View source for Thromboxane-A synthase

{{Short description|Mammalian protein found in Homo sapiens}}
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{{Infobox_gene}}
'''Thromboxane A synthase 1 ({{EnzExplorer|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]].<ref name="entrez">{{Cite web |title=Entrez Gene: TBXAS1 thromboxane A synthase 1 (platelet, cytochrome P450, family 5, subfamily A) |url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6916}}</ref><ref name="pmid1714723">{{Cite journal |vauthors=Yokoyama C, Miyata A, Ihara H, Ullrich V, Tanabe T |date=August 1991 |title=Molecular cloning of human platelet thromboxane A synthase |journal=Biochemical and Biophysical Research Communications |volume=178 |issue=3 |pages=1479–1484 |doi=10.1016/0006-291X(91)91060-P |pmid=1714723}}</ref><ref name="pmid8964509">{{Cite journal |vauthors=Baek SJ, Lee KD, Shen RF |date=September 1996 |title=Genomic structure and polymorphism of the human thromboxane synthase-encoding gene |journal=Gene |volume=173 |issue=2 |pages=251–256 |doi=10.1016/0378-1119(95)00881-0 |pmid=8964509}}</ref>

== Function ==
This gene encodes a member of the cytochrome P450 superfamily of enzymes. The [[cytochrome P450 oxidase|cytochrome P450]] proteins are monooxygenases that [[catalyze]] many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids. However, this protein is considered a member of the cytochrome P450 superfamily on the basis of sequence similarity rather than functional similarity. This endoplasmic reticulum membrane protein catalyzes the conversion of [[prostaglandin H2|prostaglandin H<sub>2</sub>]] to [[thromboxane A2|thromboxane A<sub>2</sub>]], a potent [[vasoconstrictor]] and inducer of [[platelet aggregation]], and also to '''[[12-Hydroxyheptadecatrienoic acid]]''' (i.e. '''12-(''S'')-hydroxy-5''Z'',8''E'',10''E''-heptadecatrienoic acid''' or '''12-HHT''') an agonist of '''[[Leukotriene B4 receptor]]s''' (i.e. '''BLT2''' receptors)<ref>{{Cite journal |vauthors=Okuno T, Iizuka Y, Okazaki H, Yokomizo T, Taguchi R, Shimizu T |date=April 2008 |title=12(S)-Hydroxyheptadeca-5Z, 8E, 10E-trienoic acid is a natural ligand for leukotriene B4 receptor 2 |journal=The Journal of Experimental Medicine |volume=205 |issue=4 |pages=759–766 |doi=10.1084/jem.20072329 |pmc=2292216 |pmid=18378794}}</ref> and mediator of certain [[BLT2 receptor]] actions.<ref name="pmid25480980">{{Cite journal |vauthors=Yokomizo T |date=February 2015 |title=Two distinct leukotriene B4 receptors, BLT1 and BLT2 |journal=Journal of Biochemistry |volume=157 |issue=2 |pages=65–71 |doi=10.1093/jb/mvu078 |pmid=25480980}}</ref> The enzyme plays a role in several pathophysiological processes including hemostasis, cardiovascular disease, and stroke. The gene expresses two transcript variants.<ref name="entrez" />

==<span class="anchor" id="Inhibitors"></span>Thromboxane synthase inhibitors==
<!-- This Anchor tag serves to provide a permanent target for incoming section links. Please do not remove it, nor modify it, except to add another appropriate anchor.  If you modify the section title, please anchor the old title. It is always best to anchor an old section header that has been changed so that links to it will not be broken. See [[Template:Anchor]] for details. This text is produced using {{subst:Anchor comment}} -->
{{visible anchor|Thromboxane synthase inhibitors}} are used as [[antiplatelet drug]]s. [[Picotamide]] acts both as a thromboxane synthase inhibitor and as a [[thromboxane receptor antagonist]].<ref name="pmid9754941">{{Cite journal |vauthors=Ratti S, Quarato P, Casagrande C, Fumagalli R, Corsini A |date=August 1998 |title=Picotamide, an antithromboxane agent, inhibits the migration and proliferation of arterial myocytes |journal=European Journal of Pharmacology |volume=355 |issue=1 |pages=77–83 |doi=10.1016/S0014-2999(98)00467-1 |pmid=9754941}}</ref>

