Difference between revisions of "Transformation of PGE2 to 15-Keto-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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15-hydroxyprostaglandin dehydrogenase, also known as (15-PGDH) metabolises PG into the 15-Keto variant via the oxidation of 15(S)-hydroxyl group. The enzyme is constituently expressed in the skin (Finhelm1982) and within the eicosanoid network it is reported as metabolising PGE2 and PGF2a.
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The primary catabolic pathway of prostanoids is initiated by the oxidation of the C15 hydroxyl group by 15-prostoglandin dehydrogenase (15-PGDH). 15-PGDH can accept a wide variety of prostaglandins as substrates. Two isoforms of 15-PGDH have been recognised, Type I is NAD+ specific, whereas Type II prefers NADP+. 15-PGDH Type I is prostaglandin and lipoxin specific, whereas Type II exhibits broad substrate specificity, therefore Type I is typically referred to as 15-PGDH in the literature <ref>Ensor, C. M. Tai, H. H., ''15-Hydroxyprostaglandin dehydrogenase'', J Lipid Mediat Cell Signal (1995), 12, 313-9.</ref><ref>Wermuth, B., ''Purification and properties of an NADPH-dependent carbonyl reductase from human brain. Relationship to prostaglandin 9-ketoreductase and xenobiotic ketone reductase'', J Biol Chem (1981), 256, 1206-13.</ref>.
  
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It should be noted that Judson et al found that 15-PGDH expression of the enzyme decreases in response to UVR (Judson2010).
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== Reaction ==  
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[[File:R66_15PGDH.jpg|center|500px]]
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== Reaction ==
 
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Catalysed by 15-PGDH
 
  
 
==Chemical equation==
 
==Chemical equation==
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! Species
 
! Species
 
! Notes
 
! Notes
 +
! Weight
 
! Reference
 
! Reference
 
|-
 
|-
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Temperature: 37'C
 
Temperature: 37'C
 
Substrate: PGE2 + NAD+
 
Substrate: PGE2 + NAD+
 +
|1024
 
|<ref name="Fincham1982"> [https://www.ncbi.nlm.nih.gov/pubmed/6575778 N. Fincham, Novel prostaglandin dehydrogenase in rat skin.'' Biochem J. 1983 Apr 15;212(1):129-34.]</ref>  
 
|<ref name="Fincham1982"> [https://www.ncbi.nlm.nih.gov/pubmed/6575778 N. Fincham, Novel prostaglandin dehydrogenase in rat skin.'' Biochem J. 1983 Apr 15;212(1):129-34.]</ref>  
 
|-
 
|-
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Temperature: 37'C
 
Temperature: 37'C
 
Substrate: PGE2 + NADP+
 
Substrate: PGE2 + NADP+
 +
|1024
 
|<ref name="Fincham1982"> [https://www.ncbi.nlm.nih.gov/pubmed/6575778 N. Fincham, Novel prostaglandin dehydrogenase in rat skin.'' Biochem J. 1983 Apr 15;212(1):129-34.]</ref>  
 
|<ref name="Fincham1982"> [https://www.ncbi.nlm.nih.gov/pubmed/6575778 N. Fincham, Novel prostaglandin dehydrogenase in rat skin.'' Biochem J. 1983 Apr 15;212(1):129-34.]</ref>  
 
|-
 
|-
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Temperature: 37'C
 
Temperature: 37'C
 
Substrate: PGF2a + NAD+
 
Substrate: PGF2a + NAD+
 +
|1024
 
|<ref name="Fincham1982"> [https://www.ncbi.nlm.nih.gov/pubmed/6575778 N. Fincham, Novel prostaglandin dehydrogenase in rat skin.'' Biochem J. 1983 Apr 15;212(1):129-34.]</ref>  
 
|<ref name="Fincham1982"> [https://www.ncbi.nlm.nih.gov/pubmed/6575778 N. Fincham, Novel prostaglandin dehydrogenase in rat skin.'' Biochem J. 1983 Apr 15;212(1):129-34.]</ref>  
 
