Sandbox Reserved 763: Difference between revisions
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Shikimate kinase (SK) is an enzyme which participates in the fifth step of the shikimate pathway. The functional role shikimate kinase plays in this pathway is to catalyze the ATP-dependent phosphorylation of shikimate into shikimate 3-phosphate (3-phosphoshikimate). This aids in the synthesis of chorismate, which is the precursor to aromatic amino acids and secondary metabolites. Shikimate kinase belongs to the nucleoside monophosphate (NMP) kinase family, which phosphorylates a protein leading to a functional change in the phosphorylated protein. SK is of the transferase class, which acts to transfer a functional group from the donor to acceptor molecule. The protein fold consists of 8 α-helices and 5 β-strands. The length of shikimate kinase is 173 residues and it is found in the cytoplasm. This is a subclass of α/β proteins, meaning an α/β domain exists. SK is composed of Molecule A and B, which together form the asymmetric unit, with SK functioning as a monomer. SK consists of the CORE, LID, and substrate-binding domains. ATP is the co-substrate while magnesium ion is the co-factor. The shikimate pathway is present in bacteria, fungi, higher plants, algae, and apicomplexan. This enzyme has been experimentally observed predominantly in the organism ''Mycobacterium tuberculosis'', but also in ''Helicobacter pylori'', ''Bacteroides thetaiotaomicron'', ''Campylobacter jejuni'', ''Aquifex aeolicus'', ''Coxiella burnetii'', ''Arabidopsis thaliana''. The aroK gene encodes for SK in ''Mycobacterium tuberculosis''. This enzyme is a protein target for rational drug design, which holds great potential due to shikimate kinase being absent in mammals. | Shikimate kinase (SK) is an enzyme which participates in the fifth step of the shikimate pathway. The functional role shikimate kinase plays in this pathway is to catalyze the ATP-dependent phosphorylation of shikimate into shikimate 3-phosphate (3-phosphoshikimate). This aids in the synthesis of chorismate, which is the precursor to aromatic amino acids and secondary metabolites. Shikimate kinase belongs to the nucleoside monophosphate (NMP) kinase family, which phosphorylates a protein leading to a functional change in the phosphorylated protein. SK is of the transferase class, which acts to transfer a functional group from the donor to acceptor molecule. The protein fold consists of 8 α-helices and 5 β-strands. The length of shikimate kinase is 173 residues and it is found in the cytoplasm. This is a subclass of α/β proteins, meaning an α/β domain exists. SK is composed of Molecule A and B, which together form the asymmetric unit, with SK functioning as a monomer. SK consists of the CORE, LID, and substrate-binding domains. ATP is the co-substrate while magnesium ion is the co-factor. The shikimate pathway is present in bacteria, fungi, higher plants, algae, and apicomplexan. This enzyme has been experimentally observed predominantly in the organism ''Mycobacterium tuberculosis'', but also in ''Helicobacter pylori'', ''Bacteroides thetaiotaomicron'', ''Campylobacter jejuni'', ''Aquifex aeolicus'', ''Coxiella burnetii'', ''Arabidopsis thaliana''. The ''aroK'' gene encodes for SK in ''Mycobacterium tuberculosis''. This enzyme is a protein target for rational drug design, which holds great potential due to shikimate kinase being absent in mammals. | ||
==Structure== | ==Structure== | ||
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===Inhibitors=== | ===Inhibitors=== | ||
See the section on [[#Implications or Possible Applications|Implications or Possible Applications]] | See the section on [[#Implications or Possible Applications|Implications or Possible Applications]]. | ||
==Implications or Possible Applications== | ==Implications or Possible Applications== | ||
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Studies of potential inhibitors of SK have been conducted. This is important in the identification of potential drugs against tuberculosis (TB), which is caused by the pathogen ''Mycobacterium tuberculosis.'' TB is a curable infectious disease found mainly in developing countries. Though TB is curable, 100 million people are infected annually with approximately three million resulting deaths. TB resurges as a health problem due to multi-drug resistant, extensively drug resistant, and totally-drug resistant strains of ''Mt''.<ref name="inhibitors" />Disrupting the gene encoding MtSK, ''aroK'', suggests that the shikimate pathway holds great promise for antimicrobial drug discovery.<ref name="compinhibitor" /> | Studies of potential inhibitors of SK have been conducted. This is important in the identification of potential drugs against tuberculosis (TB), which is caused by the pathogen ''Mycobacterium tuberculosis.'' TB is a curable infectious disease found mainly in developing countries. Though TB is curable, 100 million people are infected annually with approximately three million resulting deaths. TB resurges as a health problem due to multi-drug resistant, extensively drug resistant, and totally-drug resistant strains of ''Mt''.<ref name="inhibitors" />Disrupting the gene encoding MtSK, ''aroK'', suggests that the shikimate pathway holds great promise for antimicrobial drug discovery.<ref name="compinhibitor" /> | ||
===Inhibitors=== | |||
One way potential MtSK inhibitors have been studied is through molecular docking experiments. These experiments predict the conformation of a receptor-ligand complex to analyze all possible positions of the ligand to make a selection for the best position. Virtual screening was also used to identify active molecules compared to a specific protein target. These studies have been able to confirm staurosporine as a known SK inhibitor.<ref name="inhibitors" /> | One way potential MtSK inhibitors have been studied is through molecular docking experiments. These experiments predict the conformation of a receptor-ligand complex to analyze all possible positions of the ligand to make a selection for the best position. Virtual screening was also used to identify active molecules compared to a specific protein target. These studies have been able to confirm staurosporine as a known SK inhibitor.<ref name="inhibitors" /> | ||
Through docking studies, it has been found that <scene name='56/564039/Nsc162535/1'>NSC162535</scene> is a competitive inhibitor for SK.<ref name="compinhibitor" /> This inhibitor causes a shift in the SB domain due to E53 and R132 interacting instead of E53 and R57 as seen in the wild-type. The geometry of the active site is altered, leading to inhibition of SK.<ref name="compinhibitor" /> | Through docking studies, it has been found that <scene name='56/564039/Nsc162535/1'>NSC162535</scene> is a competitive inhibitor for SK.<ref name="compinhibitor" /> This inhibitor causes a shift in the SB domain due to E53 and R132 interacting instead of E53 and R57 as seen in the wild-type. The geometry of the active site is altered, leading to inhibition of SK.<ref name="compinhibitor" /> | ||
