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=Chorismate Mutase=
=Chorismate Mutase=
==Introduction==
==Introduction==
The gene Rv1885c from ''Mycobacteriam tuberculosis'' encodes for a non-functional chorismate mutase (*MtCM)<ref name="pizza" />. This non-functional mutase has a 33-amino-acid cleavable sequence <ref name="pizza" />.  It is a vital enzyme in the shikimate pathway, which allows for the synthesis of tryptophan, tyrosinem and phenylalanine <ref name="pizza" />.  Chorismate mutase provides a 2x10<sup>6</sup> fold increase in the rate of reacrion in comparision to the uncatalyzed reaction <ref > P.D. Lyne, A.J. Mulholland, W.G. Richards. Insights into chorismate mutase catalysis from a combined qm/mm simulation of the enzyme reaction. Journal of the American Chemistry Society. 1995 117(45):11345-11350</ref>.  Chorismate mutase only occurs in bacteria, higher plants, and fungi, due to the fact that the shikimate pathway is only found in these organisms <ref name="strat" />. In ''Escherichia coli'', chorismate mutase has a periplasmic destination<ref name="pizza" />. In ''M. tuberculosis'' there is in abscence of a periplasmic compartment for chorismate mutase, so it secretes into the culture filtrate of ''M. tuberculosis''<ref name="pizza" />. It is believed that a pseudoperiplasmic space might exist in ''M. tuberculosis''<ref name="pizza" />. Rv1885c is synthesized along with the 33-amino-acid terminal sequence, which when expressed with ''Escherichia coli'', is cleaved off the mature protein<ref name="pizza"  />. Chorismate mutase is the only example of an enzyme catalyzing a percyclic reaction <ref name="strat"> PMID:10960481 </ref>
The gene Rv1885c from ''Mycobacteria tuberculosis'' encodes for a non-functional chorismate mutase (*MtCM).<ref name="pizza" />  This non-functional mutase has a 33-amino-acid cleavable sequence.<ref name="pizza" /> Chorismate mutase is a vital enzyme in the shikimate pathway, which allows for the synthesis of tryptophan, tyrosine, and phenylalanine.<ref name="pizza" /> This protein acts at the first branch point of the shikimate pathway, making it a regulating step in the conversion of prephenate from chorismate.<ref name="CMW2"> PMID:11481470 </ref>  Since chorismate mutase catalyzes a claisen rearrangement it can be considered an isomerase since it catalyzes rearrangements of isomers.  Chorismate mutase provides a 2x10<sup>6</sup> fold increase in the rate of reaction in comparision to the uncatalyzed reaction.<ref > P.D. Lyne, A.J. Mulholland, W.G. Richards. Insights into chorismate mutase catalysis from a combined qm/mm simulation of the enzyme reaction. Journal of the American Chemistry Society. 1995 117(45):11345-11350 </ref>
 
Chorismate mutase only occurs in bacteria, higher plants, and fungi, due to the fact that the shikimate pathway is only found in these organisms.<ref name="strat" />  In ''Escherichia coli'', chorismate mutase has a periplasmic destination.<ref name="pizza" />  In ''M. tuberculosis'' there is in abscence of a periplasmic compartment for chorismate mutase, so it secretes into the culture filtrate of ''M. tuberculosis''.<ref name="pizza" />  It is believed that a pseudoperiplasmic space might exist in ''M. tuberculosis''.<ref name="pizza" />
 
The N-terminal sequence of ''M. tuberculosis'' chorismate mutase is able to  function in ''E. coli'' which suggests that ''M. tuberulosis'' chorismate mutase belongs to the AroQ class of the chorismate mutases.<ref name="CMArt2"> PMID:15737998 </ref>
 
Rv1885c is synthesized along with the 33-amino-acid terminal sequence, which when expressed with ''E. coli'', is cleaved off the mature protein.<ref name="pizza"  />  Chorismate mutase is the only example of an enzyme catalyzing a percyclic reaction.<ref name="strat"> PMID:10960481 </ref>


==Structure==
==Structure==
<Structure load='2f6l' size='300' frame='true' align='left' caption='Insert caption here' scene='Sandbox_Reserved_325/Chainbows/1' />
<Structure load='2f6l' size='300' frame='true' align='left' caption='Chorismate Mutase' scene='Sandbox_Reserved_325/Chainbows/1' />
 
