YfdX

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==Your Heading Here (maybe something like 'Structure')== YfdX linkage to Typhoid Fever
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<StructureSection load='6A09' caption='YfdX (PDB code [[6a09]])' scene=''>
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<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
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This is a default text for your page '''YfdX'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.
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You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.
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== Introduction == YfdX is a family protein that is encoded by several pathogenic bacteria such as Salmonella and E. coli. Particularly YfdX is encoded in Salmonella enterica serovar Typhi that causes a fatal disease called Typhoid Fever. Salmonella is a gram-negative bacterium that is excellent at infecting living organisms. They are fast replicating, mobile, and are armed with needle completes that can penetrate cells in the human digestive tract (“Salmonella Are Armed, Agile and Primed for Invasion.”). When Salmonella invade the epithelial cells lining the intestines it can survive and replicate inside membrane bond compartments called vacuoles (“Salmonella Are Armed, Agile and Primed for Invasion.”) The salmonella moves from cells to cell with a flagellum with in the intestine (“Salmonella Are Armed, Agile and Primed for Invasion.”).
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== Introduction ==
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<scene name='81/814058/Yfdx/6'>YfdX</scene> is a family protein that is encoded by several pathogenic bacteria such as ''Salmonella'' and ''E. coli.'' Particularly YfdX is encoded in ''Salmonella enterica serovar typhi'' that causes a fatal disease called Typhoid Fever. Typhoid fever is a disease that can be spread by contaminated food or water and causes symptoms of lasting fever, weakness, stomach pains, headache, loss of appetite, constipation and sometimes internal bleeding <ref name=chong>PMID: 28656014</ref>. ''S. typhi'' it is an etiologic agent, the microbial toxin that causes disease in humans.'' S typhi'' is a human restricted disease however, some higher primates can be infected experimentally <ref name=chong/>. ''S. typhi'' is 90% homologous to ''S typhimurium'' but ''S. typhimurium'' can infect both humans and primates <ref name=chong/>. ''S. typhi'' is unique for a couple of small reasons. First ''S. typhi'' has a large region specific to it, ''Salmonella'' pathogenicity island 7 that encodes the viaB locus <ref name=chong/>. This locus consists of ten genes related to the biosynthesis and export of Vi polysaccharides capsule <ref name=chong/>. This involves circumventing Toll-Like Receptors mediated immune surveillance <ref name=chong/>. Another area that is specific to ''S. typhi'' is a small island with a locus encoding five genes <ref name=chong/>. These genes include three typhoid toxins components, a bacteriophage muramidase homolog controlling typhoid toxin secretions and a small gene of unknown function <ref name=chong/>.
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== Disease == Typhoid fever is a disease that can be spread by contaminated food or water and causes symptoms of lasting fever, weakness, stomach pains, headache, loss of appetite, constipation and sometimes internal bleeding (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017). S. Typhi it is an etiologic agent, the microbial toxin that causes disease in humans. S Typhi is a human restricted disease however, some higher primates can be infected experimentally (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017)). S. Typhi is 90% homologous to S Typhimurium but S. Typhimurium can infect both humans and primates (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017)). S. Typhi is unique for a couple of small reasons. First S. Typhi has a large region specific to it, Salmonella pathogenicity island 7 that encodes the viaB locus (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017)). This locus consists of ten genes related to the biosynthesis and export of Vi polysaccharides capsule (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017)). This involves circumventing Toll-Like Receptors mediated immune surveillance (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017)). Another area that is specific to S. Typhi is a small island with a locus encoding five genes (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017)). These genes include three typhoid toxins components, a bacteriophage muramidase homolog controlling typhoid toxin secretions and a small gene of unknown function (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017)).
