Difference between revisions of "Transformation of PGH2 to PGI2"

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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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PGH2 is metabolised into the prostacyclin PGI2, by PGIS. This species has been associated with influencing the permeability of vascular compartment (Murata, Ushikubi et al. 1997). Similarly to the TX species, prostacyclins are only found in low concentration and are associated with infiltrating cells from the vascular compartment (Sugimoto, Arai et al. 2006).
+
The isomerisation of PGH2 to prostacyclin (PGI2), is performed by prostaglandin I synthase (PGIS). This protein is a member of the CYP P450 family, but unlike most CYP P450 enzymes it does not oxidise PGH2. PGI2 is generated by the rearrangement of the peroxide functional group, whereby a hydroxyl group is formed at C11, and a new epoxide ring is formed between C9 and C6. PGI2 is generated by the sequential action of COX and PGIS, which co-localise in the ER, plasma membrane and nuclear membrane <ref>Smith, W. L. DeWitt, D. L. Allen, M. L. , ''Bimodal distribution of the prostaglandin I2 synthase antigen in smooth muscle cells'', J Biol Chem (1983), 258, 5922-6.</ref>.
  
 
== Reaction ==
 
== Reaction ==
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==Chemical equation==
 
==Chemical equation==
  
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<center><math> FA \rightleftharpoons AA </math></center>
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<center><math> PGH2 \rightleftharpoons PGI2 </math></center>
  
 
== Rate equation ==
 
== Rate equation ==
  
 +
[[File:R05.PNG|center|500px]]
  
 
== Parameters ==
 
== Parameters ==
 +
=== K<sub>ms</sub> ===
  
 
{|class="wikitable sortable"  
 
{|class="wikitable sortable"  
−
|+  style="text-align: left;" | Michaelis-Menten Constants
+
|+  style="text-align: left;" | Literature values
 
|-
 
|-
 
! Value
 
! Value
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! Species
 
! Species
 
! Notes
 
! Notes
 +
! Weight
 
! Reference
 
! Reference
 
|-
 
|-
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pH:7.4
 
pH:7.4
 
Temperature: 23
 
Temperature: 23
 +
|256
 
|<ref name="Yeh2005"> [http://www.ncbi.nlm.nih.gov/pubmed/16406803 H. C. Yeh, P. Y. Hsu, Characterization of heme environment and mechanism of peroxide bond cleavage in human prostacyclin synthase.'' Biochim Biophys Acta. 2005 Dec 30;1738(1-3):121-32.]</ref>  
 
|<ref name="Yeh2005"> [http://www.ncbi.nlm.nih.gov/pubmed/16406803 H. C. Yeh, P. Y. Hsu, Characterization of heme environment and mechanism of peroxide bond cleavage in human prostacyclin synthase.'' Biochim Biophys Acta. 2005 Dec 30;1738(1-3):121-32.]</ref>  
 
|-
 
|-
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pH:7.4
 
pH:7.4
 
Temperature: 24
 
Temperature: 24
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|<ref name="Hara1994"> [http://www.ncbi.nlm.nih.gov/pubmed/8051072 Hara S. , ''Isolation and molecular cloning of prostacyclin synthase from bovine endothelial cells.'' J Biol Chem. 1994 Aug 5;269(31):19897-903.]</ref>  
+
|192
 +
|<ref name="Hara19941"> [http://www.ncbi.nlm.nih.gov/pubmed/8051072 Hara S., Isolation and molecular cloning of prostacyclin synthase from bovine endothelial cells.'' J Biol Chem. 1994 Aug 5;269(31):19897-903.]</ref>  
 
|-
 
|-
 
|}
 
|}
 +
 +
{| class="wikitable"
 +
|+  style="text-align: left;" | Description of the PGIS Kms distribution
 +
! Mode (mM) !! Confidence Interval !! Location parameter (µ) !! Scale parameter (σ)
 +
|-
 +
| 1.24E-02 || 2.46E+00 || -4.22E+00 || 4.20E-01
 +
|}
 +
 +
[[Image:17.jpg|none|thumb|500px|The estimated probability distribution for PGIS 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.  ]]
 +
 +
=== K<sub>mp</sub> ===
 +
 +
{| class="wikitable"
 +
|+  style="text-align: left;" | Description of the PGIS Kmp distribution
 +
! Mode (mM) !! Location parameter (µ) !! Scale parameter (σ)
 +
|-
 +
| 1.29E-02 || -4.182022605 || 0.414183521
 +
|}
 +
 +
[[Image:18.jpg|none|thumb|500px|The estimated probability distribution for PGIS 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"  
 
