Folate metabolism cytosolic

Folate metabolism is not limited to the cytoplasmic compartment. Most of the folate in tissues is found in the mitochondrion and cytosol (Horne et al. 1997). Individual folate-dependent pathways are compartmentalized within organelles. The cytoplasmic and mitochondrial compartments each possess a parallel array of enzymes catalysing the interconversion of folate coenzymes that carry one-carbon units. The mitochondrial folate metabolism favours incorporation of one-carbon groups from serine and release of formate, while the cytoplasmic metabolism favours incorporation of one-carbon units from formate with purine and thymidine synthesis and homocysteine remethylation. 

Many of the enzymes involved in these reactions are multifunctional and are capable of channelling substrates and one-carbon units from reaction to reaction within a protein matrix. Another feature of intracellular folate metabolism is the compart-mentation of folate coenzymes between the cytosol and the mitochondria. For instance, 5-methylTHF is associated with the cytosolic fraction of the cell, whereas most of 10-formylTHF is located in the mitochondria. Similarly, some folate-dependent enzymes are associated with one or other compartment, though some are found in both. Metabolic products of folate-dependent reactions, such as serine and glycine, are readily transported between the two locations, but the folate coenzymes are not. 

Deficiency of folate or vitamin Bn can cause hematological changes similar to hereditary orotic aciduria. Folate is directly involved in thymidylic acid synthesis and indirectly involved in vitamin Bn synthesis. Orotic aciduria without the characteristic hematological abnormalities occurs in disorders of the urea cycle that lead to accumulation of carbamoyl phosphate in mitochondria (e.g., ornithine transcarbamoylase deficiency see Chapter 17). The carbamoyl phosphate exits from the mitochondria and augments cytosolic pyrimidine biosynthesis. Treatment with allopurinol or 6-azauridine also produces orotic aciduria as a result of inhibition of orotidine-5 phosphate decarboxylase by their metabolic products. 

CHO AUXBl mutants transfected with the E. coli folylpolyglutamate S3mthetase gene (AUX-co/i) express the E. coli protein in the cytosol and metabolize folates primarily to triglutamates rather than the hexa- and... 

Two pathways have been described for formate metabolism a peroxidatic pathway via catalase and a folate dependent one carbon pathway. Treatment of rats with amino-triazole, an irreversible inhibitor of catalase, severely depressed a-oxidation activity but only slightly decreased the production of CO2 from exogenously added formate. " Whether the effect of aminotriazole is (solely) linked to the inhibition of catalase is unclear (see further). In addition to these above mentioned pathways our data point to a cytosolic NAD -dependent dehydrogenase activity that acts on the formate produced during a-oxidation. In peimeabilized cells or broken systems, suppUed with the qi-propriate cofactors (see further), almost no CO2 is formed, during a-oxidation unless NAD is added. ... 

The shikimic acid pathway leading to the production of chorismic acid is regulated in the cytosol of the fungal cells. Cytosol or intracellular fluid (cytoplasmic matrix) is a complex mixture of substances dissolved in water. These include ions (such as calcium, sodium, and potassium), macromolecules, and large complexes of enzymes that act together to carry out metabolic pathways. Production of chorismic acid in the cytosol is ultimately utilized in the synthesis of folate, ubiquinone, and amino acids, the most important of which is tryptophan which plays a major role in the biosynthesis of psilocybin. 

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