Factor Xa: Difference between revisions
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'''Factor Xa''', along with [http://en.wikipedia.org/wiki/Factor_va factor Va], calcium, and a phospholipid membrane surface to form the [http://en.wikipedia.org/wiki/Prothrombinase prothrombinase complex], and cleave [http://en.wikipedia.org/wiki/Prothrombin prothrombin] to its active form, [http://en.wikipedia.org/wiki/Prothrombin thrombin].<ref name="Greer" /> | '''Factor Xa''', along with [http://en.wikipedia.org/wiki/Factor_va factor Va], calcium, and a phospholipid membrane surface to form the [http://en.wikipedia.org/wiki/Prothrombinase prothrombinase complex], and cleave [http://en.wikipedia.org/wiki/Prothrombin prothrombin] to its active form, [http://en.wikipedia.org/wiki/Prothrombin thrombin].<ref name="Greer" /> | ||
==Relevance== | |||
Factor Xa is inhibited by [[Apixaban]] and [[Rivaroxaban]] which are anticoagulant medications. See also [[Anticoagulants]]. | |||
==Structure== | ==Structure== | ||
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===General Serine Protease Mechanism=== | ===General Serine Protease Mechanism=== | ||
During the acylation half of the reaction His57 acts as a general base to remove a proton from Ser195, allowing it to attack the carbonyl of the peptide bond to be broken within the substrate, to yield the first tetrahedral intermediate. The negative oxygen ion of the tetrahedral intermediate is stabilized through hydrogen bonding with the oxyanion hole (Gly192 and Ser195). Asp102 stabilizes the protonated His57 through hydrogen bonding. His57 protonates the amine of the scissile bond, promoting formation of the acylenzyme and release of the N-terminal portion of the substrate. | During the acylation half of the reaction His57 acts as a general base to remove a proton from Ser195, allowing it to attack the carbonyl of the peptide bond to be broken within the substrate, to yield the first tetrahedral intermediate. The negative oxygen ion of the tetrahedral intermediate is stabilized through hydrogen bonding with the oxyanion hole (Gly192 and Ser195). Asp102 stabilizes the protonated His57 through hydrogen bonding. His57 protonates the amine of the scissile bond, promoting formation of the acylenzyme and release of the N-terminal portion of the substrate. | ||
The deacylation portion repeats the same sequence. A water molecule is deprotonated by His57 and attacks the acyl enzyme, to yielding a second tetrahedral intermediate. Again, the tetrahedral intermediate is stabilized by the oxyanion hole. Upon collapse of the tetrahedral intermediate, the C-terminal portion of the protein is released.<ref name="specificity">PMID:12475199</ref>[[Image:Serine protease mechanism.gif.png| | The deacylation portion repeats the same sequence. A water molecule is deprotonated by His57 and attacks the acyl enzyme, to yielding a second tetrahedral intermediate. Again, the tetrahedral intermediate is stabilized by the oxyanion hole. Upon collapse of the tetrahedral intermediate, the C-terminal portion of the protein is released.<ref name="specificity">PMID:12475199</ref> | ||
[[Image:Serine protease mechanism.gif.png|400px|center|'''Serine protease reaction mechanism''' <ref> www.bmolchem.wisc.edu/</ref> />]] | |||
===Controversial Mechanisms=== | ===Controversial Mechanisms=== | ||
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====Low Barrier Hydrogen Bonds==== | ====Low Barrier Hydrogen Bonds==== | ||
