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1vrd

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    Comparing version 17:32, 12 Mar 2013 by Admin with version 19:13, 13 May 2015 by cawprice.
    {{ template.Protein{ leadContact:"", title:"Crystal structure of Inosine-5'-monophosphate dehydrogenase (TM1347) from THERMOTOGA MARITIMA at 2.18 A resolution. To be published",site:'JCSG', status:'In PDB', date:"2005-05-18", targetid:"283208", pdbid:"1vrd", source:"Thermotoga maritima msb8", relatedPDBs:[], refids:"TM1347, 282192", molwt:"52011.54", residues:"482", isopoint:"6.37", sequence:"mkealtfddvllvpqysevlpkdvkidtrltrqiriniplvsaamdtvteaalakalareggigiihkn ltpdeqarqvsivkktengiiydpitvtpdmtvkeaidlmaeykigglpvvdeegrlvglltnrdvrfe knlskkikdlmtpreklivappdislekakeilhqhrieklplvskdnklvglitikdimsviehpnaa rdekgrllvgaavgtspetmerveklvkagvdvividtahghsrrvietlemikadypdlpvvagnvat pegtealikagadavkvgvgpgsicttrvvagvgvpqltavmecsevarkydvpiiadggirysgdivk alaagaesvmvgsifagteeapgetilyqgrkykayrgmgslgamrsgsadrygqegenkfvpegiegm vpykgtvkdvvhqlvgglrsgmgyigartikelqekavfvkitpagvkeshphdiiitkespnywvqa", method:"XRAY", numchains:"2", resolution:"2.18", rfree:"0.25759", mattcoeff:"3.80", rfactor:"0.21653", waters:"206", solcontent:"67.42", ligands:"", metals:"", model:"False", uniprot:"Q9X168", pubmed:"" } }}

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    Inosine monophosphate dehydrogenase activity of TM1347 (1VRD)

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    The Thermotoga maritima TM1347 ORF (1VRD) was annotated as a putative inosine 5’-monophosphate dehydrogenase (IMPDH; 1.1.1.205) based on structure and sequence comparisons. TM1347 sequence is similar to IMPDH from Streptococcus pyogenes (1ZFJ; 58% identity, 74% similarity) and Borrelia burgdorferi (1EEP; 58% identity, 76% similarity), both of which have been functionally characterized1-5.TM1347 also contains the TIM barrel catalytic domain and CBS subdomain commonly found in conjunction with the IMPDH domain of IMPDH proteins3. The catalytic domain contains an active site loop with a trio of catalytic residues essential to enzymatic activity: C301, D334 and E409.

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    Michaelis-Menten kinetics data demonstrate TM1347 has IMPDH activity. TM1347 catalyzes the conversion of inosine 5’-monophosphate (IMP) to xanthosine 5’-monophosphate (KM = 31 µM and kcat= 0.028 s-1at 37 °C) (Figure 1). Because TM1347 may exhibit positive cooperativity with inosine 5’-monophosphate (n=1.8) (Figure 1B; different from the positive cooperativity observed with monovalent cations4,6), kinetic parameters are based on curve-fitting to the data using the Hill equation. TM1347 showed an increased kcat (0.10 s-1) and KM (71 µM) when tested at 70 °C (T. maritima optimal growth temperature). The KM for TM1347 is comparable to that of IMPDH from B. burgdorferi (29 ± 8 µM) and similar to that of IMPDH from S. pyogenes (62 ± 19 µM), though the activity (kcat) is much lower compared to both (S. pyogenes, 24.3 ± 3 s-1; B. burgdorferi, 2.6 ±0.3 s-1)2,3.

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    The dependence on and specificity of TM1347 for monocovalent cations was determined at 70 °C, pH 8.0, by substitution of K+ in the standard assay (50 mMTris [pH 8.5], 1 mM β-mercaptoethanol, 3 mM EDTA, and 1 mM NAD+) with either Li+, Na+, or no cation. There was an approximately 50% decrease in reaction rate when K+ was substituted or removed (Figure 2). These data support the observation that IMPDHs are activated ~100 fold by K+ and similar monovalent cations4.TM1347 activity decreased as the size of the monovalent cation decreases in size (K+>Na+>Li+) and was lowest in the absence of monovalent cation.

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    BioLEd Contributors: Jacqueline Stevens ,Evans Wralstad, Alice Yeh, Vernon Forrester, Bridget Bailey, Ahmed Ragab, Tomasz Kabzinski, Kaitlin Bailey, Cameron Mura, Carol Price, Linda Columbus. Funded by NSF DUE 1044858.