{|class="wikitable sortable"  
−
|+  style="text-align: left;" | Enzyme Turnover Numbers
+
|+  style="text-align: left;" | Literature values
 
|-
 
|-
 
! Value
 
! Value
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! Species
 
! Species
 
! Notes
 
! Notes
 +
! Weight
 
! Reference
 
! Reference
 
|-
 
|-
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pH:7.4
 
pH:7.4
 
Temperature: 24
 
Temperature: 24
−
| <ref name="Hara1994"> [www.ncbi.nlm.nih.gov/pubmed/8051072 Hara S. , ''Isolation and molecular cloning of prostacyclin synthase from bovine endothelial cells.'' J Biol Chem. 1994 Aug 5;269(31):19897-903.]</ref>  
+
|192
 +
| <ref name="Hara19942"> [http://www.ncbi.nlm.nih.gov/pubmed/8051072 Hara S., Isolation and molecular cloning of prostacyclin synthase from bovine endothelial cells.'' J Biol Chem. 1994 Aug 5;269(31):19897-903.]</ref>  
 
|}
 
|}
 +
 +
{| class="wikitable"
 +
|+  style="text-align: left;" | Description of the PGIS kcat distribution
 +
! Mode (min-1) !! Confidence Interval !! Location parameter (µ) !! Scale parameter (σ)
 +
|-
 +
| 1.41E+02 || 1.35E+00 || 5.028213628 || 0.287348692
 +
|}
 +
 +
[[Image:19.jpg|none|thumb|500px|The estimated probability distribution for PGIS 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"  
 
{|class="wikitable sortable"  
−
|+  style="text-align: left;" | PGIS Abundance
+
|+  style="text-align: left;" | Literature values
 
|-
 
|-
 
! Value
 
! Value
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! Species
 
! Species
 
! Notes
 
! Notes
 +
! Weight
 
! Reference
 
! Reference
 
|-
 
|-
Line 79: Line 123:
 
pH: 7.5
 
pH: 7.5
 
Temperature: 37 °C
 
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>
 
|<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>
 
|-
 
|-
Line 88: Line 133:
 
pH: 7.5
 
pH: 7.5
 
Temperature: 37 °C
 
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>
 
|<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>
 
|-
 
|-
Line 97: Line 143:
 
pH: 7.5
 
pH: 7.5
 
Temperature: 37 °C
 
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>
 
|<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>
 
|-
 
|-
Line 106: Line 153:
 
pH: 7.5
 
pH: 7.5
 
Temperature: 37 °C
 
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>
 
|<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>
 
|-
 
|-
 
|}
 
|}
  
 +
{| class="wikitable"
 +
|+  style="text-align: left;" | Description of the PGIS concentration distribution
 +
! Mode (ppm) !! Mode (mM) !!  Confidence Interval !! Location parameter (µ) !! Scale parameter (σ)
 +
|-
 +
| 1.13E+02 ||6.25E-04 || 4.13E+00 || 5.67E+00 || 9.68E-01
 +
|-
 +
|}
 +
 +
[[Image:164.jpg|none|thumb|500px|The estimated probability distribution for PGIS 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.  ]]
 +
 +
=== K<sub>eq</sub> ===
 
{|class="wikitable sortable"  
 
{|class="wikitable sortable"  
−
|+  style="text-align: left;" | Gibbs Free Energy Change
+
|+  style="text-align: left;" | Literature values
 
|-
 
|-
−
! Value
+
! Gibbs Free Energy Change
 
! Units
 
! Units
 
! Species
 
! Species
 
! Notes
 
! Notes
 +
! Weight
 
! Reference
 
! Reference
 
|-
 
|-
−
|325.0658
+
| 0.04
−
|kcal/mol
 
−
|Not stated
 
−
|Estimated
 
−
Enzyme: LAT
 
−
Substrate: acyl CoA
 
−
Product: Phosphatidylcholine
 
−
pH: 7.3
 
−
ionic strength: 0.25
 
−
|<ref name="MetaCyc”>[http://metacyc.org/META/NEW-IMAGE?type=REACTION&object=PROSTAGLANDIN-I-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>
 
−
|-
 
−
|-331.11646
 
−
|kcal/mol
 
−
|Not stated
 
−
|Estimated
 
−
Enzyme: FACL4
 
−
Substrate: FA
 
−
Product: FA-acyl CoA
 
−
pH: 7.3
 
−
ionic strength: 0.25
 
−
|<ref name="MetaCyc”>[http://metacyc.org/META/NEW-IMAGE?type=REACTION&object=PROSTAGLANDIN-I-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>
 
−
|-
 
−
|-8.398743
 
 
|kcal/mol
 
|kcal/mol
 
|Not stated
 
|Not stated
Line 150: Line 188:
 
pH: 7.3  
 
pH: 7.3  
 
ionic strength: 0.25
 
ionic strength: 0.25
 +
|64
 
|<ref name="MetaCyc”>[http://metacyc.org/META/NEW-IMAGE?type=REACTION&object=PROSTAGLANDIN-I-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>
 
|<ref name="MetaCyc”>[http://metacyc.org/META/NEW-IMAGE?type=REACTION&object=PROSTAGLANDIN-I-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 PGIS Keq distribution
 +
! Mode !! Confidence Interval !! Location parameter (µ) !! Scale parameter (σ)
 +
|-
 +
| 9.35E-01 || 1.00E+01 || 7.30E-01 || 8.90E-01
 +
|}
 +
 +
[[Image:20.jpg|none|thumb|500px|The estimated probability distribution for PGIS 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.  ]]
  
