Difference between revisions of "Transformation of TXA2 to TXB2"

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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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Thromboxane A2 is a bioactive molecule which affects vasoactivity and promotes thrombosis. It is unstable due to the epoxide functional group, and as a consequence has a short half-life of 20- 30 seconds.  The hydrolysis reaction results in the generation of biologically inactive TXB2.  
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Upon generating the unstable metabolite TXA2, it is rapidly hydrolysed into TXB2 via a non-enzymatic reaction under physiological conditions. This inactive metabolite is produced by the incorporation of two hydrogens and one oxygen at C9 and C11, resulting in the opening of the trimethylene oxide ring, and the generation of two hydroxyl groups on the tetrahydropyran ring.  
  
 
== Reaction ==
 
== Reaction ==
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! Conditions
 
! Conditions
 
! Substrate
 
! Substrate
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! Weight
 
! Reference
 
! Reference
 
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Temperature: 25°C
 
Temperature: 25°C
 
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|<ref name="Ross1982”>[http://pubs.acs.org/doi/pdf/10.1021/ja00370a035 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665]</ref>
 
|<ref name="Ross1982”>[http://pubs.acs.org/doi/pdf/10.1021/ja00370a035 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665]</ref>
 
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Temperature: 25°C
 
Temperature: 25°C
 
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|<ref name="Ross1982”>[http://pubs.acs.org/doi/pdf/10.1021/ja00370a035 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665]</ref>
 
|<ref name="Ross1982”>[http://pubs.acs.org/doi/pdf/10.1021/ja00370a035 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665]</ref>
 
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Temperature: 25°C
 
Temperature: 25°C
 
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|<ref name="Ross1982”>[http://pubs.acs.org/doi/pdf/10.1021/ja00370a035 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665]</ref>
 
|<ref name="Ross1982”>[http://pubs.acs.org/doi/pdf/10.1021/ja00370a035 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665]</ref>
 
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Temperature: 25°C
 
Temperature: 25°C
 
|4
 
|4
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|<ref name="Ross1982”>[http://pubs.acs.org/doi/pdf/10.1021/ja00370a035 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665]</ref>
 
|<ref name="Ross1982”>[http://pubs.acs.org/doi/pdf/10.1021/ja00370a035 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665]</ref>
 
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Temperature: 25°C
 
Temperature: 25°C
 
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|5
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|32
 
|<ref name="Ross1982”>[http://pubs.acs.org/doi/pdf/10.1021/ja00370a035 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665]</ref>
 
|<ref name="Ross1982”>[http://pubs.acs.org/doi/pdf/10.1021/ja00370a035 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665]</ref>
 
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Temperature: 25°C
 
Temperature: 25°C
 
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|<ref name="Ross1982”>[http://pubs.acs.org/doi/pdf/10.1021/ja00370a035 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665]</ref>
 
|<ref name="Ross1982”>[http://pubs.acs.org/doi/pdf/10.1021/ja00370a035 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665]</ref>
 
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Temperature: 25°C
 
Temperature: 25°C
 
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|<ref name="Ross1982”>[http://pubs.acs.org/doi/pdf/10.1021/ja00370a035 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665]</ref>
 
|<ref name="Ross1982”>[http://pubs.acs.org/doi/pdf/10.1021/ja00370a035 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665]</ref>
 
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Temperature: 25°C
 
Temperature: 25°C
 
|8
 
|8
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|32
 
|<ref name="Ross1982”>[http://pubs.acs.org/doi/pdf/10.1021/ja00370a035 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665]</ref>
 
|<ref name="Ross1982”>[http://pubs.acs.org/doi/pdf/10.1021/ja00370a035 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665]</ref>
 
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Temperature: 25°C
 
Temperature: 25°C
 
|8
 
|8
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|32
 
|<ref name="Ross1982”>[http://pubs.acs.org/doi/pdf/10.1021/ja00370a035 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665]</ref>
 
|<ref name="Ross1982”>[http://pubs.acs.org/doi/pdf/10.1021/ja00370a035 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665]</ref>
 