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== Toxicity of Typhoid Toxin ==
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When a person is infected with typhoid it is spread through the intestinal tract the bloodstream. The reason this disease is so toxic is from <scene name='81/814058/Typhoid_toxin/9'>typhoid toxin</scene>, a unique factor produced by S. typhi <ref name=chong/>. The toxin is a different type <scene name='81/814058/Ab_toxin/1'>AB toxin</scene> which means it is made up of one A subunit and 1 B subunit <ref name=chong/>. Typhoid toxin has 2 types of A subunits and 1 B subunit. The A subunits are <scene name='81/814058/Ptla/1'>PltA</scene> and <scene name='81/814058/Cdtb/1'>CdtB</scene>, and the B subunit is <scene name='81/814058/Ptlb/1'>PltB</scene> <ref name=chong/>. Research has shown that the toxin is made up of 1 molecule of each PltA and CdtB with <scene name='81/814058/5_molecules_of_ptlb/1'>5 molecules of PltB</scene> <ref name=chong/>. The combination of Typhoid toxin subunits is what leads it to be very toxic. The typhoid toxin can bind to a wide variety of cells by attaching to certain types of proteins presents on the surface of many cells <ref name=chong/>. These proteins have a specific carbohydrate called glycan and typhoid toxin binds very well to this. Research has shown if there is a reduction in glycans leads to a reduction in typhoid toxin binding <ref name=chong/>. The PltB is thought to be responsible to the binding of the glycans because it has a pocket for the binding of glycans. Typhoid toxin primarily targets immune cells and the central nervous system, leading to the reason why the symptoms are so severe <ref name=chong/>.
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== Toxicity of Typhoid Toxin == When a person is infected with typhoid it is spread through the intestinal tract the bloodstream. The reason this disease is so toxic is from typhoid toxin, a unique factor produced by S. typhi (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017)). The toxin is a different type AB toxin which means it is made up of one A subunit and 1 B subunit (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017)). Typhoid toxin has 2 types of A subunits and 1 B subunit. The A subunits are PltA and CdtB, and the B subunit is PltB (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017)). Research has shown that the toxin is made up of 1 molecule of each PltA and CdtB with 5 molecules of PltB (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017)). The combination of Typhoid toxin subunits is what leads it to be very toxic. The typhoid toxin can bind to a wide variety of cells by attaching to certain types of proteins presents on the surface of many cells (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017)). These proteins have a specific carbohydrate called glycan and typhoid toxin binds very well to this. Research has shown if there is a reduction in glycans leads to a reduction in typhoid toxin binding (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017)). The PltB is thought to be responsible to the binding of the glycans because it has a pocket for the binding of glycans. Typhoid toxin primarily targets immune cells and the central nervous system, leading to the reason why the symptoms are so severe (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017)).
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== Structural highlights of Typhoid Toxin ==
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The two A subunits are enzymatic, and this is important because it shows molecular evolution and how these two separate toxins fused together and became one <ref name=chong/>. Thus, leading to its incredible virulence because it’s becoming more complex and harder for organisms to deal with the infection. A similar toxin that has the similar structure of the two A enzymatic subunits is Anthrax toxin however, it has A subunits from two individual toxin complexes that have one A subunit <ref name=chong/>. This means that the typhoid toxin is the first to be discovered of its kind. Along with the two enzymatic subunits becoming one it’s trafficking mechanism is also different from typical AB toxin <ref name=chong/>. Typhoid toxin is exclusively produced in the intracellular infected cells, which in most cases is a vacuole in the epithelial lining of the intestines, leads to believe that the infected cells are apart of the export trafficking of typhoid toxin to extracellular milieu <ref name=chong/>.This type of mechanism allows the typhoid toxin to be extremely virulent and spread so quickly.
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== Structural highlights of Typhoid Toxin == The two A subunits are enzymatic, and this is important because it shows molecular evolution and how these two separate toxins fused together and became one (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017)). Thus, leading to its incredible virulence because it’s becoming more complex and harder for organisms to deal with the infection. A similar toxin that has the similar structure of the two A enzymatic subunits is Anthrax toxin however, it has A subunits from two individual toxin complexes that have one A subunit (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017)). This means that the typhoid toxin is the first to be discovered of its kind. Along with the two enzymatic subunits becoming one it’s trafficking mechanism is also different from typical AB toxin (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017)). Typhoid toxin is exclusively produced in the intracellular infected cells, which in most cases is a vacuole in the epithelial lining of the intestines, leads to believe that the infected cells are apart of the export trafficking of typhoid toxin to extracellular milieu (Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017)). This type of mechanism allows the typhoid toxin to be extremely virulent and spread so quickly.
