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 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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== Reaction ==
 
== Reaction ==
 
[[File:R10_PGH2_-_PGE2.jpg|center|500px]]
 
[[File:R10_PGH2_-_PGE2.jpg|center|500px]]
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==Chemical equation==
 
==Chemical equation==
  
−
<center><math> FA \rightleftharpoons AA </math></center>
+
<center><math> PGH2 \rightleftharpoons PGE2 </math></center>
  
 
== Rate equation ==
 
== Rate equation ==
 +
[[File:R10.PNG|center|500px]]
 +
 +
== Parameters ==
 +
=== K<sub>ms</sub> ===
 +
{|class="wikitable sortable"
 +
|+  style="text-align: left;" | Literature values
 +
|-
 +
! Value
 +
! Units
 +
! Species
 +
! Notes
 +
! Weight
 +
! Reference
 +
|-
 +
|1.6E-01 ± 4.00E-03
 +
|<math> mM </math>
 +
|Human
 +
|Expression Vector: E. Coli
 +
Enzyme: PGES
 +
pH: 8
 +
Temperature: 37
 +
|512
 +
|<ref name="Pettersson2005"> [http://www.ncbi.nlm.nih.gov/pubmed/16399384 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.]</ref> 
 +
|-
 +
|2.15E-01
 +
|<math> mM </math>
 +
|Human
 +
|Wild Type Enzyme
 +
|1024
 +
|<ref name="Hamza2010"> [http://www.ncbi.nlm.nih.gov/pubmed/20369883 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.]</ref>
 +
|-
 +
|1.49E-02
 +
|<math> mM </math>
 +
|Human
 +
|Expression Vector: E. Coli
 +
Enzyme: PGES
 +
pH: Unknown
 +
Temperature: Unknown
 +
 +
Other: cPGES, casein kinase II and Hsp90
 +
|64
 +
|<ref name="Kobayashi04"> [http://www.ncbi.nlm.nih.gov/pubmed/15040786 Kobayashi T. , "Regulation of cytosolic prostaglandin E synthase by phosphorylation.'' Biochem J. 2004 Jul 1;381(Pt 1):59-69.]</ref> 
 +
|-
 +
|6.66E-02
 +
|<math> mM </math>
 +
|Human
 +
|Expression Vector: E. Coli
 +
Enzyme: PGES
 +
pH: Unknown
 +
Temperature: Unknown
 +
|64
 +
|<ref name="Kobayashi04"></ref> 
 +
|-
 +
|}
 +
 +
{| class="wikitable"
 +
|+  style="text-align: left;" | 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
 +
|}
 +
 +
[[Image:29.jpg|none|thumb|500px|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.  ]]
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 +
=== K<sub>mp</sub>===
 +
This is a “Dependent parameter”, meaning that the log-normal distribution for this parameter was calculated using multivariate distributions  (this is discussed in detail[[Quantification of parameter uncertainty | here]]). As a result, no confidence interval factor or literature values were cited for this parameter. 
 +
{| class="wikitable"
 +
|+  style="text-align: left;" | Description of the PGES Kmp distribution
 +
! Mode (mM) !! Location parameter (µ) !! Scale parameter (σ)
 +
|-
 +
| 1.93E-01 || -1.15E+00 || 7.02E-01 (mM)
 +
|}
 +
 +
[[Image:30.jpg|none|thumb|500px|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.  ]]
 +
 +
=== k<sub>cat</sub>===
 +
{|class="wikitable sortable"
 +
|+  style="text-align: left;" | 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
 +
| <ref name="Pettersson20005"> [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.]</ref>
 +
|-
 +
|}
 +
 +
{| class="wikitable"
 +
|+  style="text-align: left;" | 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
 +
|}
 +
 +
[[Image:31.jpg|none|thumb|500px|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 [[Common equations#Enzyme concentration (mM)|equation]] was used.
 +
 +
{|class="wikitable sortable"
 +
|+  style="text-align: left;" | Literature values
 +
|-
 +
! Value
 +
! Units
 +
! Species
 +
! Notes
 +
! Weight
 +
! Reference
 +
|-
 +
|220
 +
|<math> ppm </math>
 +
|Human
 +
|Expression Vector: Placenta
 +
Enzyme: PGES
 +
pH: 7.5
 +
Temperature: 37 °C
 +
|1024
 +
|<ref name="Wilhelm2014"> [http://www.nature.com/nature/journal/v509/n7502/pdf/nature13319.pdf M. Wilhelm ''Mass-spectrometry-based draft of the human proteome'' Nature, 2014 509, 582–587]</ref>
 +
|-
 +
|75.3
 +
|<math> ppm </math>
 +
|Human
 +
|Expression Vector: Urinary Bladder
 +
Enzyme: PGES
 +
pH: 7.5
 +
Temperature: 37 °C
 +
|1024
 +
|<ref name="Kim2014"> [http://www.nature.com/nature/journal/v509/n7502/pdf/nature13302.pdf M. Kim ''A draft map of the human proteome'' Nature, 2014 509, 575–581]</ref>
 +
|-
 +
|208
 +
|<math> ppm </math>
 +
|Human
 +
|Expression Vector: Stomach
 +
Enzyme: PGES
 +
pH: 7.5
 +
Temperature: 37 °C
 +
|1024
 +
|<ref name="Wilhelm2014"> [http://www.nature.com/nature/journal/v509/n7502/pdf/nature13319.pdf M. Wilhelm ''Mass-spectrometry-based draft of the human proteome'' Nature, 2014 509, 582–587]</ref>
 +
|-
 +
|28.1
 +
|<math> ppm </math>
 +
|Human
 +
|Expression Vector: Lung
 +
Enzyme: PGES
 +
pH: 7.5
 +
Temperature: 37 °C
 +
|1024
 +
|<ref name="Kim2014"> [http://www.nature.com/nature/journal/v509/n7502/pdf/nature13302.pdf M. Kim ''A draft map of the human proteome'' Nature, 2014 509, 575–581]</ref>
 +
|-
 +
|11.6
 +
|<math> ppm </math>
 +
|Human
 +
|Expression Vector: Colon
 +
Enzyme: PGES
 +
pH: 7.5
 +
Temperature: 37 °C
 +
|1024
 +
|<ref name="Kim2014"> [http://www.nature.com/nature/journal/v509/n7502/pdf/nature13302.pdf M. Kim ''A draft map of the human proteome'' Nature, 2014 509, 575–581]</ref>
 +
|-
 +
|}
 +
 +
{| class="wikitable"
 +
|+  style="text-align: left;" | 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
 +
|}
  
