Phosphorylation

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Serine in an amino acid chain, before and after phosphorylation. Phosporylation of a serine residue, before and after shot.png
Serine in an amino acid chain, before and after phosphorylation.

In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor [1] or the addition of a phosphate group to a molecule. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols:

Contents

[Adenosyl−O−PO2−O−PO2−O−PO3]4− + ROH → Adenosyl−O−PO2−O−PO3H]2− + [RO−P−O3]2−

This equation can be written in several ways that are nearly equivalent that describe the behaviors of various protonated states of ATP, ADP, and the phosphorylated product. As is clear from the equation, a phosphate group per se is not transferred, but a phosphoryl group (PO3-). Phosphoryl is an electrophile. [2] This process and its inverse, dephosphorylation, are common in biology. [3] Protein phosphorylation often activates (or deactivates) many enzymes. [4] [5]

ATP is produced by phosphorylation

Although most often discussed in terms of the consumption of ATP (GTP and others), phosphorylation must also be involved in the production of these energy-rich species.l ATP is produced by:

Phosphorylation of glucose

Glucose metabolism

Phosphorylation of sugars is often the first stage in their catabolism. Phosphorylation allows cells to accumulate sugars because the phosphate group prevents the molecules from diffusing back across their transporter. Phosphorylation of glucose is a key reaction in sugar metabolism. The chemical equation for the conversion of D-glucose to D-glucose-6-phosphate in the first step of glycolysis is given by:

D-glucose + ATP → D-glucose 6-phosphate + ADP
ΔG° = −16.7 kJ/mol (° indicates measurement at standard condition)
Glycolysis is a process that breaks down glucose into 2 pyruvate molecules, using ATP and NADH as well as producing it. Glycolysis Simple Diagram.jpg
Glycolysis is a process that breaks down glucose into 2 pyruvate molecules, using ATP and NADH as well as producing it.

Glucose is converted to glucose-6-phosphate catalyzed by the enzyme hexokinase. Fructose-6-phosphate is converted to fructose 1,6-bisphosphate. This reaction is catalyzed by phosphofructokinase.

Glyceraldehyde 3-phosphate is again phosphorylated to give 1,3-bisphosphoglycerate. This reaction is catalyzed by glyceraldehyde-3-phosphate dehydrogenase (GAPDH).

Glycogen synthesis

The phosphorylation of glucose to glucose 6-phosphate has role in regulating glycogen synthase.

Glucose is phosphorylated to glucose 6-phosphate to allow its transport across the membrane by ATP-D-glucose 6-phosphotransferase and non-specific hexokinase (ATP-D-hexose 6-phosphotransferase). [6] [7] Liver cells are freely permeable to glucose, and the initial rate of phosphorylation of glucose is the rate-limiting step in glucose metabolism by the liver. [6]

The liver's crucial role in controlling blood sugar concentrations by breaking down glucose into carbon dioxide and glycogen is characterized by the negative Gibbs free energy (ΔG) value, which indicates that this is a point of regulation with.[ clarification needed ] The hexokinase enzyme has a low Michaelis constant (Km), indicating a high affinity for glucose, so this initial phosphorylation can proceed even when glucose levels at nanoscopic scale within the blood.

The phosphorylation of glucose can be enhanced by the binding of fructose 6-phosphate (F6P), and lessened by the binding fructose 1-phosphate (F1P). Fructose consumed in the diet is converted to F1P in the liver. This negates the action of F6P on glucokinase, [6] which ultimately favors the forward reaction. The capacity of liver cells to phosphorylate fructose exceeds capacity to metabolize fructose-1-phosphate. Consuming excess fructose ultimately results in an imbalance in liver metabolism, which indirectly exhausts the liver cell's supply of ATP. [8]

Allosteric activation by glucose-6-phosphate, which acts as an effector, stimulates glycogen synthase, and glucose-6-phosphate may inhibit the phosphorylation of glycogen synthase by cyclic AMP-stimulated protein kinase. [7]