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== Where YfdX Comes From ==
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YfdX is a product of yfdXWUVE operon and is said to be under the control of <scene name='81/814058/Evga/1'>EvgA</scene>. EvgA come from the EvgAS. EvgAS is a two-component system that modulates drug resistance of E. coli by regulating the expression of the drug transporters <ref name=nishino>PMID: 12670992</ref>. EvgA research has shown that the toxin is made up of 1 molecule of each PltA and CdtB with 5 molecules of PltB <ref name=nishino/>. EvgA is the response regulator and modulates the expression of emrKY, which encodes a bile salt specific exporter and yhiUV which encodes a multidrug exporter <ref name=nishino/> However, over expression of EvgA gives potential an acid resistant phenotype <ref name=nishino/>. The acid resistance is somewhat got in rid of by the deletion of ydeP, yhiE, or ydeO, genes induced by EvgA overexpression <ref name=nishino/>. Along with EvgA most likely planning major role in tolerance to outside forces the yfdXWUVE operon does as well. The yfdXWUVE operon appears to encode proteins that enhance the ability of Salmonella to survive under acidic conditions <ref name=cory>PMID: 18245280</ref>.
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== Where YfdX Comes From == YfdX is a product of yfdXWUVE operon and is said to be under the control of EvgA. EvgA come from the EvgAS. EvgAS is a two-component system that modulates drug resistance of E. coli by regulating the expression of the drug transporters (Nishino, K., Inazumi, Y., & Yamaguchi, A. (2003)). EvgA research has shown that the toxin is made up of 1 molecule of each PltA and CdtB with 5 molecules of PltB (Nishino, K., Inazumi, Y., & Yamaguchi, A. (2003)). EvgA is the response regulator and modulates the expression of emrKY, which encodes a bile salt specific exporter and yhiUV which encodes a multidrug exporter (Nishino, K., Inazumi, Y., & Yamaguchi, A. (2003)). However, over expression of EvgA gives potential an acid resistant phenotype (Nishino, K., Inazumi, Y., & Yamaguchi, A. (2003)). The acid resistance is somewhat got in rid of by the deletion of ydeP, yhiE, or ydeO, genes induced by EvgA overexpression (Nishino, K., Inazumi, Y., & Yamaguchi, A. (2003)). Along with EvgA most likely planning major role in tolerance to outside forces the yfdXWUVE operon does as well. The yfdXWUVE operon appears to encode proteins that enhance the ability of Salmonella to survive under acidic conditions (Toyota, Cory G., et al).
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== Structural highlights of YfdX ==
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YfdX weighs around 42kDa and is suggested to be a dimer in solution <ref name=lee>PMID: 30692978</ref>. It has 10-186 residues from its total 199 amino acids <ref name=lee/>. It is composed of six α-helices, one 310-helix, and three β-strands. These arrange into three subdomains: a four helical bundle, and antiparallel β-sheet, and two helical bundles <ref name=lee/>. The importance of YfdX is that it plays a major role in Salmonella susceptibility to two β-lactam antibiotics, penicillin G and carbenicillin <ref name=lee/>). Without the YfdX protein the Salmonella virulence was enhanced. One specific type of YfdX protein is <scene name='81/814058/Sty3178/3'>STY3178</scene>. This comes from a multidrug resistant strain of Salmonella Typhi <ref name=sara>PMID: 26892637</ref>. The multidrug resistant strains of S. Typhi. have been reported to be resistant to antibiotics such as ciprofloxacin, rifampin, ampicillin, etc. <ref name=sara/>. The structure of STY3178 was found in a study to be a well folded and predominately α-helical protein containing β-sheets elements <ref name=sara/>. STY3178 is existing in a trimetric oligomerization state in solution. <ref name=sara/>. Its ability to bind to antibiotics was found to demonstrate that different small antibiotics are capable of binding to STY3178 such as ciprofloxacin, rifampin, and ampicillin <ref name=sara/>. Studies show that the binding of ciprofloxacin binding is stronger than rifampin flowed by ampicillin <ref name=sara/>. This is important to note because if a patient were to come down with typhoid fever and had the STY3178 protein it would be best to see which antibiotic would bind best to the STY3178 protein.
