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Substrate-level phosphorylation is a metabolism reaction that results in the production ofATP orGTP supported by the energy released from another high-energy bond that leads to phosphorylation ofADP orGDP to ATP or GTP (note that the reaction catalyzed by creatine kinase is not considered as "substrate-level phosphorylation"). This process uses some of the releasedchemical energy, theGibbs free energy, to transfer aphosphoryl (PO3) group to ADP or GDP. Occurs inglycolysis and in the citric acid cycle.[1]
Unlikeoxidative phosphorylation, oxidation and phosphorylation are not coupled in the process of substrate-level phosphorylation, and reactive intermediates are most often gained in the course ofoxidation processes incatabolism. Most ATP is generated by oxidative phosphorylation inaerobic oranaerobic respiration while substrate-level phosphorylation provides a quicker, less efficient source of ATP, independent of externalelectron acceptors. This is the case in humanerythrocytes, which have nomitochondria, and in oxygen-depleted muscle.
Adenosine triphosphate (ATP) is a major "energy currency" of the cell.[2] The high energy bonds between the phosphate groups can be broken to power a variety of reactions used in all aspects of cell function.[3]
Substrate-level phosphorylation occurs in the cytoplasm of cells duringglycolysis and in mitochondria either during theKrebs cycle or byMTHFD1L (EC 6.3.4.3), an enzyme interconverting ADP + phosphate + 10-formyltetrahydrofolate to ATP + formate + tetrahydrofolate (reversibly), under bothaerobic andanaerobic conditions. In thepay-off phase of glycolysis, a net of 2 ATP are produced by substrate-level phosphorylation.
The first substrate-level phosphorylation occurs after the conversion of 3-phosphoglyceraldehyde and Pi and NAD+ to 1,3-bisphosphoglycerate viaglyceraldehyde 3-phosphate dehydrogenase. 1,3-bisphosphoglycerate is then dephosphorylated viaphosphoglycerate kinase, producing 3-phosphoglycerate and ATP through a substrate-level phosphorylation.
The second substrate-level phosphorylation occurs by dephosphorylatingphosphoenolpyruvate, catalyzed bypyruvate kinase, producingpyruvate and ATP.
During the preparatory phase, each 6-carbon glucose molecule is broken into two 3-carbon molecules. Thus, in glycolysis dephosphorylation results in the production of 4 ATP. However, the prior preparatory phase consumes 2 ATP, so the net yield in glycolysis is 2 ATP. 2 molecules of NADH are also produced and can be used in oxidative phosphorylation to generate more ATP.
ATP can be generated by substrate-level phosphorylation inmitochondria in a pathway that is independent from theproton motive force. In thematrix there are three reactions capable of substrate-level phosphorylation, utilizing eitherphosphoenolpyruvate carboxykinase orsuccinate-CoA ligase, ormonofunctional C1-tetrahydrofolate synthase.
Mitochondrial phosphoenolpyruvate carboxykinase is thought to participate in the transfer of the phosphorylation potential from the matrix to the cytosol and vice versa.[4][5][6][7][8] However, it is strongly favored towards GTP hydrolysis, thus it is not really considered as an important source of intra-mitochondrial substrate-level phosphorylation.
Succinate-CoA ligase is a heterodimer composed of an invariant α-subunit and a substrate-specific ß-subunit, encoded by either SUCLA2 or SUCLG2. This combination results in either anADP-forming succinate-CoA ligase (A-SUCL, EC 6.2.1.5) or aGDP-forming succinate-CoA ligase (G-SUCL, EC 6.2.1.4). The ADP-forming succinate-CoA ligase is potentially the only matrix enzyme generating ATP in the absence of a proton motive force, capable of maintaining matrix ATP levels under energy-limited conditions, such as transienthypoxia.
This enzyme is encoded byMTHFD1L and reversibly interconverts ADP + phosphate + 10-formyltetrahydrofolate to ATP + formate + tetrahydrofolate.
In working skeletal muscles and the brain,Phosphocreatine is stored as a readily available high-energy phosphate supply, and the enzymecreatine phosphokinase transfers a phosphate from phosphocreatine to ADP to produce ATP. Then the ATP releases giving chemical energy. This is sometimes erroneously considered to be substrate-level phosphorylation, although it is atransphosphorylation.
Duringanoxia, provision of ATP by substrate-level phosphorylation in the matrix is important not only as a mere means of energy, but also to prevent mitochondria from straining glycolytic ATP reserves by maintaining theadenine nucleotide translocator in ‘forward mode’ carrying ATP towards the cytosol.[9][10][11]
An alternative method used to create ATP is throughoxidative phosphorylation, which takes place duringcellular respiration. This process utilizes the oxidation ofNADH to NAD+, yielding 3 ATP, and of FADH2 toFAD, yielding 2 ATP. Thepotential energy stored as anelectrochemical gradient of protons (H+) across the inner mitochondrial membrane is required to generate ATP from ADP and Pi (inorganic phosphate molecule), a key difference from substrate-level phosphorylation. This gradient is exploited byATP synthase acting as a pore, allowing H+ from the mitochondrialintermembrane space to move down its electrochemical gradient into the matrix and coupling the release of free energy to ATP synthesis. Conversely, electron transfer provides the energy required to actively pump H+ out of the matrix.
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