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| 25°C, in imidazole buffer and also in phosphate buffers,  
 
| 25°C, in imidazole buffer and also in phosphate buffers,  
 
| CO2 to H2CO3
 
| CO2 to H2CO3
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|32
 
| <ref name="Gibbons1963”>[http://www.jbc.org/content/238/10/3502.full.pdf B. Gibbons "Rate of Hydration of Carbon Dioxide and Dehydration of Carbonic Acid at 25" J Biol Chem. 1963 Oct;238:3502-7]</ref>
 
| <ref name="Gibbons1963”>[http://www.jbc.org/content/238/10/3502.full.pdf B. Gibbons "Rate of Hydration of Carbon Dioxide and Dehydration of Carbonic Acid at 25" J Biol Chem. 1963 Oct;238:3502-7]</ref>
 
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! Conditions
 
! Conditions
 
! Substrate
 
! Substrate
 +
! Weight
 
! Reference
 
! Reference
 
|-
 
|-
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|Temperature: 35°C
 
|Temperature: 35°C
 
Vector:Mosquito
 
Vector:Mosquito
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Note: "In solution, it undergoes rapid hydrolysis to form TXB2, a stable but physiologically inactive compound." - therefore they used stable analogues.
 
Note: "In solution, it undergoes rapid hydrolysis to form TXB2, a stable but physiologically inactive compound." - therefore they used stable analogues.
 
|carbocyclic TXA2 (analogue of TXA2)
 
|carbocyclic TXA2 (analogue of TXA2)
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|24
 
|<ref name="Alvarenga2010”>[http://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.1000547&type=printable P. H. Alvarenga "The Function and Three-Dimensional Structure of a Thromboxane A2/Cysteinyl Leukotriene-Binding Protein from the Saliva of a Mosquito Vector of the Malaria Parasite" PLoS Biol. 2010 Nov 30;8(11):e1000547. doi: 10.1371/journal.pbio.1000547.]</ref>
 
|<ref name="Alvarenga2010”>[http://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.1000547&type=printable P. H. Alvarenga "The Function and Three-Dimensional Structure of a Thromboxane A2/Cysteinyl Leukotriene-Binding Protein from the Saliva of a Mosquito Vector of the Malaria Parasite" PLoS Biol. 2010 Nov 30;8(11):e1000547. doi: 10.1371/journal.pbio.1000547.]</ref>
 
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Note: "In solution, it undergoes rapid hydrolysis to form TXB2, a stable but physiologically inactive compound." - therefore they used stable analogues.
 
Note: "In solution, it undergoes rapid hydrolysis to form TXB2, a stable but physiologically inactive compound." - therefore they used stable analogues.
 
|[3H]IONO NT-126, a TXA z antagonist,
 
|[3H]IONO NT-126, a TXA z antagonist,
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|36
 
|<ref name="Nakahata1992”>[http://ac.els-cdn.com/S0006899310800137/1-s2.0-S0006899310800137-main.pdf?_tid=b2ab095e-155f-11e7-94f0-00000aab0f26&acdnat=1490888822_58d1d45dc3238dede94e4a2f15cada82 N Nakahata et al. "The Presence of Thromboxane A2 Receptors in Cultured Astrocytes From Rabbit Brain" Brain Res 583 (1-2), 100-104. 1992 Jun 26]</ref>
 
|<ref name="Nakahata1992”>[http://ac.els-cdn.com/S0006899310800137/1-s2.0-S0006899310800137-main.pdf?_tid=b2ab095e-155f-11e7-94f0-00000aab0f26&acdnat=1490888822_58d1d45dc3238dede94e4a2f15cada82 N Nakahata et al. "The Presence of Thromboxane A2 Receptors in Cultured Astrocytes From Rabbit Brain" Brain Res 583 (1-2), 100-104. 1992 Jun 26]</ref>
 
