Difference between revisions of "Transformation of PGH2 to PGE2"

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[[Welcome to the In-Silico Model of Cutaneous Lipids Wiki | Return to overview]]
 
[[Welcome to the In-Silico Model of Cutaneous Lipids Wiki | Return to overview]]
  
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PGE2 is an incredibly bioactive compound, which upon binding with the receptors, an immune cellular response is triggered. For example in the binding of PGE2 to EP2 and EP4, dendritic cell (DC) migration and maturation is activated (Legler, Krause et al. 2006, van Helden, Krooshoop et al. 2006). This event results in the activation of Th2 cells, which produce cytokines that in turn stimulates further inflammatory species (McIlroy, Caron et al. 2006, Theiner, Gessner et al. 2006). Furthermore binding of PGE2 to EP4 stimulates infiltration of macrophages from the bloodstream.
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PGE2 is produced by the isomerisation of the PGH2 peroxide, into a ketone at C9 and an alcohol at C11 by PGES, yielding PGE2. This reaction is catalysed by isoforms of PGES, such as cPGES (also known as PGES-3), mPGES-1 and mPGES-2 <ref>Samuelsson, B. Morgenstern, R. Jakobsson, P. J. , ''Membrane prostaglandin E synthase-1: a novel therapeutic target'', Pharmacol Rev (2007), 59, 207-24.</ref>. cPGES is the cytosolic isoform of PGES which is constitutively expressed in the cytosol of various cells <ref>Tanioka, T. Nakatani, Y. Semmyo, N. Murakami, M. Kudo, I., ''Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis'', J Biol Chem (2000), 275, 32775-82.</ref>, whereas mPGES-1/-2 are Golgi membrane-associated proteins which only become cytosolic following spontaneous cleavage of a hydrophobic domain <ref>Murakami, M. Nakashima, K. Kamei, D. Masuda, S. Ishikawa, Y. Ishii, T. Ohmiya, Y. Watanabe, K. Kudo, I., ''Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2'', J Biol Chem (2003), 278, 37937-47.</ref><ref>Tanioka, T. Nakatani, Y. Semmyo, N. Murakami, M. Kudo, I., ''Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis'', J Biol Chem (2000), 275, 32775-82.</ref>. It has been suggested that a functional coupling of cPGES and COX-1 may occur in vitro as cPGES appears to convert only COX-1 derived PGH2 and not COX-2 derived PGH2 <ref>Tanioka, T. Nakatani, Y. Semmyo, N. Murakami, M. Kudo, I., ''Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis'', J Biol Chem (2000), 275, 32775-82.</ref>. Interestingly, the opposite has been observed for mPGES and COX-2 <ref>Murakami, M. Nakashima, K. Kamei, D. Masuda, S. Ishikawa, Y. Ishii, T. Ohmiya, Y. Watanabe, K. Kudo, I., ''Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2'', J Biol Chem (2003), 278, 37937-47.</ref>.  
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PGE2 is synthesised from PGH2 via the prostaglandin E synthase (PGES) enzyme. This influential species is produced by almost all cutaneous cell types and as a consequence is in high concentrations in the skin (Ziboh 1992, Cho, Park et al. 2005, Gledhill, Rhodes et al. 2010). In addition to affecting DCs, the species acts as a chemoattractant for keratinocyte cells (Parekh, Sandulache et al. 2009) and in normal and inflamed epithelial cells PGE2 possess an inhibitory effect on the release of leukotrienes (Shaf96).  
 
  
  

Latest revision as of 08:48, 21 August 2019

Return to overview

PGE2 is produced by the isomerisation of the PGH2 peroxide, into a ketone at C9 and an alcohol at C11 by PGES, yielding PGE2. This reaction is catalysed by isoforms of PGES, such as cPGES (also known as PGES-3), mPGES-1 and mPGES-2 [1]. cPGES is the cytosolic isoform of PGES which is constitutively expressed in the cytosol of various cells [2], whereas mPGES-1/-2 are Golgi membrane-associated proteins which only become cytosolic following spontaneous cleavage of a hydrophobic domain [3][4]. It has been suggested that a functional coupling of cPGES and COX-1 may occur in vitro as cPGES appears to convert only COX-1 derived PGH2 and not COX-2 derived PGH2 [5]. Interestingly, the opposite has been observed for mPGES and COX-2 [6].


Reaction

R10 PGH2 - PGE2.jpg

Chemical equation

PGH2 \rightleftharpoons PGE2

Rate equation

R10.PNG

Parameters

Kms

Literature values
Value Units Species Notes Weight Reference
1.6E-01 ± 4.00E-03 mM Human Expression Vector: E. Coli

Enzyme: PGES pH: 8 Temperature: 37

512 [7]
2.15E-01 mM Human Wild Type Enzyme 1024 [8]
1.49E-02 mM Human Expression Vector: E. Coli

Enzyme: PGES pH: Unknown Temperature: Unknown

Other: cPGES, casein kinase II and Hsp90

64 [9]
6.66E-02 mM Human Expression Vector: E. Coli

Enzyme: PGES pH: Unknown Temperature: Unknown

64 [9]
Description of the PGES Kms distribution
Mode (mM) Confidence Interval Location parameter (µ) Scale parameter (σ)
1.97E-01 1.73E+00 -1.39E+00 4.91E-01
The estimated probability distribution for PGES Kms. The value and weight of the literature values used to define the distribution are indicated by an orange dashed line. The x axis is plotted on a log-scale.

Kmp

This is a “Dependent parameter”, meaning that the log-normal distribution for this parameter was calculated using multivariate distributions (this is discussed in detail here). As a result, no confidence interval factor or literature values were cited for this parameter.

