Transformation of AA to PGH2 (COX-1)

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The COX enzyme possesses two isoforms, COX-1 and COX-2, of which both produce bioactive eicosanoids. The two isoforms have nearly identical active site residues (Simmons et al. 2004), but COX-1 is a constitutive enzyme, whereas COX-2 is an inducible enzyme. Both enzymes add molecular oxygen to arachidonic acid, generating an endoperoxide species, PGH2, by catalysing the two-step reaction of cycloooxygenation and oxygenation, followed by a hydroperoxide reduction.

PGH2 possesses a short life time due to the formation of a reactive functional group. The endoperoxide undergoes rapid isomerisation reactions, catalysed by a series of synthase enzymes (PGES, PGDS, PGIS, PGFS and TXAS). The resultant species of the isomerisation reactions are PGs (PGE2, PGD2, PGJ2, deoxy-PGJ2 and PGF2α), TXs (TXA2 and TXB2) and prostacyclin (PGI2), all of which have varying effects on the immune system.

Reaction

R2 AA-PGH2.jpg

Chemical equation

AA \rightleftharpoons PGH2

Rate equation

R65.PNG

Enzyme Parameters

Keq

Literature values
Value Units Species Notes Weight Reference
(-30) kcal/mol Unspecified Calculations with a Gaussian98 suite of programs

Enzyme: COX (Unspecific) Substrate: Arachidonate Temperature: 298.15 K Pressure: 1 bar

64 [1]
Description of the COX-1 Keq distribution
Mode Confidence Interval Location parameter (µ) Scale parameter (σ)
4.18E+28 1.00E+01 6.67E+01 8.90E-01
The estimated probability distribution for COX-1 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.

Kms

Literature values
Value Units Species Notes Weight Reference
0.0088 ± 0.0022 mM Human Expression Vector: Human

Enzyme: Cyclooxygenase-1 pH: 7.6 - 8.4 Temperature: 37 °C

2048 [2]
0.0019 ± 0.0002 mM Ram Expression Vector: Ram

Enzyme: Cyclooxygenase-1 pH: 8 Temperature: 30 ± 0.2 °C

192 [3]
Description of the COX-1 Kms distribution
Mode (mM) Confidence Interval Location parameter (µ) Scale parameter (σ)
8.30E-03 1.62E+00 -4.60E+00 4.41E-01
The estimated probability distribution for COX-1 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 COX-1 Kmp distribution
Mode (mM) Location parameter (μ) Scale parameter (σ)
8.20E-03 -4.60E+00 4.49E-01
The estimated probability distribution for COX-1 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
8820 ± 360 per minute Ram Expression Vector: Ram

Enzyme: Cyclooxygenase-1 pH: 8 Temperature: 30 ± 0.2 °C

192 [3]
Description of the COX-1 kcat distribution
Mode (min-1) Confidence Interval Location parameter (μ) Scale parameter (σ)
8.81E+03 1.04E+00 9.09E+00 4.08E-02
The estimated probability distribution for COX-1 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.

Enzyme concentration

Literature values
Value Units Species Notes Weight Reference
849 ppm Human Expression Vector: Platlet

Enzyme: Cyclooxygenase-1 (PGTS1) pH: 7.5 Temperature: 37 °C

1024 [4]
208 ppm Human Expression Vector: Stomach

Enzyme: Cyclooxygenase-1 (PGTS1) pH: 7.5 Temperature: 37 °C

1024 [5]
130 ppm Human Expression Vector: Esophagus

Enzyme: Cyclooxygenase-1 (PGTS1) pH: 7.5 Temperature: 37 °C

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

Enzyme: Cyclooxygenase-1 (PGTS1) pH: 7.5 Temperature: 37 °C

1024 [5]
19.1 ppm Human Expression Vector: Lung

Enzyme: Cyclooxygenase-1 (PGTS1) pH: 7.5 Temperature: 37 °C

1024 [4]
Description of the COX-1 concentration distribution
Mode (ppm) Mode (mM) Confidence Interval Location parameter (μ) Scale parameter (σ)
129 7.14E-04 1.00E+01 6.67E+01 8.90E-01

To convert the enzyme concentration from ppm to mM, the following equation was used.


The estimated probability distribution for COX-1 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.

References

  1. ↑ P. Silva, "A theoretical study of radical-only and combined radical/carbocationic mechanisms of arachidonic acid cyclooxygenation by prostaglandin H synthase" Theor Chem Acc (2003) 110: 345
  2. ↑ Y. Noreen Development of a Radiochemical Cyclooxygenase-1 and -2 in Vitro Assay for Identification of Natural Products as Inhibitors of Prostaglandin BiosynthesisJ. Nat. Prod., 1998, 61 (1), pp 2–7)
  3. ↑ 3.0 3.1 Mukherjee Molecular Oxygen Dependent Steps in Fatty Acid Oxidation by Cyclooxygenase-1 Biochemistry, 2007, 46 (13), pp 3975–3989
  4. ↑ 4.0 4.1 M. Kim A draft map of the human proteome Nature, 2014 509, 575–581
  5. ↑ 5.0 5.1 5.2 [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]

Related Reactions

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