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|Hydroxysulfamic acid
 
|Hydroxysulfamic acid
 
[[File:HSA.PNG ‎|center|500px]]
 
[[File:HSA.PNG ‎|center|500px]]
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|16
 
|<ref name="Littlejohn1989”>[http://www.nrcresearchpress.com/doi/pdf/10.1139/v89-243 D. LITTLEJOHN "The dissociation constant and acid hydrolysis rate of hydroxysulfamic acid"  Can. J. Chem. 67, 1596 (1989).]</ref>
 
|<ref name="Littlejohn1989”>[http://www.nrcresearchpress.com/doi/pdf/10.1139/v89-243 D. LITTLEJOHN "The dissociation constant and acid hydrolysis rate of hydroxysulfamic acid"  Can. J. Chem. 67, 1596 (1989).]</ref>
 
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In vitro
 
In vitro
 
|H2O2
 
|H2O2
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|<ref name="Littlejohn1989”>[http://pubs.rsc.org/-/content/articlepdf/1949/tf/tf9494500224  M. G. EVAN "The dissociation constant and acid hydrolysis rate of hydroxysulfamic acid"  Trans. Faraday Soc., 1949,45, 224-230]</ref>
+
|16
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|<ref name="Evan1949”>[http://pubs.rsc.org/-/content/articlepdf/1949/tf/tf9494500224  M. G. EVAN "The dissociation constant and acid hydrolysis rate of hydroxysulfamic acid"  Trans. Faraday Soc., 1949,45, 224-230]</ref>
 
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|5.9 E-8
 
|5.9 E-8
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|Oxaliplatin
 
|Oxaliplatin
 
|[[File:Oxaliplatin.PNG ‎|center|500px]]
 
|[[File:Oxaliplatin.PNG ‎|center|500px]]
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|16
 
|<ref name="Jerremalm”>[http://www.sciencedirect.com/science/article/pii/S0022354916311649  Elin Jerremalm "Hydrolysis of Oxaliplatin—Evaluation of the Acid Dissociation Constant for the Oxalato Monodentate Complex"  Journal of Pharmaceutical Sciences Volume 92, Issue 2, February 2003, Pages 436–438]</ref>
 
|<ref name="Jerremalm”>[http://www.sciencedirect.com/science/article/pii/S0022354916311649  Elin Jerremalm "Hydrolysis of Oxaliplatin—Evaluation of the Acid Dissociation Constant for the Oxalato Monodentate Complex"  Journal of Pharmaceutical Sciences Volume 92, Issue 2, February 2003, Pages 436–438]</ref>
 
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Latest revision as of 11:07, 2 November 2019

Return to overview

Upon generating the unstable metabolite TXA2, it is rapidly hydrolysed into TXB2 via a non-enzymatic reaction under physiological conditions. This inactive metabolite is produced by the incorporation of two hydrogens and one oxygen at C9 and C11, resulting in the opening of the trimethylene oxide ring, and the generation of two hydroxyl groups on the tetrahydropyran ring.

Reaction

R6 TXA2 - TXB2.jpg

Chemical equation

TXA2 \rightleftharpoons TXB2

Rate equation

R06.PNG

Parameters

Association Rate Constant (Kf)

Literature values
Value Units Conditions Substrate Weight Reference
3.7e3 ± 0.1e3 M-1 s-1 NaCl04 (0.1 - 0.2 M)

Temperature: 25°C

3 32 [1]
8.7e3 M-1 s-1 KCl (1 M)

Temperature: 25°C

3 32 [1]
1.1e4 ± 0.1e4 M-1 s-1 NaCl04 (0.1 - 0.2 M)

Temperature: 25°C

4 32 [1]
2.4 e4 M-1 s-1 KCl (1M)

Temperature: 25°C

4 32 [1]
3.7e3 ± 0.1e3 M-1 s-1 NaCl04 (0.1 - 0.2 M)

Temperature: 25°C

5 32 [1]
3.6 ± 0.2 M-1 s-1 NaCl04 (0.1 - 0.2 M)

