Thromboxane-A synthase

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Thromboxane synthase inhibitors
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TBXAS1
Identifiers
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000059377

ENSMUSG00000029925

UniProt

P24557

P36423

RefSeq (mRNA)

NM_011539

RefSeq (protein)

NP_035669

Location (UCSC)Chr 7: 139.78 – 140.02 MbChr 6: 38.85 – 39.06 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Thromboxane A synthase 1 (EC 5.3.99.5, platelet, cytochrome P450, family 5, subfamily A), also known as TBXAS1, is a cytochrome P450 enzyme that, in humans, is encoded by the TBXAS1 gene.[5][6][7]

Function

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The

BLT2 receptor actions.[9] The enzyme plays a role in several pathophysiological processes including hemostasis, cardiovascular disease, and stroke. The gene expresses two transcript variants.[5]

Thromboxane synthase inhibitors

Thromboxane synthase inhibitors are used as

thromboxane receptor antagonist.[10]

Structure

The human

kDa cytochrome P450 protein with 533 amino acids and a heme prosthetic group. This enzyme, anchored to the endoplasmic reticulum, is found in platelets, monocytes, and several other cell types. The NH2 terminus contains two hydrophobic segments whose secondary structure is believed to be helical. Evidence suggests that the peptides serve as a membrane anchor for the enzyme.[11] Moreover, the study of cDNA clones made possible by polymerase chain reaction techniques has further elucidated the TXA synthase's primary structure. Similar to other members in the cytochrome P450 family, TXA synthase has a heme group coordinated to the thiolate group of a cysteine residue, specifically cysteine 480.[12] Mutagenesis studies that made substitutions at that position resulted in loss of catalytic activity and minimal heme binding. Other residues that had similar results were W133, R478, N110, and R413. Located near the heme propionate groups or the distal face of the heme, these residues are also important for proper integration of heme into the apoprotein.[13] Unfortunately, researchers have found it difficult to obtain a crystal structure of TXA synthase due to the requirement of detergent treatment extraction from the membrane but they have utilized homology modeling to create a 3D structure. One model showed two domains, an alpha-helix-rich domain and a beta-sheet-rich domain. The heme was found to be sandwiched between helices I and L.[14]

Mechanism

This isomerization mechanism shows prostaglandin H2 being converted to thromboxane. A heme group coordinated to a cysteine residue from the enzyme, thromboxane synthase, is involved in the mechanism.

Thromboxane A (TXA) is derived from the prostaglandin H2 (PGH2) molecule. PGH2 contains a relatively weak epidioxy bond, and a possible mechanism is known to involve homolytic cleavage of the epidioxide and a rearrangement to TXA.[15] A heme group in the active site of TXA synthase plays an important role in the mechanism. Stopped-flow kinetic studies with a substrate analog and recombinant TXA synthase revealed that substrate binding occurs in two steps.[13] First, there is a fast initial binding to the protein and then a subsequent ligation to the heme iron. In the first step of the mechanism, the heme iron coordinates to the C-9 endoperoxide oxygen. It participates in homolytic cleavage of the O-O bond in the endoperoxide, which represents the rate-limiting step, and undergoes a change in redox state from Fe(III) to Fe(IV).[16] A free oxygen radical forms at C-11, and this intermediate undergoes ring cleavage. With the free radical now at C-12, the iron heme then oxidizes this radical to a carbocation.[17] The molecule is now ready for intramolecular ring formation. The negatively charged oxygen attacks the carbonyl, and the electrons from one of the double bonds are drawn to the carbocation, thus closing the ring.

Biological significance

Maintaining a balance between prostacyclins and

thrombotic vascular events. Furthermore, the importance of thromboxanes and their syntheses in vascular homeostasis is illustrated by findings that patients whose platelets were unresponsive to TXA displayed hemostatic defects and that a deficiency of platelet TXA production led to bleeding disorders.[19]

Furthermore, it has been found that the expression of TXA synthase may be of critical importance to the development and progression of cancer. An overall increase in TXA synthase expression has been observed in a variety of cancers, such as

renal cancer. Cancer cells are known for their limitless cellular replicative potential, and it has been hypothesized that changes in eicosanoid profile affect cancer growth. Research has led to the proposal that TXA synthase contributes to a range of tumor survival pathways, including growth, apoptosis inhibition, angiogenesis, and metastasis.[20]

Pathway

  • Thromboxane synthesis
    Thromboxane synthesis
  • Eicosanoid synthesis
    Eicosanoid synthesis

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000059377 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029925 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: TBXAS1 thromboxane A synthase 1 (platelet, cytochrome P450, family 5, subfamily A)".
  6. PMID 1714723
    .
  7. PMID 8964509
    .
  8. PMID 18378794
    .
  9. PMID 25480980
    .
  10. PMID 9754941
    .
  11. PMID 8063711
    .
  12. PMID 1730669
    .
  13. ^
    PMID 12432933
    .
  14. PMID 11097184
    .
  15. PMID 2491846
    .
  16. PMID 8777569
    .
  17. doi:10.1002/anie.199419111
    .
  18. S2CID 207215183
    .
  19. PMID 9678486
    .
  20. PMID 20122998
    .

Further reading

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Thromboxane-A_synthase&oldid=1204838849#Inhibitors"