing.
Molecular basis for the synergy between interferon-gamma and lipopolysaccharide. J Biol Chem 3 — PubMed Abstract Google Scholar. Induction of nitric oxide synthase in mouse dendritic cells by IFN-gamma, endotoxin, and interaction with allogeneic T cells: nitric oxide production is associated with dendritic cell apoptosis.
J Immunol 8 — Persistent inhibition of cell respiration by nitric oxide: crucial role of S-nitrosylation of mitochondrial complex I and protective action of glutathione. Blood 3 — Regulation of glut1 mRNA by hypoxia-inducible factor Interaction between H-ras and hypoxia. J Biol Chem 12 — Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1.
J Biol Chem 51 — Cell Metab 21 1 — Nat Commun J Immunol 12 — J Immunol 11 — TSC2 mediates cellular energy response to control cell growth and survival.
Cell 5 — How metabolism generates signals during innate immunity and inflammation. J Biol Chem 32 —8. Succinate: a metabolic signal in inflammation. Trends Cell Biol 24 5 — Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages.
Cell 2 — Nature — J Biol Chem 50 —9. Cell 1 — A conserved family of Prolylhydroxylases that modify HIF. Science — The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.
Nature —5. J Clin Invest 10 — HIFmediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3 3 — Regulation of mammalian pyruvate dehydrogenase complex by phosphorylation: complexity of multiple phosphorylation sites and kinases. Exp Mol Med —7. The mitochondrial citrate carrier: a new player in inflammation. Biochem J 3 —6.
Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab 24 1 — Nat Immunol 15 4 — ATP-citrate lyase links cellular metabolism to histone acetylation. Akram M. Citric acid cycle and role of its intermediates in metabolism. Cell Biochem Biophys 68 3 —8. Palmieri F. The mitochondrial transporter family SLC25 : physiological and pathological implications.
Pflugers Arch 5 — Saggerson D. Malonyl-CoA, a key signaling molecule in mammalian cells. Annu Rev Nutr 28 1 — Inhibition of carnitine palmitoyltransferase I augments sphingolipid synthesis and palmitate-induced apoptosis.
J Biol Chem 6 —9. Isoforms of acetyl-CoA carboxylase: structures, regulatory properties and metabolic functions. Biochem Soc Trans 25 4 —8. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab 21 6 — Exp Mol Pathol 86 3 —9. Regulation of pyruvate dehydrogenase in muscle. Inhibition by citrate. J Biol Chem 17 —3. Google Scholar. Correlation of the effects of citric acid cycle metabolites on succinate oxidation by rat liver mitochondria and submitochondrial particles.
J Bioenerg 7 1 :1— The mechanism of tricarboxylic acid cycle regulation of fatty acid synthesis. J Biol Chem 6 — Iacobazzi V, Infantino V. Citrate — new functions for an old metabolite.
Biol Chem 4 — Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42 3 — Biochim Biophys Acta 11 — ATP-citrate lyase is essential for macrophage inflammatory response. Biochem Biophys Res Commun 1 — Acetyl-coenzyme A synthetase AMP forming. Cell Mol Life Sci 61 16 — J Immunol 9 — Biochim Biophys Acta 8 — J Biol Chem 10 — Prognostic and therapeutic implications of increased ATP citrate lyase expression in human epithelial ovarian cancer.
Oncol Rep 27 4 — ATP citrate lyase knockdown induces growth arrest and apoptosis through different cell- and environment-dependent mechanisms.
Mol Cancer Ther 11 9 ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer. Cancer Res 68 20 — ATP citrate lyase is increased in human breast cancer, depletion of which promotes apoptosis.
Tumor Biol 39 4 ATP-citrate lyase: a key player in cancer metabolism. Cancer Res 72 15 — Inhibition of ATP citrate lyase induces an anticancer effect via reactive oxygen species: AMPK as a predictive biomarker for therapeutic impact.
Am J Pathol 5 — FEBS J 2 — Srebp-controlled glucose metabolism is essential for NK cell functional responses. Nat Immunol 18 11 — Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes.
The mitochondrial citrate carrier: metabolic role and regulation of its activity and expression. Nuclear sterol regulatory element-binding proteins activate genes responsible for the entire program of unsaturated fatty acid biosynthesis in transgenic mouse liver.
J Biol Chem 52 — The roles of sterol regulatory element-binding proteins in the transactivation of the rat ATP citrate-lyase promoter. J Biol Chem 39 —6. Inhibition of hypoxia-inducible factor HIF hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J Biol Chem 7 — The asparaginyl hydroxylase factor inhibiting HIF-1alpha is an essential regulator of metabolism. Cell Metab 11 5 — The growing landscape of lysine acetylation links metabolism and cell signalling.
Nat Rev Mol Cell Biol 15 8 — Shi L, Tu BP. Acetyl-CoA and the regulation of metabolism: mechanisms and consequences. Curr Opin Cell Biol — Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27 1 — Mehta V, Namboodiri MA. N-acetylaspartate as an acetyl source in the nervous system.
Brain Res Mol Brain Res 31 1—2 —7. N-acetylaspartate catabolism determines cytosolic acetyl-CoA levels and histone acetylation in brown adipocytes. Sci Rep ATP-citrate lyase controls a glucose-to-acetate metabolic switch. Cell Rep 17 4 —
0コメント