Temperature: 25°C

6 32 [1]
1.7 ± 0.1 M-1 s-1 NaCl04 (0.1 - 0.2 M)

Temperature: 25°C

7 32 [1]
26.7 ± 0.9 M-1 s-1 NaCl04 (0.1 - 0.2 M)

Temperature: 25°C

8 32 [1]
35 M-1 s-1 KCl (1M)

Temperature: 25°C

8 32 [1]
2.25 ± 0.12 M-1 min-1 25°C, in imidazole buffer and also in phosphate buffers, CO2 to H2CO3 32 [2]
Description of the reaction 6 Kf distribution
Mode (M-1 s-1) Confidence Interval Location parameter (µ) Scale parameter (σ)
3.70E+03 3.44E+01 1.10E+01 1.66E+00
The estimated probability distribution for reaction 6 Kf. 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.

Dissociation Rate Constant (Kr)

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 reaction 6 Kr distribution
Mode Location parameter (µ) Scale parameter (σ)
5.28E+01 5.63E+00 1.29E+00
The estimated probability distribution for reaction 6 Kr. 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.

Dissociation Constant

Literature values
Value Units Conditions Substrate Weight Reference
0.000038 mM Temperature: 35°C

Vector:Mosquito Note: "In solution, it undergoes rapid hydrolysis to form TXB2, a stable but physiologically inactive compound." - therefore they used stable analogues.

carbocyclic TXA2 (analogue of TXA2) 24 [3]
0.00000023 mM Temperature: 35°C

Vector:Rabbit cultured astrocytes

Note: "In solution, it undergoes rapid hydrolysis to form TXB2, a stable but physiologically inactive compound." - therefore they used stable analogues.

[3H]IONO NT-126, a TXA z antagonist, 36 [4]
1500 ± 500 (excluded) mM Temperature: 25°C

In vitro

Hydroxysulfamic acid
HSA.PNG
 16 [5]
H202.PNG
 N/A Temperature: 20°C

In vitro

H2O2 16 [6]
5.9 E-8 N/A Oxaliplatin
Oxaliplatin.PNG
 16 [7]
Description of the reaction 6 KD distribution
Mode (M-1 s-1) Confidence Interval Location parameter (µ) Scale parameter (σ)
2.35E-07 1.76E+04 -6.86E+00 2.90E+00
The estimated probability distribution for reaction 6 Kr. 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.

Related Reactions

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 A. Ross "Vinyl epoxide hydrolysis reactions" J. Am. Chem. Soc., 1982, 104 (6), pp 1658–1665
  2. ↑ B. Gibbons "Rate of Hydration of Carbon Dioxide and Dehydration of Carbonic Acid at 25" J Biol Chem. 1963 Oct;238:3502-7
  3. ↑ P. H. Alvarenga "The Function and Three-Dimensional Structure of a Thromboxane A2/Cysteinyl Leukotriene-Binding Protein from the Saliva of a Mosquito Vector of the Malaria Parasite" PLoS Biol. 2010 Nov 30;8(11):e1000547. doi: 10.1371/journal.pbio.1000547.
  4. ↑ N Nakahata et al. "The Presence of Thromboxane A2 Receptors in Cultured Astrocytes From Rabbit Brain" Brain Res 583 (1-2), 100-104. 1992 Jun 26
  5. ↑ D. LITTLEJOHN "The dissociation constant and acid hydrolysis rate of hydroxysulfamic acid" Can. J. Chem. 67, 1596 (1989).
  6. ↑ M. G. EVAN "The dissociation constant and acid hydrolysis rate of hydroxysulfamic acid" Trans. Faraday Soc., 1949,45, 224-230
  7. ↑ Elin Jerremalm "Hydrolysis of Oxaliplatin—Evaluation of the Acid Dissociation Constant for the Oxalato Monodentate Complex" Journal of Pharmaceutical Sciences Volume 92, Issue 2, February 2003, Pages 436–438
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