< | <scene name='Factor_Xa/Lbhb/1'>Possible LBHB between His57 and Asp102</scene>. The mechanism by which the transition state is stabilized has been the topic of recent debate. Some groups suggest that His57 and Asp102 form and especially strong hydrogen bond, called a [http://en.wikipedia.org/wiki/Low-barrier_hydrogen_bond low barrier hydrogen bond (LBHB)]. They hypothesize that this hydrogen bond could promote formation of the transition state by stabilizing the Asp –His association and enhancing the bascisity of His57. <ref> PMID: 7661899</ref> <ref name="Frey alone">Frey, Perry A. Strong hydrogen bonding in chymotrypsin and other serine proteases. Journal of Physical Organic Chemistry (2004), 17(6-7), 511-520. </ref> This would enhance catalysis in the first step of the reaction. Formation of a LBHB requires a ΔpKa of approximately zero and a donor-to-acceptor distance of less then 2.65 Å for a nitrogen-oxygen pair like His57 and Asp102. Unlike a standard hydrogen bond, in which the hydrogen is located on the donor atom, a hydrogen in a LBHB is located equidistant between the 2 atoms. <ref name="subang"> PMID: 16834383 </ref> In 1998 Kuhn and colleagues published a crystal structure of ''Bacillus lentus'' subtilisn, another serine proetase, with 0.78 Å resolution at pH 5.9. The structure showed a distance of approximately 2.62 Å between the His57 nitrogen and the Asp102 oxygen, suggesting a LBHB. <ref> PMID: 9753430 </ref> | ||
The mechanism by which the transition state is stabilized has been the topic of recent debate. Some groups suggest that His57 and Asp102 form and especially strong hydrogen bond, called a [http://en.wikipedia.org/wiki/Low-barrier_hydrogen_bond low barrier hydrogen bond (LBHB)]. They hypothesize that this hydrogen bond could promote formation of the transition state by stabilizing the Asp –His association and enhancing the bascisity of His57. <ref> PMID: 7661899</ref> <ref name="Frey alone">Frey, Perry A. Strong hydrogen bonding in chymotrypsin and other serine proteases. Journal of Physical Organic Chemistry (2004), 17(6-7), 511-520. </ref> This would enhance catalysis in the first step of the reaction. Formation of a LBHB requires a ΔpKa of approximately zero and a donor-to-acceptor distance of less then 2.65 Å for a nitrogen-oxygen pair like His57 and Asp102. Unlike a standard hydrogen bond, in which the hydrogen is located on the donor atom, a hydrogen in a LBHB is located equidistant between the 2 atoms. <ref name="subang"> PMID: 16834383 </ref> In 1998 Kuhn and colleagues published a crystal structure of ''Bacillus lentus'' subtilisn, another serine proetase, with 0.78 Å resolution at pH 5.9. The structure showed a distance of approximately 2.62 Å between the His57 nitrogen and the Asp102 oxygen, suggesting a LBHB. <ref> PMID: 9753430 </ref> | |||
A more recent crystal structure of α-Lytic protease, published in 2006 with 0.82 Å resolution argues against both the his flip mechanism and the presence of a LBHB between His57 and Asp102 (2.755 Å in this structure). Fuhrmann ''et al'' suggests that a LBHB may have been present in the subtilisin strucutre, it is not required for the serine protease mechanism. Instead they state that the chymotrypsin-like proteases may use a network of optimized hydrogen bonds to position the stabilize the tetrahedral intermediate and position the catalytic triad. Ser195 undergoes a shift of ~1Å upon protonation of His57 that destabilizes the His57-Ser195 H-bond. This conformation change would prevent His57 from reprotonating Ser195 leading to regeneration of the substrate.<ref name="subang" /> | A more recent crystal structure of α-Lytic protease, published in 2006 with 0.82 Å resolution argues against both the his flip mechanism and the presence of a LBHB between His57 and Asp102 (2.755 Å in this structure). Fuhrmann ''et al'' suggests that a LBHB may have been present in the subtilisin strucutre, it is not required for the serine protease mechanism. Instead they state that the chymotrypsin-like proteases may use a network of optimized hydrogen bonds to position the stabilize the tetrahedral intermediate and position the catalytic triad. Ser195 undergoes a shift of ~1Å upon protonation of His57 that destabilizes the His57-Ser195 H-bond. This conformation change would prevent His57 from reprotonating Ser195 leading to regeneration of the substrate.<ref name="subang" /> | ||