Folate cytosolic

The folate receptor facilitates the cellular uptake of folate and 5-methyltetrahydrofolate via receptor-mediated endocytosis at caveolae (caveolae are plasma membrane invaginations distinct from the classical clathrin-coated pits) (6). It has been hypothesized that the folate receptor is functionally coupled to an anion transporter to mediate cytosolic folate delivery by a process defined as potocytosis (6). More recent studies suggest that folate receptor endocytosis also occurs at clathrin-coated pits (7). Studies by Low and coworkers at Purdue University have shown that folate conjugates are also taken up by the folate receptor (8-10), but not by the reduced folate carrier. Figure 2 illustrates an endocytic pathway of the type envisioned for folate conjugates. Unfortunately, the subcellular transport pathway of the folate conjugates has been only partially characterized and may well be affected by the properties of the molecule attached to folate. 

Pterins make no contributions to the colors of plants and microorganisms. One important pterin is the folate produced by plants and microorganisms. Folate and its derivatives are present in plants in various concentrations in mitochondria, cytosols, vacuoles, and plastids. The total amount of fohc acid depends on the plant species, on the developmental stage, and on external factors. Good sources of folates are beans, lentils, spinach, and wheat germ. ... 

Min H, Shane B, and Stokstad EL (1988) Identification of 10-formyltetrahydrofolate dehydrogenase-hydrolase as a major folate binding protein in liver cytosol. Bio-... 

MCF-7 cells and their xenograph tumors, and compared with DOX-loaded pH-insensitive micelles made of PLLA-PEG with folate targeting groups (PHlM/f) [99]. The cellular localization of the nanoparticles was confirmed by confocal microscopy (Fig. 10.13). DOX delivered by PHSM/f was found uniformly distributed in the cytosol as well as in the nucleus, while DOX/PHlM/f was entrapped in endosome and multivesicular bodies. It was thus hypothesized that PHis, which is known to have an endosomal membrane-disruption activity induced by a proton sponge mechanism of its imidazole groups [209, 210], disrupted the compartment membrane and released DOX into the cytosol. As a result, DOX/PHSM/f showed much higher in vitro and in vivo anticancer activities toward DOX-resistant cells (Fig. 10.14). 

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. 

Fig. 2. Cytosolic responses recorded in wild-type cells in response to 1 pM cAMP (cells at 6 h development) (a) and 1 pM folate (vegetative cells) (b). The chemoattractants were delivered within 1 s of the onset of recording as indicated by the arrows. Both folate- and cAMP-induced Ca + responses are developmentally regulated and exhibit similar kinetics. They are dependent on the relative rather than the absolute magnitude of increases in attractant concentration. Responses began after a short delay of 5-10 s. The [Ca +J reaches a maximum after 25 s and then returns to basal level within 60 s after stimulation.

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. ... 

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. 

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. 

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. 

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