Other processes

Phosphorylation of glucose is imperative in processes within the body. For example, phosphorylating glucose is necessary for insulin-dependent mechanistic target of rapamycin pathway activity within the heart. This further suggests a link between intermediary metabolism and cardiac growth. [9]

Protein phosphorylation

Protein phosphorylation is the most common post-translational modification in eukaryotes. The most common phospho-amino acid residues are those serine, threonine, and tyrosine at a ratio of 1800:200:1. [10] Phosphorylation of the side chains of these residues through phosphoester bond formation, on histidine, lysine and arginine through phosphoramidate bonds, and on aspartic acid and glutamic acid through mixed anhydride linkages.

Protein phosphorylation is common on human non-canonical amino acids, including motifs containing phosphorylated histidine, aspartate, glutamate, cysteine, arginine and lysine in HeLa cell extracts. [11] Histidine phosphorylates at both the 1 and 3 N-atoms of the imidazole ring. [12] [13] Phospho-tyrosine is much more stable than phospho-serine and -threonine which are in turn more stable than other phospho-amino acids, [10] hence the analysis of phosphorylated histidine (and other non-canonical amino acids) using standard biochemical and mass spectrometric approaches is much more challenging [11] [14] [15] and special procedures and separation techniques are required for their preservation alongside classical Ser, Thr and Tyr phosphorylation. [16]

The prominent role of protein phosphorylation in biochemistry is illustrated by the many publication on the subject (as of March 2015, the MEDLINE database returns over 240,000 articles, mostly on protein phosphorylation).

Further reading

[17] [18] [19] [20]