|-
 
|-
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Temperature: 37'C
 
Temperature: 37'C
 
Substrate: PGF2a + NADP+
 
Substrate: PGF2a + NADP+
 +
|1024
 
|<ref name="Fincham1982"> [https://www.ncbi.nlm.nih.gov/pubmed/6575778 N. Fincham, Novel prostaglandin dehydrogenase in rat skin.'' Biochem J. 1983 Apr 15;212(1):129-34.]</ref>  
 
|<ref name="Fincham1982"> [https://www.ncbi.nlm.nih.gov/pubmed/6575778 N. Fincham, Novel prostaglandin dehydrogenase in rat skin.'' Biochem J. 1983 Apr 15;212(1):129-34.]</ref>  
 
|-
 
|-
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Temperature: 37'C
 
Temperature: 37'C
 
Substrate: PGE2  
 
Substrate: PGE2  
 +
|1024
 
|<ref name="Zhou2001"> [http://onlinelibrary.wiley.com/doi/10.1046/j.1432-1327.2001.02218.x/epdf Zhou H., C-Terminal region of human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase is involved in the interaction with prostaglandin substrates.'' Eur J Biochem. 2001 Jun;268(12):3368-74.]</ref>
 
|<ref name="Zhou2001"> [http://onlinelibrary.wiley.com/doi/10.1046/j.1432-1327.2001.02218.x/epdf Zhou H., C-Terminal region of human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase is involved in the interaction with prostaglandin substrates.'' Eur J Biochem. 2001 Jun;268(12):3368-74.]</ref>
 
|-
 
|-
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Temperature: 37'C
 
Temperature: 37'C
 
Substrate: PGE2  
 
Substrate: PGE2  
 +
|512
 
|<ref name="Zhou2001"> [http://onlinelibrary.wiley.com/doi/10.1046/j.1432-1327.2001.02218.x/epdf Zhou H., C-Terminal region of human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase is involved in the interaction with prostaglandin substrates.'' Eur J Biochem. 2001 Jun;268(12):3368-74.]</ref>
 
|<ref name="Zhou2001"> [http://onlinelibrary.wiley.com/doi/10.1046/j.1432-1327.2001.02218.x/epdf Zhou H., C-Terminal region of human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase is involved in the interaction with prostaglandin substrates.'' Eur J Biochem. 2001 Jun;268(12):3368-74.]</ref>
 
|-
 
|-
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Temperature: 25
 
Temperature: 25
 
Substrate: PGE2 + NAD+
 
Substrate: PGE2 + NAD+
 +
|1024
 
|<ref name="Niesen2010"> [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013719 F. Niesen,, High-Affinity Inhibitors of Human NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase: Mechanisms of Inhibition and Structure-Activity Relationships'' PLoS One. 2010 Nov 2;5(11):e13719.]</ref>  
 
|<ref name="Niesen2010"> [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013719 F. Niesen,, High-Affinity Inhibitors of Human NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase: Mechanisms of Inhibition and Structure-Activity Relationships'' PLoS One. 2010 Nov 2;5(11):e13719.]</ref>  
 
|-
 
|-
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! Species
 
! Species
 
! Notes
 
! Notes
 +
! Weight
 
! Reference
 
! Reference
 
|-
 
|-
Line 132: Line 138:
 
Temperature: 25
 
Temperature: 25
 
Substrate: PGE2 + NAD+
 
Substrate: PGE2 + NAD+
 +
|128
 
|<ref name="Niesen2010"> [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013719 F. Niesen,, High-Affinity Inhibitors of Human NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase: Mechanisms of Inhibition and Structure-Activity Relationships'' PLoS One. 2010 Nov 2;5(11):e13719.]</ref>  
 
|<ref name="Niesen2010"> [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013719 F. Niesen,, High-Affinity Inhibitors of Human NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase: Mechanisms of Inhibition and Structure-Activity Relationships'' PLoS One. 2010 Nov 2;5(11):e13719.]</ref>  
 