Description of the PGES Kmp distribution
Mode (mM) Location parameter (µ) Scale parameter (σ)
1.93E-01 -1.15E+00 7.02E-01 (mM)
The estimated probability distribution for PGES Kmp. The value and weight of the literature values used to define the distribution are indicated by an orange dashed line. The x axis is plotted on a log-scale.

kcat

Literature values
Value Units Species Notes Weight Reference
3000 ± 360 per minute Human Expression Vector: E. Coli.

Enzyme: Microsomal Prostaglandin E Synthase pH: 7.5 Temperature: 37

1024 [10]
Description of the PGES kcat distribution
Mode (min-1) Confidence Interval Location parameter (µ) Scale parameter (σ)
2.98E+03 1.13E+00 8.01E+00 1.19E-01
The estimated probability distribution for PGES kcat. The value and weight of the literature values used to define the distribution are indicated by an orange dashed line. The x axis is plotted on a log-scale.

Enzyme concentration

To convert the enzyme concentration from ppm to mM, the following equation was used.

Literature values
Value Units Species Notes Weight Reference
220 ppm Human Expression Vector: Placenta

Enzyme: PGES pH: 7.5 Temperature: 37 °C

1024 [11]
75.3 ppm Human Expression Vector: Urinary Bladder

Enzyme: PGES pH: 7.5 Temperature: 37 °C

1024 [12]
208 ppm Human Expression Vector: Stomach

Enzyme: PGES pH: 7.5 Temperature: 37 °C

1024 [11]
28.1 ppm Human Expression Vector: Lung

Enzyme: PGES pH: 7.5 Temperature: 37 °C

1024 [12]
11.6 ppm Human Expression Vector: Colon

Enzyme: PGES pH: 7.5 Temperature: 37 °C

1024 [12]
Description of the PGES concentration distribution
Mode (ppm) Mode (mM) Confidence Interval Location parameter (µ) Scale parameter (σ)
7.49E+01 4.15E-04 3.15E+00 5.03E+00 8.44E-01
The estimated probability distribution for PGES concentration. The value and weight of the literature values used to define the distribution are indicated by an orange dashed line. The x axis is plotted on a log-scale.

Keq

Gibbs Free Energy Change
Value Units Species Notes Weight Reference
5.72 kcal/mol Not stated Estimated

Enzyme: PGES Substrate: Arachidonate Product: PGE2 pH: 7.3 ionic strength: 0.25

64 [13]
Description of the PGES Keq distribution
Mode Confidence Interval Location parameter (µ) Scale parameter (σ)
7.46E+04 1.00E+01 1.20E+01 8.90E-01
The estimated probability distribution for PGES Keq. The value and weight of the literature values used to define the distribution are indicated by an orange dashed line. The x axis is plotted on a log-scale.

References

  1. ↑ Samuelsson, B. Morgenstern, R. Jakobsson, P. J. , Membrane prostaglandin E synthase-1: a novel therapeutic target, Pharmacol Rev (2007), 59, 207-24.
  2. ↑ Tanioka, T. Nakatani, Y. Semmyo, N. Murakami, M. Kudo, I., Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis, J Biol Chem (2000), 275, 32775-82.
  3. ↑ Murakami, M. Nakashima, K. Kamei, D. Masuda, S. Ishikawa, Y. Ishii, T. Ohmiya, Y. Watanabe, K. Kudo, I., Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2, J Biol Chem (2003), 278, 37937-47.
  4. ↑ Tanioka, T. Nakatani, Y. Semmyo, N. Murakami, M. Kudo, I., Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis, J Biol Chem (2000), 275, 32775-82.
  5. ↑ Tanioka, T. Nakatani, Y. Semmyo, N. Murakami, M. Kudo, I., Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis, J Biol Chem (2000), 275, 32775-82.
  6. ↑ Murakami, M. Nakashima, K. Kamei, D. Masuda, S. Ishikawa, Y. Ishii, T. Ohmiya, Y. Watanabe, K. Kudo, I., Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2, J Biol Chem (2003), 278, 37937-47.
  7. ↑ Pettersson P. , "Identification of beta-trace as prostaglandin D synthase. FASEB J. 2010 Dec;24(12):4668-77. doi: 10.1096/fj.10-164863. Epub 2010 Jul 28.
  8. ↑ Hamza A. , "Understanding microscopic binding of human microsomal prostaglandin E synthase-1 (mPGES-1) trimer with substrate PGH2 and cofactor GSH: insights from computational alanine scanning and site-directed mutagenesis. J Phys Chem B. 2010 Apr 29;114(16):5605-16. doi: 10.1021/jp100668y.
  9. ↑ 9.0 9.1 Kobayashi T. , "Regulation of cytosolic prostaglandin E synthase by phosphorylation. Biochem J. 2004 Jul 1;381(Pt 1):59-69.
  10. ↑ [www.ncbi.nlm.nih.gov/pubmed/16399384 Pettersson P., "Human microsomal prostaglandin E synthase 1: a member of the MAPEG protein superfamily. Methods Enzymol. 2005;401:147-61.]
  11. ↑ 11.0 11.1 M. Wilhelm Mass-spectrometry-based draft of the human proteome Nature, 2014 509, 582–587
  12. ↑ 12.0 12.1 12.2 M. Kim A draft map of the human proteome Nature, 2014 509, 575–581
  13. ↑ Caspi et al 2014, "The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of Pathway/Genome Databases," Nucleic Acids Research 42:D459-D471


Related Reactions

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