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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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>.
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== Reaction ==
 
== Reaction ==
 
[[File:R5_PGH2_-_PGI2.jpg|center|500px]]
 
[[File:R5_PGH2_-_PGI2.jpg|center|500px]]
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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
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|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
−
|<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
 +
|}
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 +
[[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.  ]]
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 +
=== 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.  ]]
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 +
 +
===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.  ]]
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 +
=== Enzyme concentration ===
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 +
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
 +
|-
 +
|412
 +
|<math> ppm </math>
 +
|Human
 +
|Expression Vector: Urinary bladder
 +
Enzyme: PGIS
 +
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>
 +
|-
 +
|206
 +
|<math> ppm </math>
 +
|Human
 +
|Expression Vector: Lung
 +
Enzyme: PGIS
 +
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>
 +
|-
 +
|60.1
 +
|<math> ppm </math>
 +
|Human
 +
|Expression Vector: Esophagus
 +
Enzyme: PGIS
 +
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>
 +
|-
 +
|9.93
 +
|<math> ppm </math>
 +
|Human
 +
|Expression Vector: Oral Cavity
 +
Enzyme: PGIS
 +
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>
 +
|-
 +
|}
 +
 +
{| 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.  ]]
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 +
=== K<sub>eq</sub> ===
 +
{|class="wikitable sortable"
 +
|+  style="text-align: left;" | 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
 +
|<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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