 
== References ==
 
== References ==

Latest revision as of 10:58, 2 November 2019

Return to overview

The isomerisation of PGH2 to prostacyclin (PGI2), is performed by prostaglandin I synthase (PGIS). This protein is a member of the CYP P450 family, but unlike most CYP P450 enzymes it does not oxidise PGH2. PGI2 is generated by the rearrangement of the peroxide functional group, whereby a hydroxyl group is formed at C11, and a new epoxide ring is formed between C9 and C6. PGI2 is generated by the sequential action of COX and PGIS, which co-localise in the ER, plasma membrane and nuclear membrane [1].

Reaction

R5 PGH2 - PGI2.jpg

Chemical equation

PGH2 \rightleftharpoons PGI2

Rate equation

R05.PNG

Parameters

Kms

Literature values
Value Units Species Notes Weight Reference
1.33E-02 ± 1.40E-03 mM Human Expression Vector: Bovine Endothelial and Aorta Cells

Enzyme: Human PGIS pH:7.4 Temperature: 23

256 [2]
9.00E-03 ± 5.00E-03 mM Bovine Expression Vector: Bovine Endothelial and Aorta Cells

Enzyme: Bovine PGIS pH:7.4 Temperature: 24

192 [3]
Description of the PGIS Kms distribution
Mode (mM) Confidence Interval Location parameter (µ) Scale parameter (σ)
1.24E-02 2.46E+00 -4.22E+00 4.20E-01
The estimated probability distribution for PGIS 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

Description of the PGIS Kmp distribution
Mode (mM) Location parameter (µ) Scale parameter (σ)
1.29E-02 -4.182022605 0.414183521
The estimated probability distribution for PGIS 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
147 ± 45 per minute Cattle Expression Vector: E. Coli

Enzyme: Bovine PGIS pH:7.4 Temperature: 24

192 [4]
Description of the PGIS kcat distribution
Mode (min-1) Confidence Interval Location parameter (µ) Scale parameter (σ)
1.41E+02 1.35E+00 5.028213628 0.287348692
The estimated probability distribution for PGIS 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
412 ppm Human Expression Vector: Urinary bladder

Enzyme: PGIS pH: 7.5 Temperature: 37 °C

1024 [5]
206 ppm Human Expression Vector: Lung

Enzyme: PGIS pH: 7.5 Temperature: 37 °C

1024 [5]
60.1 ppm Human Expression Vector: Esophagus

Enzyme: PGIS pH: 7.5 Temperature: 37 °C

1024 [5]
9.93 ppm Human Expression Vector: Oral Cavity

Enzyme: PGIS pH: 7.5 Temperature: 37 °C

1024 [6]
Description of the PGIS concentration distribution
Mode (ppm) Mode (mM) Confidence Interval Location parameter (µ) Scale parameter (σ)
1.13E+02 6.25E-04 4.13E+00 5.67E+00 9.68E-01
The estimated probability distribution for PGIS 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

Literature values
Gibbs Free Energy Change Units Species Notes Weight Reference
0.04 kcal/mol Not stated Estimated

Enzyme: Transacylase Substrate: Product: pH: 7.3 ionic strength: 0.25

64 [7]
Description of the PGIS Keq distribution
Mode Confidence Interval Location parameter (µ) Scale parameter (σ)
9.35E-01 1.00E+01 7.30E-01 8.90E-01
The estimated probability distribution for PGIS 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.

References

  1. ↑ Smith, W. L. DeWitt, D. L. Allen, M. L. , Bimodal distribution of the prostaglandin I2 synthase antigen in smooth muscle cells, J Biol Chem (1983), 258, 5922-6.
  2. ↑ H. C. Yeh, P. Y. Hsu, Characterization of heme environment and mechanism of peroxide bond cleavage in human prostacyclin synthase. Biochim Biophys Acta. 2005 Dec 30;1738(1-3):121-32.
  3. ↑ Hara S., Isolation and molecular cloning of prostacyclin synthase from bovine endothelial cells. J Biol Chem. 1994 Aug 5;269(31):19897-903.
  4. ↑ Hara S., Isolation and molecular cloning of prostacyclin synthase from bovine endothelial cells. J Biol Chem. 1994 Aug 5;269(31):19897-903.
  5. ↑ 5.0 5.1 5.2 M. Kim A draft map of the human proteome Nature, 2014 509, 575–581
  6. ↑ M. Wilhelm Mass-spectrometry-based draft of the human proteome Nature, 2014 509, 582–587
  7. ↑ 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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