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ascorbate recycling (cytosolic)

General Background |FRAME: ASCORBATE| (vitamin C, ascorbic acid) is a reducing agent and water-soluble antioxidant. It can be biosynthesized by plants (see |FRAME: PWY-882|), some bacteria (see |FRAME: PWY-5521|) and many, but not all, vertebrates (see |FRAME: PWY3DJ-35471|). It is used in the pharmaceutical industry for the production of vitamin supplements, cosmetics and therapeutic preparations. It is also used in the food, beverage and animal feed industries (reviewed in |CITS:[17222174]|). |FRAME: ASCORBATE| is an essential vitamin in the diet of humans, non-human primates and certain other vertebrates that cannot biosynthesize it (some fish and birds, bats and guinea pigs). These species rely on mechanisms for efficient uptake and recycling of this vitamin. It is taken up in the intestine, transported in plasma and delivered to tissues. It has roles in collagen biosynthesis, as an antioxidant, as a cofactor in reactions catalyzed by some metal-dependent mono- and dioxygenases, and may be involved in cell signaling reactions and transcription factor activation. A deficiency of ascorbate leads to the disorder scurvy (reviewed in |CITS: [16516325] [17222174]|. About This Pathway The anionic form of L-ascorbic acid, |FRAME: ASCORBATE|, is predominantly present at physiological pH |CITS: [SHASKUS84]|. |FRAME: ASCORBATE| is actively transported into cells via the |FRAME: NA+|-dependent cotransporters SVCT1 and SVCT2 (not shown) and used as an antioxidant. It reduces various oxidized substrates and produces the oxidized product |FRAME: CPD-318| and a reduced substrate. This is represented in this pathway by the general reaction |FRAME: RXN-10981|. |FRAME: ASCORBATE| is also used as an enzyme cofactor for |FRAME: CU+2|-dependent monooxygenases (such as EC and EC and |FRAME: FE+2|-dependent dioxygenases (such as EC and EC which leads to its one-electron oxidation to |FRAME: CPD-318| (semidehydroascorbate) (reviewed in |CITS: [17222174] [11028916]|). Two molecules of |FRAME: CPD-318| spontaneously form one molecule of |FRAME: L-DEHYDRO-ASCORBATE| and one molecule of |FRAME: ASCORBATE| in a disproportionation reaction, as shown in this pathway (|FRAME: RXN-3523|) |CITS: [11020669]| and reviewed in |CITS: [17222174]|. Several enzyme systems described below can reduce |FRAME: CPD-318| and |FRAME: L-DEHYDRO-ASCORBATE| back to |FRAME: ASCORBATE|. The mechanisms used appear to depend upon the cell type, with the erythrocyte being well-studied |CITS: [11687303]|. |FRAME: CPD-318| is considered to be the quantitatively most important oxidation product of |FRAME: ASCORBATE|. Cellular compartments involved in ascorbate recycling include the cytosol (this pathway), secretory vesicles, the mitochondrion and the extracellular space. Membrane transporters and membrane electron transfer systems are also involved (as discussed below). Reviewed in |CITS: [17222174]|. Reduction of cytosolic |FRAME: CPD-318| to |FRAME: ASCORBATE| in a one-electron step may involve the participation of either of two enzymes that have |FRAME: CPD-318| reductase activity: NADH cytochrome b5 reductase EC (of the mitochondrial outer membrane), or |FRAME: CPLX-7940| EC Reviewed in |CITS: [17222174]|. Intracellular |FRAME: L-DEHYDRO-ASCORBATE| is formed by either spontaneous disproportionation of |FRAME: CPD-318|, or by its facilitative transport into the cell. Transport occurs via glucose transporters, driven by intracellular reduction of |FRAME: L-DEHYDRO-ASCORBATE| to |FRAME: ASCORBATE|. Reviewed in |CITS: [17222174]|. Intracellular reduction of |FRAME: L-DEHYDRO-ASCORBATE| to |FRAME: ASCORBATE| in a two-electron step can be catalyzed by five different enzymes that have |FRAME: NADPH|-dependent, or |FRAME: GLUTATHIONE|-dependent |FRAME: L-DEHYDRO-ASCORBATE| reductase activity: |FRAME: HS04268-MONOMER| (glutaredoxin) EC, |FRAME: CPLX-7941| EC, |FRAME: CPLX-6081| (omega class glutathione transferase) EC, |FRAME: MONOMER-14305| EC, or |FRAME: CPLX-7940| EC |FRAME: L-DEHYDRO-ASCORBATE| can also be reduced by spontaneous reaction with |FRAME: GLUTATHIONE| presumably via adduct formation (not shown in this pathway), but this is thought to be slow at physiological concentrations of |FRAME: GLUTATHIONE|. Reviewed in |CITS: [17222174]|. In the lumen of secretory vesicles, trans-membrane electron transfer systems (not shown in this pathway) can reduce |FRAME: CPD-318| to |FRAME: ASCORBATE|. In the lumen of neuroendocrine secretory vesicles reduction of vesicular |FRAME: CPD-318| uses electrons from cytosolic |FRAME: ASCORBATE| and a cytochrome b561-mediated trans-membrane electron transfer system that is thermodynamically driven by a pH gradient and membrane potential created by a proton-translocating membrane ATPase. Reduction of |FRAME: CPD-318| produced by peptidylglycine monooxygenase (EC, or |FRAME: CPLX66-141| (EC can occur in this manner. Reviewed in |CITS: [17222174] [16301310]|. In the extracellular space, trans-membrane electron transfer systems (not shown in this pathway) can also reduce |FRAME: CPD-318| to |FRAME: ASCORBATE|. Intracellular |FRAME: ASCORBATE| donates electrons to extracellular |FRAME: CPD-318| via an as yet unidentified membrane redox system. Reviewed in |CITS: [17222174] [16301310]|. Mitochondria have also been shown to take up and recycle |FRAME: ASCORBATE| |CITS: [11368176] [18198400]|. The catabolism of |FRAME: ASCORBATE| has been described for bacteria (see pathway |FRAME: PWY0-301|), but it remains poorly defined in mammals (reviewed in |CITS: [17222174]|).

from BIOCYC source record: META_PWY-6370
Type: pathway
Taxonomic scope
conserved biosystem

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