== Structure ==

The human [[thromboxane]] A (TXA) synthase is a 60 [[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.<ref>{{Cite journal |vauthors=Ruan KH, Li P, Kulmacz RJ, Wu KK |date=August 1994 |title=Characterization of the structure and membrane interaction of NH2-terminal domain of thromboxane A2 synthase |journal=The Journal of Biological Chemistry |volume=269 |issue=33 |pages=20938–20942 |doi=10.1016/S0021-9258(17)31912-9 |pmid=8063711 |doi-access=free}}</ref> 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.<ref>{{Cite journal |vauthors=Ohashi K, Ruan KH, Kulmacz RJ, Wu KK, Wang LH |date=January 1992 |title=Primary structure of human thromboxane synthase determined from the cDNA sequence |journal=The Journal of Biological Chemistry |volume=267 |issue=2 |pages=789–793 |doi=10.1016/S0021-9258(18)48353-6 |pmid=1730669 |doi-access=free}}</ref> 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.<ref name="Wang LH, Kulmacz RJ 2002 409–422">{{Cite journal |vauthors=Wang LH, Kulmacz RJ |date=August 2002 |title=Thromboxane synthase: structure and function of protein and gene |journal=Prostaglandins & Other Lipid Mediators |volume=68-69 |pages=409–422 |doi=10.1016/s0090-6980(02)00045-x |pmid=12432933}}</ref>  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.<ref>{{Cite journal |vauthors=Hsu PY, Tsai AL, Wang LH |date=November 2000 |title=Identification of thromboxane synthase amino acid residues involved in heme-propionate binding |journal=Archives of Biochemistry and Biophysics |volume=383 |issue=1 |pages=119–127 |doi=10.1006/abbi.2000.2041 |pmid=11097184}}</ref>

==Mechanism==

[[File:Thromboxane Synthase Mechanism.png|thumb|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.<ref>{{Cite journal |vauthors=Hecker M, Ullrich V |date=January 1989 |title=On the mechanism of prostacyclin and thromboxane A2 biosynthesis |journal=The Journal of Biological Chemistry |volume=264 |issue=1 |pages=141–150 |doi=10.1016/S0021-9258(17)31235-8 |pmid=2491846 |doi-access=free}}</ref> 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.<ref name="Wang LH, Kulmacz RJ 2002 409–422" /> 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).<ref>{{Cite journal |vauthors=Tanabe T, Ullrich V |date=October 1995 |title=Prostacyclin and thromboxane synthases |journal=Journal of Lipid Mediators and Cell Signalling |volume=12 |issue=2–3 |pages=243–255 |doi=10.1016/0929-7855(95)00031-k |pmid=8777569}}</ref> 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.<ref>{{Cite journal |vauthors=Brugger R, Ullrich V |date=2003 |title=Prostacyclin and Thromboxane Synthase: New Aspects of Hemethiolate Catalysis |journal=Angewandte Chemie |volume=33 |issue=19 |pages=1911–1919 |doi=10.1002/anie.199419111}}</ref> 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 [[thromboxanes]] is important in the body, particularly because these two [[eicosanoids]] exert opposing effects. In catalyzing the synthesis of thromboxanes, TXA synthase is involved in a flux pathway that can modulate the amount of thromboxane produced. This control becomes an important factor in several processes, such as blood pressure regulation, clotting, and inflammatory responses. Dysregulation of TXA synthase and an imbalance in the prostacyclin-thromboxane ratio are thought to underlie many pathological conditions, such as [[pulmonary hypertension]].<ref>{{Cite journal |vauthors=Praticò D, Dogné JM |date=September 2009 |title=Vascular biology of eicosanoids and atherogenesis |journal=Expert Review of Cardiovascular Therapy |volume=7 |issue=9 |pages=1079–1089 |doi=10.1586/erc.09.91 |pmid=19764861 |s2cid=207215183}}</ref> Because thromboxanes play a role in [[vasoconstriction]] and platelet aggregation, their dominance can disrupt vascular homeostasis and cause [[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.<ref>{{Cite journal |vauthors=Shen RF, Tai HH |date=1998 |title=Thromboxanes: synthase and receptors |journal=Journal of Biomedical Science |volume=5 |issue=3 |pages=153–172 |doi=10.1007/bf02253465 |pmid=9678486}}</ref>

