Substrate-level phosphorylation

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Substrate-level phosphorylation exemplified with the conversion of ADP to ATP

Substrate-level phosphorylation is a metabolism reaction that results in the production of

phosphoryl (PO3) group to ADP or GDP. Occurs in glycolysis and in the citric acid cycle.[1]

Unlike

erythrocytes, which have no mitochondria
, and in oxygen-depleted muscle.

Overview

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 during

Krebs cycle or by MTHFD1L (EC 6.3.4.3), an enzyme interconverting ADP + phosphate + 10-formyltetrahydrofolate to ATP + formate + tetrahydrofolate (reversibly), under both aerobic and anaerobic conditions. In the pay-off phase of glycolysis
, a net of 2 ATP are produced by substrate-level phosphorylation.

Glycolysis

Main article: Glycolysis

The first substrate-level phosphorylation occurs after the conversion of 3-phosphoglyceraldehyde and Pi and NAD+ to 1,3-bisphosphoglycerate via glyceraldehyde 3-phosphate dehydrogenase. 1,3-bisphosphoglycerate is then dephosphorylated via phosphoglycerate kinase, producing 3-phosphoglycerate and ATP through a substrate-level phosphorylation.

The second substrate-level phosphorylation occurs by dephosphorylating

pyruvate
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.

Mitochondria

ATP can be generated by substrate-level phosphorylation in

proton motive force. In the matrix there are three reactions capable of substrate-level phosphorylation, utilizing either phosphoenolpyruvate carboxykinase or succinate-CoA ligase, or monofunctional C1-tetrahydrofolate synthase
.

Phosphoenolpyruvate carboxykinase

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

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 an

hypoxia
.

Monofunctional C1-tetrahydrofolate synthase

This enzyme is encoded by MTHFD1L and reversibly interconverts ADP + phosphate + 10-formyltetrahydrofolate to ATP + formate + tetrahydrofolate.

Other mechanisms

In working skeletal muscles and the brain,

creatine 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 a transphosphorylation
.

Importance of substrate-level phosphorylation in anoxia

During

anoxia, 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 the adenine nucleotide translocator in ‘forward mode’ carrying ATP towards the cytosol.[9][10][11]

Oxidative phosphorylation

Main article: Oxidative phosphorylation

An alternative method used to create ATP is through

NADH to NAD+, yielding 3 ATP, and of FADH2 to FAD, yielding 2 ATP. The potential energy stored as an electrochemical 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 by ATP synthase acting as a pore, allowing H+ from the mitochondrial intermembrane 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.

References
  1. OCLC 1043972098.{{cite book}}: CS1 maint: location missing publisher (link
    )
  2. ISBN 978-3-642-33430-6
    .
  3. S2CID 46974766
    .
  4. PMID 15234968
    .
  5. PMID 6263728
    .
  6. PMID 12489642
    .
  7. PMID 6885788
    .
  8. PMID 9765291
    .
  9. PMID 20207940
    .
  10. S2CID 24773903
    .
  11. PMID 21541983
    .
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