|-
 
|-
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Temperature: 25
 
Temperature: 25
 
Substrate: PGE2 + NAD+ + Inhibitor
 
Substrate: PGE2 + NAD+ + Inhibitor
 +
|128
 
|<ref name="Niesen2010"> [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013719 F. Niesen,, High-Affinity Inhibitors of Human NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase: Mechanisms of Inhibition and Structure-Activity Relationships'' PLoS One. 2010 Nov 2;5(11):e13719.]</ref>  
 
|<ref name="Niesen2010"> [http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013719 F. Niesen,, High-Affinity Inhibitors of Human NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase: Mechanisms of Inhibition and Structure-Activity Relationships'' PLoS One. 2010 Nov 2;5(11):e13719.]</ref>  
 
|-
 
|-
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===Enzyme concentration ===
 
===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;" | Literature values
 
|+  style="text-align: left;" | Literature values
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! Species
 
! Species
 
! Notes
 
! Notes
 +
! Weight
 
! Reference
 
! Reference
 
|-
 
|-
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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>
 
|-
 
|-
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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>
 
|-
 
|-
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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>
 
|-
 
|-
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pH: 7.5
 
pH: 7.5
 
Temperature: 37 °C
 
Temperature: 37 °C
 +
|2048
 
|Paxdb - Unknown
 
|Paxdb - Unknown
 
|}
 
|}
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{| class="wikitable"
 
{| class="wikitable"
 
|+  style="text-align: left;" | Description of the 15-PGDH concentration distribution
 
|+  style="text-align: left;" | Description of the 15-PGDH concentration distribution
−
! Mode (mM) !! Confidence Interval  !! Location parameter (μ) !! Scale parameter (σ)
+
! Mode (ppm) !! Mode (mM) !! Confidence Interval  !! Location parameter (μ) !! Scale parameter (σ)
 
|-
 
|-
−
| 1.12E+01 || 2.32E+00 || 2.87E+00 || 6.80E-01
+
| 1.12E+01 || 6.20E-05 || 2.32E+00 || 2.87E+00 || 6.80E-01
 
|}
 
|}
  
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! Species
 
! Species
 
! Notes
 
! Notes
 +
! Weight
 
! Reference
 
! Reference
 
|-
 
|-
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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=ARACHIDONATE-12-LIPOXYGENASE-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=ARACHIDONATE-12-LIPOXYGENASE-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>
 
|}
 
|}

Latest revision as of 07:57, 21 August 2019

Return to overview

The primary catabolic pathway of prostanoids is initiated by the oxidation of the C15 hydroxyl group by 15-prostoglandin dehydrogenase (15-PGDH). 15-PGDH can accept a wide variety of prostaglandins as substrates. Two isoforms of 15-PGDH have been recognised, Type I is NAD+ specific, whereas Type II prefers NADP+. 15-PGDH Type I is prostaglandin and lipoxin specific, whereas Type II exhibits broad substrate specificity, therefore Type I is typically referred to as 15-PGDH in the literature [1][2].

Reaction

R66 15PGDH.jpg

Chemical equation

PGE2 \rightleftharpoons 15-Keto-PGE2

Rate equation

R66.PNG

Enzyme Parameters

Kms

Literature values
Value Units Species Notes Weight Reference
0.008 mM Rat Skin Method:

pH:7.4 Temperature: 37'C Substrate: PGE2 + NAD+

1024 [3]
0.0075 mM Rat Skin Method:

pH:7.4 Temperature: 37'C Substrate: PGE2 + NADP+

1024 [3]
0.024 mM Rat Skin Method:

pH:7.4 Temperature: 37'C Substrate: PGF2a + NAD+

1024 [3]
0.023 mM Rat Skin Method:

pH:7.4 Temperature: 37'C Substrate: PGF2a + NADP+

1024 [3]
0.0039 mM Purified Human 15-PGDH Method: In vitro

Expression Vector: E. coli pH:7.5 Temperature: 37'C Substrate: PGE2

1024 [4]
0.0099 mM Purified Rat 15-PGDH Method: In vitro

Expression Vector: E. coli pH:7.5 Temperature: 37'C Substrate: PGE2

512 [4]
0.0055 ± 0.0006 mM Human Method:In vitro

Expression Vector: E. Coli pH:8 Temperature: 25 Substrate: PGE2 + NAD+

1024 [5]
Description of the 15-PGDH Kms distribution
Mode (mM) Confidence Interval Location parameter (μ) Scale parameter (σ)
7.64E-03 5.05E+00 -4.41E+00 6.80E-01
The estimated probability distribution for 15-PGDH 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 15-PGDH Kmp distribution
Mode (mM) Location parameter (μ) Scale parameter (σ)
7.70E-03 -4.41E+00 6.72E-01
The estimated probability distribution for 15-PGDH 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
816 ± 18 per minute Human Method: In vitro

Expression Vector: E. Coli pH:8 Temperature: 25 Substrate: PGE2 + NAD+

128 [5]
366 ± 12 - 846 ± 12 per minute Human Method: In vitro

Expression Vector: E. Coli pH:8 Temperature: 25 Substrate: PGE2 + NAD+ + Inhibitor

128 [5]
Description of the 15-PGDH kcat distribution
Mode (min-1) Confidence Interval Location parameter (μ) Scale parameter (σ)
8.12E+02 5.38E+00 7.19E+00 7.01E-01
The estimated probability distribution for 15-PGDH 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
69.8 ppm Human Expression Vector: Esophagus

Enzyme: 15-PGDH pH: 7.5 Temperature: 37 °C

1024 [6]
22.1 ppm Human Expression Vector: Heart

Enzyme: 15-PGDH pH: 7.5 Temperature: 37 °C

1024 [7]
11.2 ppm Human Expression Vector: Esophagus

Enzyme: 15-PGDH pH: 7.5 Temperature: 37 °C

1024 [7]
7.68 ppm Human Expression Vector: Skin

Enzyme: 15-PGDH pH: 7.5 Temperature: 37 °C

2048 Paxdb - Unknown
Description of the 15-PGDH concentration distribution
Mode (ppm) Mode (mM) Confidence Interval Location parameter (μ) Scale parameter (σ)
1.12E+01 6.20E-05 2.32E+00 2.87E+00 6.80E-01
The estimated probability distribution for 15-PGDH 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
(-0.46818542) kcal/mol Calculated Estimated

Enzyme: 15-PGDH Substrate: PGE2 Product: 15-dehydro-PGE2 pH: 7.3 ionic strength: 0.25

64 [8]
Description of the 15-PGDH Keq distribution
Mode Confidence Interval Location parameter (μ) Scale parameter (σ)
2.21E+00 1.00E+01 1.58E+00 8.91E-01
The estimated probability distribution for 15-PGDH 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. ↑ Ensor, C. M. Tai, H. H., 15-Hydroxyprostaglandin dehydrogenase, J Lipid Mediat Cell Signal (1995), 12, 313-9.
  2. ↑ Wermuth, B., Purification and properties of an NADPH-dependent carbonyl reductase from human brain. Relationship to prostaglandin 9-ketoreductase and xenobiotic ketone reductase, J Biol Chem (1981), 256, 1206-13.
  3. ↑ 3.0 3.1 3.2 3.3 N. Fincham, Novel prostaglandin dehydrogenase in rat skin. Biochem J. 1983 Apr 15;212(1):129-34.
  4. ↑ 4.0 4.1 Zhou H., C-Terminal region of human NAD+-dependent 15-hydroxyprostaglandin dehydrogenase is involved in the interaction with prostaglandin substrates. Eur J Biochem. 2001 Jun;268(12):3368-74.
  5. ↑ 5.0 5.1 5.2 F. Niesen,, High-Affinity Inhibitors of Human NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase: Mechanisms of Inhibition and Structure-Activity Relationships PLoS One. 2010 Nov 2;5(11):e13719.
  6. ↑ M. Wilhelm Mass-spectrometry-based draft of the human proteome Nature, 2014 509, 582–587
  7. ↑ 7.0 7.1 M. Kim A draft map of the human proteome Nature, 2014 509, 575–581
  8. ↑ 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
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