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 [[papillary thyroid carcinoma]], [[prostate cancer]], and [[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]].<ref>{{Cite journal |vauthors=Cathcart MC, Reynolds JV, O'Byrne KJ, Pidgeon GP |date=April 2010 |title=The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer |journal=Biochimica et Biophysica Acta (BBA) - Reviews on Cancer |volume=1805 |issue=2 |pages=153–166 |doi=10.1016/j.bbcan.2010.01.006 |pmid=20122998 |hdl-access=free |hdl=2262/36848}}</ref>

==Pathway==
{{
Gallery |title= |footer= |width=300 |Image:Thromboxane synthesis.png|Thromboxane synthesis
|Image:Eicosanoid synthesis.svg|Eicosanoid synthesis
}}

== See also ==
* [[Prostanoid]]
* [[12-Hydroxyheptadecatrienoic acid]]

== References ==
{{reflist}}

== Further reading ==
{{refbegin | 2}}
* {{Cite journal |vauthors=Shen RF, Tai HH |year=1998 |title=Thromboxanes: synthase and receptors |journal=Journal of Biomedical Science |volume=5 |issue=3 |pages=153–172 |doi=10.1007/BF02253465 |pmid=9678486}}
* {{Cite journal |vauthors=Smith G, Stubbins MJ, Harries LW, Wolf CR |date=December 1998 |title=Molecular genetics of the human cytochrome P450 monooxygenase superfamily |journal=Xenobiotica; the Fate of Foreign Compounds in Biological Systems |volume=28 |issue=12 |pages=1129–1165 |doi=10.1080/004982598238868 |pmid=9890157}}
* {{Cite journal |vauthors=Wang LH, Kulmacz RJ |date=August 2002 |title=Thromboxane synthase: structure and function of protein and gene |journal=Prostaglandins & Other Lipid Mediators |volume=68-69 |pages=409–422 |doi=10.1016/S0090-6980(02)00045-X |pmid=12432933}}
* {{Cite journal |display-authors=6 |vauthors=Itoh S, Yanagimoto T, Tagawa S, Hashimoto H, Kitamura R, Nakajima Y, Okochi T, Fujimoto S, Uchino J, Kamataki T |date=March 1992 |title=Genomic organization of human fetal specific P-450IIIA7 (cytochrome P-450HFLa)-related gene(s) and interaction of transcriptional regulatory factor with its DNA element in the 5' flanking region |journal=Biochimica et Biophysica Acta |volume=1130 |issue=2 |pages=133–138 |doi=10.1016/0167-4781(92)90520-a |pmid=1562592}}
* {{Cite journal |vauthors=Yokoyama C, Miyata A, Ihara H, Ullrich V, Tanabe T |date=August 1991 |title=Molecular cloning of human platelet thromboxane A synthase |journal=Biochemical and Biophysical Research Communications |volume=178 |issue=3 |pages=1479–1484 |doi=10.1016/0006-291X(91)91060-P |pmid=1714723}}
* {{Cite journal |vauthors=Ohashi K, Ruan KH, Kulmacz RJ, Wu KK, Wang LH |date=January 1992 |title=Primary structure of human thromboxane synthase determined from the cDNA sequence |journal=The Journal of Biological Chemistry |volume=267 |issue=2 |pages=789–793 |doi=10.1016/S0021-9258(18)48353-6 |pmid=1730669 |doi-access=free}}
* {{Cite journal |vauthors=Jones DA, Fitzpatrick FA, Malcolm KC |date=October 1991 |title=Thromboxane A2 synthesis in human erythroleukemia cells |journal=Biochemical and Biophysical Research Communications |volume=180 |issue=1 |pages=8–14 |doi=10.1016/S0006-291X(05)81247-1 |pmid=1930241}}
* {{Cite journal |vauthors=Wang LH, Ohashi K, Wu KK |date=May 1991 |title=Isolation of partial complementary DNA encoding human thromboxane synthase |journal=Biochemical and Biophysical Research Communications |volume=177 |issue=1 |pages=286–291 |doi=10.1016/0006-291X(91)91980-Q |pmid=2043115}}