Chorismate mutase is a homodimer which has a predominantly α-helical structure.<ref name="pizza" />  There are 10 α-helices spread across the two monomers of chorismate mutase.<ref name="pizza" />  Approximately 86% of the amino acid residues are in the α-helical formations.<ref name="pizza" />  The α-helical structure of *MtCM are similar to the chorismate mutases of ''S. cerevisae'' and ''E. coli''.<ref name="pizza" />  It holds its dimeric state in a protein concentration as low as 5 nM.<ref name="pizza" /> There are no β-sheets present in chorismate mutase.<ref name="CMArt2" />  


has dimeric state in concentrations as low as 5nM
Chorismate has an active site, which is used for the catalysis of the shikimate pathway.<ref name="pizza" />  The <scene name='Sandbox_Reserved_325/Active_site/1'>active site</scene> is made of Arg <sub>49</sub>,Lys <sub>60</sub>, Arg <sub>72</sub>, Thr <sub>105</sub>, Glu <sub>109</sub>, and Arg <sub>134</sub>.<ref name="pizza" /> This active site exists through electrostatic interactions with chorismate and hydrogen bonding between the amino acids <ref name="CMArt2" />.  The active site forms within a single chain.<ref name="pizza" /> The active site can form without any help from the second half of the dimer.<ref name="pizza" />
has an all alpha helical structure
active site forms in single chain without help from second half of dimer
active site is critical for catalysis. it is made up of Arg 49, Lys 60, Arg 72, Thr 105, Glu 109, and Arg 134
not regulated by aromatic amino acids, which is supported by the fact that there are no allosteric regulatory sites.
  alpha helicalstruc similar to e coli CM and S. cerevisae CM
quaternary structure determined by molecular sieve chromatography
MW 36,00 Da
based on monomeric mass of 18,474 Da clearly shows it is dimeric
All naturally occuring CMS function as dimers or trimers
works best at 37 deg C ph 7.5
166 redidue mature CM forms all alpha helix strruc
10 aplha helix
86% of residues in alpha helicies
1 S-S bond between Cys 160 and cys 193
ph tolerance from 4.0 to 7.5 for optimal activity
active site exists though hydrogen bonding and electrostatic interactions with chorismate


The molecular weight of *MtCM is 36,000 Da.<ref name="pizza" />  Based on that each monomeric subunit has a molecular weight of 18,474 Da, the molecular weight of the molecule supports the theory that it is a dimer.<ref name="pizza" />  This is also supported by that all chorismate mutases that occur naturally are either trimers or dimers.<ref name="pizza" /> ''M. tuberculosis'' chorismate mutase is similar to the chorismate mutases of yeast and ''E. coli'' in the regards that they all are homodimers.<ref name="CMArt2" />
There are no allosteric regulatory sites on *MtCM, which supports the theory that chorismate mutase is not regulated by the aromatic amino acids that are the products of the shikimate pathway.<ref name="pizza" />
There is one <scene name='Sandbox_Reserved_325/Disulfide/1'>disulfide bridge</scene> in chorismate mutase.<ref name="pizza" /> It is between Cys <sub>160</sub> and Cys <sub>193</sub>.<ref name="pizza" />
*MtCM has a 33-amino-acid cleavable sequence.<ref name="pizza" /> The N-terminal sequence of ''M. tuberculosis'' chorismate mutase is able to  function in ''E. coli'' which suggests that ''M. tuberulosis'' chorismate mutase belongs to the AroQ class of the chorismate mutases.<ref name="CMArt2" />  Another factor that suggests that ''M. tuberculosis'' chorismate mutase belongs to the AroQ class of chorismate mutases is that it has has a predominantly α-helical structure, which is similar to the chorismate mutases of ''E. coli'' and yeast, which also belong to the AroQ group of chorismate mutases.<ref name="CMArt2" />


