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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====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" /> | ||