* {{Cite journal |vauthors=Nüsing R, Schneider-Voss S, Ullrich V |date=August 1990 |title=Immunoaffinity purification of human thromboxane synthase |journal=Archives of Biochemistry and Biophysics |volume=280 |issue=2 |pages=325–330 |doi=10.1016/0003-9861(90)90337-X |pmid=2195994}}
* {{Cite journal |vauthors=Mestel F, Oetliker O, Beck E, Felix R, Imbach P, Wagner HP |date=January 1980 |title=Severe bleeding associated with defective thromboxane synthetase |journal=Lancet |volume=1 |issue=8160 |pages=157 |doi=10.1016/S0140-6736(80)90642-X |pmid=6101498 |s2cid=29803926}}
* {{Cite journal |vauthors=Miyata A, Yokoyama C, Ihara H, Bandoh S, Takeda O, Takahashi E, Tanabe T |date=September 1994 |title=Characterization of the human gene (TBXAS1) encoding thromboxane synthase |journal=European Journal of Biochemistry |volume=224 |issue=2 |pages=273–279 |doi=10.1111/j.1432-1033.1994.00273.x |pmid=7925341 |doi-access=free}}
* {{Cite journal |vauthors=Wang LH, Tazawa R, Lang AQ, Wu KK |date=December 1994 |title=Alternate splicing of human thromboxane synthase mRNA |journal=Archives of Biochemistry and Biophysics |volume=315 |issue=2 |pages=273–278 |doi=10.1006/abbi.1994.1500 |pmid=7986068}}
* {{Cite journal |vauthors=Maruyama K, Sugano S |date=January 1994 |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides |journal=Gene |volume=138 |issue=1–2 |pages=171–174 |doi=10.1016/0378-1119(94)90802-8 |pmid=8125298}}
* {{Cite journal |vauthors=Lee KD, Baek SJ, Shen RF |date=May 1994 |title=Cloning and characterization of the human thromboxane synthase gene promoter |journal=Biochemical and Biophysical Research Communications |volume=201 |issue=1 |pages=379–387 |doi=10.1006/bbrc.1994.1712 |pmid=8198598}}
* {{Cite journal |vauthors=Chase MB, Baek SJ, Purtell DC, Schwartz S, Shen RF |date=June 1993 |title=Mapping of the human thromboxane synthase gene (TBXAS1) to chromosome 7q34-q35 by two-color fluorescence in situ hybridization |journal=Genomics |volume=16 |issue=3 |pages=771–773 |doi=10.1006/geno.1993.1264 |pmid=8325653}}
* {{Cite journal |vauthors=Ruan KH, Wang LH, Wu KK, Kulmacz RJ |date=September 1993 |title=Amino-terminal topology of thromboxane synthase in the endoplasmic reticulum |journal=The Journal of Biological Chemistry |volume=268 |issue=26 |pages=19483–19490 |doi=10.1016/S0021-9258(19)36541-X |pmid=8366093 |doi-access=free}}
* {{Cite journal |vauthors=Tazawa R, Green ED, Ohashi K, Wu KK, Wang LH |date=October 1996 |title=Characterization of the complete genomic structure of human thromboxane synthase gene and functional analysis of its promoter |journal=Archives of Biochemistry and Biophysics |volume=334 |issue=2 |pages=349–356 |doi=10.1006/abbi.1996.0464 |pmid=8900410}}
* {{Cite journal |vauthors=Baek SJ, Lee KD, Shen RF |date=September 1996 |title=Genomic structure and polymorphism of the human thromboxane synthase-encoding gene |journal=Gene |volume=173 |issue=2 |pages=251–256 |doi=10.1016/0378-1119(95)00881-0 |pmid=8964509}}
* {{Cite journal |vauthors=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S |date=October 1997 |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library |journal=Gene |volume=200 |issue=1–2 |pages=149–156 |doi=10.1016/S0378-1119(97)00411-3 |pmid=9373149}}
{{refend}}

== External links ==
* {{MeshName|Thromboxane-A+Synthase}}

{{Cytochrome P450}}
{{Metabolism of complex lipids}}
{{Prostanoid signaling modulators}}
{{Intramolecular oxidoreductases}}
{{Enzymes}}
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[[Category:EC 5.3]]