here is a <scene name='Sandbox_Reserved_325/Disulfide/1'>disulfide bridge</scene>
==Mechanism==
==Mechanism==
in michaelis menten kinetics it has Km of 0.5 ± 0.05 mM and Kcat of 60 s<sup>-1 </sup>
in Michaelis-Menten kinetics chorismate mutase has Km of 0.5 ± 0.05 mM and Kcat of 60 s<sup>-1 </sup>.<ref name="pizza" />
Chorismate mutase is an essential enzyme in the shikimate pathway <ref name="pizza"> PMID:17146044 </ref>. This pathway allows for the biosynthesis of aromatic amino acids tryptophan, tyrosine, and phenylalanine <ref name="pizza" />. The production of tyrosine and phenylalanine is achieved by what is called a Claisen arrangement. first converting chorismate to prephenate.  Prephenate then reacts with prephenate dehydratase and prephenate dehydrogenase which forms phenylpyruvate and hydroxyphenylpyruvate.  After this occursm aminotransferase converts hydroxy-phenylpyruvate and phenylpyruvate to phenylalanine and tyrosine.  Chorismate mutase provides a 2x10<sup>6</sup> fold increase in the rate of reaction, in comparison to the uncatalyzed reaction <ref > P.D. Lyne, A.J. Mulholland, W.G. Richards. Insights into chorismate mutase catalysis from a combined qm/mm simulation of the enzyme reaction. Journal of the American Chemistry Society. 1995 117(45):11345-11350</ref>. It is the only example of an enzyme catalyzing a percyclic reaction <ref name="strat"> PMID:10960481 </ref>
 
Chorismate mutase is an essential enzyme in the shikimate pathway.<ref name="pizza"> PMID:17146044 </ref>  This pathway allows for the biosynthesis of aromatic amino acids tryptophan, tyrosine, and phenylalanine.<ref name="pizza" />  The production of tyrosine and phenylalanine is achieved by what is called a Claisen rearrangement.<ref name="pizza" /> First by converting chorismate to prephenate.<ref name="pizza" /> Prephenate then reacts with prephenate dehydratase and prephenate dehydrogenase which forms phenylpyruvate and hydroxyphenylpyruvate.<ref name="pizza" /> After this occurs, aminotransferase converts hydroxy-phenylpyruvate and phenylpyruvate to phenylalanine and tyrosine.<ref name="pizza" /> Chorismate mutase provides a 2x10<sup>6</sup> fold increase in the rate of reaction, in comparison to the uncatalyzed reaction.<ref> P.D. Lyne, A.J. Mulholland, W.G. Richards. Insights into chorismate mutase catalysis from a combined qm/mm simulation of the enzyme reaction. Journal of the American Chemistry Society. 1995 117(45):11345-11350 </ref>  It is the only example of an enzyme catalyzing a percyclic reaction. <ref name="strat"> PMID:10960481 </ref>
 
Chorismate mutase has optimal performance at 37 degrees Celcius and at pH 7.5, but it can still optimally a pH range from pH 4.0 to 7.5 <ref name="pizza" />
 


==Chorismate Mutase and Tuberculosis==
==Chorismate Mutase and Tuberculosis==
may be involved in pathogenesis.
Tuberculosis has developed various mechanisms to survive in hostile environments.<ref name="CMArt2" />  The emergence of multi-drug resistant tuberculosis and other diseases such as AIDS compound the problem of how to treat tuberculosis.<ref name="CMArt2" />  Chorismate mutase may be involved in pathogenesis.<ref name="pizza" />  Researchers are currently looking into new antimicrobial drugs for diseases such as tuberculosis.<ref name="pizza" />  These new drugs would take advantage of the fact that chorismate mutase and the shikimate pathway do not occur in humans, to target and treat various forms of tuberculosis.<ref name="pizza" />  Chorismate mustase is believed to have a role in the survival of ''M. tuberculosis''.<ref name="CMArt2" />  Two genes in ''M. tuberculosis'', Rv0948c and Rv1885c code for chorismate mutase.<ref name="CMArt2" /> These help support ''M. tuberculosis'' when aromatic amino acids, such as tryptophan, tyrosine, and phenylalanine, are deficient.<ref name="CMArt2" />  Some researchers have proposed that a proline-rich section of ''M. tuberculosis'' chorismate mutase might be responsible for it binding to the surface receptors on the host cell marcophages
one can take advantage of non-occurance of CMs in humans to try to develop antimicrobial drugs for human pathogens such as tb
.<ref name="CMW1"> PMID: 16752890 </ref>
no func in non-shik pathways like those of macrophages of mammals. target this for TB infection
 
ph is 4.5 om tb macrophage enviro. acidic.
==References==
==References==
<references/>
<references/>
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