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== Structural highlights of YfdX == YfdX weighs around 42kDa and is suggested to be a dimer in solution (Lee, Hye Seon, et al.). It has 10-186 residues from its total 199 amino acids (Lee, Hye Seon, et al.). It is composed of six α-helices, one 310-helix, and three β-strands. These arrange into three subdomains: a four helical bundle, and antiparallel β-sheet, and two helical bundles (Lee, Hye Seon, et al.). The importance of YfdX is that it plays a major role in Salmonella susceptibility to two β-lactam antibiotics, penicillin G and carbenicillin (Lee, Hye Seon, et al.). Without the YfdX protein the Salmonella virulence was enhanced. One specific type of YfdX protein is STY3178. This comes from a multidrug resistant strain of Salmonella Typhi (Saha, P., Manna, C., Das, S., & Ghosh, M. (2016)). The multidrug resistant strains of S. Typhi. have been reported to be resistant to antibiotics such as ciprofloxacin, rifampin, ampicillin, etc. (Saha, P., Manna, C., Das, S., & Ghosh, M. (2016)). The structure of STY3178 was found in a study to be a well folded and predominately α-helical protein containing β-sheets elements (Saha, P., Manna, C., Das, S., & Ghosh, M. (2016)). STY3178 is existing in a trimetric oligomerization state in solution. (Saha, P., Manna, C., Das, S., & Ghosh, M. (2016)). Its ability to bind to antibiotics was found to demonstrate that different small antibiotics are capable of binding to STY3178 such as ciprofloxacin, rifampin, and ampicillin (Saha, P., Manna, C., Das, S., & Ghosh, M. (2016)). Studies show that the binding of ciprofloxacin binding is stronger than rifampin flowed by ampicillin (Saha, P., Manna, C., Das, S., & Ghosh, M. (2016)). This is important to note because if a patient were to come down with typhoid fever and had the STY3178 protein it would be best to see which antibiotic would bind best to the STY3178 protein.
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== Summary ==
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Typhoid Fever is one of the worst infections to get for it is fatal and is damaging to the body. It is not like most bacterial infections for it as some unique features to it that make it special. It is human- restricted and has a unique Typhoid Toxin with an atypical AB toxin structure, one that has been yet to be seen by any other bacteria. Its two enzymatic A subunits most likely contribute to why it is so virulent. Along with what makes typhoid fever such a harsh disease the protein YfdX is the protein that makes that makes a strain of Salmonella, S. Typhi. YfdX is a product of yfdXWUVE operon which helps the S. Typhi resists acidic conditions. Along with EvgA that controls the YfdX protein. Evg is the response regulator and modulates which encodes a bile salt specific exporter and encodes a multidrug exporter. Lastly the YfdX specific protein STY3178 is present in some multidrug resistant strains of S. Typhi. This gene was specifically looked at to show that it does allow binding of antibiotics. This is important because a multidrug resistant S. Typhi is potentially dangerous and medical professionals need to know what antibiotic to use in a case of Typhoid Fever.
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== Summary == Typhoid Fever is one of the worst infections to get for it is fatal and is damaging to the body. It is not like most bacterial infections for it as some unique features to it that make it special. It is human- restricted and has a unique Typhoid Toxin with an atypical AB toxin structure, one that has been yet to be seen by any other bacteria. Its two enzymatic A subunits most likely contribute to why it is so virulent. Along with what makes typhoid fever such a harsh disease the protein YfdX is the protein that makes that makes a strain of Salmonella, S. Typhi. YfdX is a product of yfdXWUVE operon which helps the S. Typhi resists acidic conditions. Along with EvgA that controls the YfdX protein. Evg is the response regulator and modulates which encodes a bile salt specific exporter and encodes a multidrug exporter. Lastly the YfdX specific protein STY3178 is present in some multidrug resistant strains of S. Typhi. This gene was specifically looked at to show that it does allow binding of antibiotics. This is important because a multidrug resistant S. Typhi is potentially dangerous and medical professionals need to know what antibiotic to use in a case of Typhoid Fever.