 +
[[Image:162.jpg|none|thumb|500px|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.  ]]
  
−
== Parameters ==
+
=== K<sub>eq </sub> ===
  
−
{|class="wikitable"  
+
{|class="wikitable sortable"  
−
! Name
+
|+  style="text-align: left;" | Gibbs Free Energy Change
 +
|-
 
! Value
 
! Value
 
! Units
 
! Units
 
! Species
 
! Species
 +
! Notes
 +
! Weight
 
! Reference
 
! Reference
 
|-
 
|-
−
| X
+
|5.72
−
| Y
+
|kcal/mol
−
| Z
+
|Not stated
−
| A
+
|Estimated
−
| B
+
Enzyme: PGES
 +
Substrate: Arachidonate
 +
Product: PGE2
 +
pH: 7.3
 +
ionic strength: 0.25
 +
|64
 +
|<ref name="MetaCyc”>[http://metacyc.org/META/NEW-IMAGE?type=REACTION&object=PROSTAGLANDIN-E-SYNTHASE-RXN 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]</ref>
 +
|}
 +
 
 +
{| class="wikitable"
 +
|+  style="text-align: left;" | 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
 
|}
 
|}
 +
 +
[[Image:32.jpg|none|thumb|500px|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 ==
 +
<references/>
 +
  
 
== Related Reactions ==
 
== Related Reactions ==
  
 
* [[Transformation of AA to PGH2 |Transformation of AA to PGH2]]
 
* [[Transformation of AA to PGH2 |Transformation of AA to PGH2]]

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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