See also

References

  1. ↑ "phosphorylation" . IUPAC Gold Book. 2014. doi:10.1351/goldbook.PT06790.
  2. ↑ Adams, Joseph A. (2001). "Kinetic and Catalytic Mechanisms of Protein Kinases". Chemical Reviews. 101 (8): 2271–2290. doi:10.1021/cr000230w. PMID   11749373.
  3. ↑ Chen J, He X, Jakovlić I (November 2022). "Positive selection-driven fixation of a hominin-specific amino acid mutation related to dephosphorylation in IRF9". BMC Ecology and Evolution. 22 (1) 132. doi: 10.1186/s12862-022-02088-5 . PMC   9650800 . PMID   36357830. S2CID   253448972. CC-BY icon.svg Text was copied from this source, which is available under a Creative Commons Attribution 4.0 International License.
  4. ↑ Oliveira AP, Sauer U (March 2012). "The importance of post-translational modifications in regulating Saccharomyces cerevisiae metabolism". FEMS Yeast Research. 12 (2): 104–117. doi: 10.1111/j.1567-1364.2011.00765.x . PMID   22128902.
  5. ↑ Tripodi F, Nicastro R, Reghellin V, Coccetti P (April 2015). "Post-translational modifications on yeast carbon metabolism: Regulatory mechanisms beyond transcriptional control". Biochimica et Biophysica Acta (BBA) - General Subjects. 1850 (4): 620–627. doi:10.1016/j.bbagen.2014.12.010. hdl: 10281/138736 . PMID   25512067.
  6. 1 2 3 Walker DG, Rao S (February 1964). "The role of glucokinase in the phosphorylation of glucose by rat liver". The Biochemical Journal. 90 (2): 360–368. doi:10.1042/bj0900360. PMC   1202625 . PMID   5834248.
  7. 1 2 Villar-Palasí C, Guinovart JJ (June 1997). "The role of glucose 6-phosphate in the control of glycogen synthase". FASEB Journal. 11 (7): 544–558. doi: 10.1096/fasebj.11.7.9212078 . PMID   9212078. S2CID   2789124.
  8. ↑ "Regulation of Glycolysis". cmgm.stanford.edu. Archived from the original on 2009-03-03. Retrieved 2017-11-18.
  9. ↑ Sharma S, Guthrie PH, Chan SS, Haq S, Taegtmeyer H (October 2007). "Glucose phosphorylation is required for insulin-dependent mTOR signalling in the heart". Cardiovascular Research. 76 (1): 71–80. doi:10.1016/j.cardiores.2007.05.004. PMC   2257479 . PMID   17553476.
  10. 1 2 Mann, Matthias; Ong, Shao En; Grønborg, Mads; Steen, Hanno; Jensen, Ole N.; Pandey, Akhilesh (June 2002). "Analysis of protein phosphorylation using mass spectrometry: deciphering the phosphoproteome". Trends in Biotechnology. 20 (6): 261–268. doi:10.1016/s0167-7799(02)01944-3. ISSN   0167-7799. PMID   12007495.
  11. 1 2 Hardman G, Perkins S, Brownridge PJ, Clarke CJ, Byrne DP, Campbell AE, et al. (October 2019). "Strong anion exchange-mediated phosphoproteomics reveals extensive human non-canonical phosphorylation". The EMBO Journal. 38 (21) e100847. doi: 10.15252/embj.2018100847 . PMC   6826212 . PMID   31433507.
  12. ↑ Fuhs SR, Hunter T (April 2017). "pHisphorylation: the emergence of histidine phosphorylation as a reversible regulatory modification". Current Opinion in Cell Biology. 45: 8–16. doi:10.1016/j.ceb.2016.12.010. PMC   5482761 . PMID   28129587.
  13. ↑ Fuhs SR, Meisenhelder J, Aslanian A, Ma L, Zagorska A, Stankova M, et al. (July 2015). "Monoclonal 1- and 3-Phosphohistidine Antibodies: New Tools to Study Histidine Phosphorylation". Cell. 162 (1): 198–210. doi:10.1016/j.cell.2015.05.046. PMC   4491144 . PMID   26140597.
  14. ↑ Gonzalez-Sanchez MB, Lanucara F, Hardman GE, Eyers CE (June 2014). "Gas-phase intermolecular phosphate transfer within a phosphohistidine phosphopeptide dimer". International Journal of Mass Spectrometry. 367: 28–34. Bibcode:2014IJMSp.367...28G. doi:10.1016/j.ijms.2014.04.015. PMC   4375673 . PMID   25844054.
  15. ↑ Gonzalez-Sanchez MB, Lanucara F, Helm M, Eyers CE (August 2013). "Attempting to rewrite History: challenges with the analysis of histidine-phosphorylated peptides". Biochemical Society Transactions. 41 (4): 1089–1095. doi:10.1042/bst20130072. PMID   23863184.
  16. ↑ Hardman G, Perkins S, Ruan Z, Kannan N, Brownridge P, Byrne DP, Eyers PA, Jones AR, Eyers CE (2017). "Extensive non-canonical phosphorylation in human cells revealed using strong-anion exchange-mediated phosphoproteomics". bioRxiv   10.1101/202820 .
  17. ↑ Johnson, Louise N.; Lewis, Richard J. (2001). "Structural Basis for Control by Phosphorylation". Chemical Reviews. 101 (8): 2209–2242. doi:10.1021/cr000225s. PMID   11749371.
  18. ↑ Saito, Haruo (2001). "Histidine Phosphorylation and Two-Component Signaling in Eukaryotic Cells". Chemical Reviews. 101 (8): 2497–2510. doi:10.1021/cr000243+. PMID   11749385.
  19. ↑ Ahn, Natalie (2001). "Introduction: Protein Phosphorylation and Signaling". Chemical Reviews. 101 (8): 2207–2208. doi: 10.1021/cr010144b .
  20. ↑ Dimakos, Victoria; Taylor, Mark S. (2018). "Site-Selective Functionalization of Hydroxyl Groups in Carbohydrate Derivatives". Chemical Reviews. 118 (23): 11457–11517. doi:10.1021/acs.chemrev.8b00442. PMID   30507165.
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