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==3D structures of YfdX==
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Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
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[[6a09]], [[6a02]], [[6a07]] – YfdX – ''Salmonella typhi''<br />
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[[6uxt]] – YfdX – ''Shigeella flexneri''<br />
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[[3dza]] – YfdX – ''Klebsiella pneumoniae''<br />
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</StructureSection>
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== References ==
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<references/>
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
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[[Category:Topic Page]]
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</StructureSection>
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== References ==
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Saha, P. et al. Antibiotic binding of STY3178, a yfdX protein from Salmonella Typhi. Sci. Rep. 6, 21305; doi: 10.1038/srep21305 (2016).
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Chong, A., Lee, S., Yang, Y. A., & Song, J. (2017). The Role of Typhoid Toxin in Salmonella Typhi Virulence
. The Yale journal of biology and medicine, 90(2), 283-290.
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“Salmonella Are Armed, Agile and Primed for Invasion.” National Institutes of Health, U.S. Department of Health and Human Services, 6 July 2015, Nishino, K., Inazumi, Y., & Yamaguchi, A. (2003). Global analysis of genes regulated by EvgA of the two-component regulatory system in Escherichia coli. Journal of bacteriology, 185(8), 2667-72.
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Toyota, Cory G., et al. “Differential Substrate Specificity and Kinetic Behavior of Escherichia Coli YfdW and Oxalobacter Formigenes Formyl Coenzyme A Transferase.” Journal of Bacteriology, American Society for Microbiology Journals, 1 Apr. 2008, jb.asm.org/content/190/7/2556#skip-link.
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Lee, Hye Seon, et al. “Structural and Physiological Exploration of Salmonella Typhi YfdX Uncovers Its Dual Function in Bacterial Antibiotic Stress and Virulence.” Frontiers in Microbiology, Frontiers Media S.A., 14 Jan. 2019,
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Saha, P., Manna, C., Das, S., & Ghosh, M. (2016). Antibiotic binding of STY3178, a yfdX protein from Salmonella Typhi. Scientific reports, 6, 21305. doi:10.1038/srep21305 <references/>
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Current revision

YfdX (PDB code 6a09)

Drag the structure with the mouse to rotate

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 Chong A, Lee S, Yang YA, Song J. The Role of Typhoid Toxin in Salmonella Typhi Virulence. Yale J Biol Med. 2017 Jun 23;90(2):283-290. eCollection 2017 Jun. PMID:28656014
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Nishino K, Inazumi Y, Yamaguchi A. Global analysis of genes regulated by EvgA of the two-component regulatory system in Escherichia coli. J Bacteriol. 2003 Apr;185(8):2667-72. PMID:12670992
  3. ↑ Toyota CG, Berthold CL, Gruez A, Jonsson S, Lindqvist Y, Cambillau C, Richards NG. Differential substrate specificity and kinetic behavior of Escherichia coli YfdW and Oxalobacter formigenes formyl coenzyme A transferase. J Bacteriol. 2008 Apr;190(7):2556-64. Epub 2008 Feb 1. PMID:18245280 doi:10.1128/JB.01823-07
  4. ↑ 4.0 4.1 4.2 4.3 Lee HS, Lee S, Kim JS, Lee HR, Shin HC, Lee MS, Jin KS, Kim CH, Ku B, Ryu CM, Kim SJ. Structural and Physiological Exploration of Salmonella Typhi YfdX Uncovers Its Dual Function in Bacterial Antibiotic Stress and Virulence. Front Microbiol. 2019 Jan 14;9:3329. doi: 10.3389/fmicb.2018.03329. eCollection, 2018. PMID:30692978 doi:http://dx.doi.org/10.3389/fmicb.2018.03329
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Saha P, Manna C, Das S, Ghosh M. Antibiotic binding of STY3178, a yfdX protein from Salmonella Typhi. Sci Rep. 2016 Feb 19;6:21305. doi: 10.1038/srep21305. PMID:26892637 doi:http://dx.doi.org/10.1038/srep21305

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