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    References

    1.      Shu, Q., and Nair, V. 2008. Inosine Monophosphate Dehydrogenase (IMPDH) as a Target in Drug Discovery. Med. Res. Rev. 28:219-232.

    2.      Zhang, R. G., Evans, GRotella, F. J., Westbrook, E. M., Beno, D., Huberman, E., Joachimiak, A., and Collart, F. R. 1999 Characteristics and Crystal Structure of Bacterial inosine-5'-monophosphate dehydrogenase. Biochemistry. 38(15):4691-4700.

    3.      Zhou, X., Cahoon, M., Rosa, P., and Hedstrom, L. 1997. Expression, Purification, and Characterization of Inosine 5'-Monophosphate Dehydrogenase from Borreliaburgdorferi. J. Biol. Chem. 272(35):21977-21981.

    4.      Hedstrom, L. 2009. IMP Dehydrogenase: Structure, Mechanism, and Inhibition. Chem. Rev. 109:2903-2928.

    5.      Pimkin, M., and Markham, G. D. 2008. The CBS Subdomain of Inosine 5'-Monophosphate Dehydrogenase Regulates Purine Nucleotide Turnover. Mol. Microbiol. 68:342-359.

    6.      Riera, T. V., Zheng, L., Josephine, H. R., Min, D., Yang, W., and Hedstrom, L. 2011. Allosteric Activation via Kinetic Control: Potassium Accelerates a Conformational Change in IMP Dehydrogenase. Biochemistry. 50:8508-8518.

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    Other changes:

    1. /body/p/a/@class: " external""external"
    2. /body/p/a[2]/@class: " external""external"

    Version from 17:32, 12 Mar 2013

    This revision modified by Admin (Ban)
    {{ template.Protein{ leadContact:"", title:"Crystal structure of Inosine-5'-monophosphate dehydrogenase (TM1347) from THERMOTOGA MARITIMA at 2.18 A resolution. To be published",site:'JCSG', status:'In PDB', date:"2005-05-18", targetid:"283208", pdbid:"1vrd", source:"Thermotoga maritima msb8", relatedPDBs:[], refids:"TM1347, 282192", molwt:"52011.54", residues:"482", isopoint:"6.37", sequence:"mkealtfddvllvpqysevlpkdvkidtrltrqiriniplvsaamdtvteaalakalareggigiihkn ltpdeqarqvsivkktengiiydpitvtpdmtvkeaidlmaeykigglpvvdeegrlvglltnrdvrfe knlskkikdlmtpreklivappdislekakeilhqhrieklplvskdnklvglitikdimsviehpnaa rdekgrllvgaavgtspetmerveklvkagvdvividtahghsrrvietlemikadypdlpvvagnvat pegtealikagadavkvgvgpgsicttrvvagvgvpqltavmecsevarkydvpiiadggirysgdivk alaagaesvmvgsifagteeapgetilyqgrkykayrgmgslgamrsgsadrygqegenkfvpegiegm vpykgtvkdvvhqlvgglrsgmgyigartikelqekavfvkitpagvkeshphdiiitkespnywvqa", method:"XRAY", numchains:"2", resolution:"2.18", rfree:"0.25759", mattcoeff:"3.80", rfactor:"0.21653", waters:"206", solcontent:"67.42", ligands:"", metals:"", model:"False", uniprot:"Q9X168", pubmed:"" } }}

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    Version as of 19:13, 13 May 2015

    This revision modified by cawprice (Ban)
    {{ template.Protein{ leadContact:"", title:"Crystal structure of Inosine-5'-monophosphate dehydrogenase (TM1347) from THERMOTOGA MARITIMA at 2.18 A resolution. To be published",site:'JCSG', status:'In PDB', date:"2005-05-18", targetid:"283208", pdbid:"1vrd", source:"Thermotoga maritima msb8", relatedPDBs:[], refids:"TM1347, 282192", molwt:"52011.54", residues:"482", isopoint:"6.37", sequence:"mkealtfddvllvpqysevlpkdvkidtrltrqiriniplvsaamdtvteaalakalareggigiihkn ltpdeqarqvsivkktengiiydpitvtpdmtvkeaidlmaeykigglpvvdeegrlvglltnrdvrfe knlskkikdlmtpreklivappdislekakeilhqhrieklplvskdnklvglitikdimsviehpnaa rdekgrllvgaavgtspetmerveklvkagvdvividtahghsrrvietlemikadypdlpvvagnvat pegtealikagadavkvgvgpgsicttrvvagvgvpqltavmecsevarkydvpiiadggirysgdivk alaagaesvmvgsifagteeapgetilyqgrkykayrgmgslgamrsgsadrygqegenkfvpegiegm vpykgtvkdvvhqlvgglrsgmgyigartikelqekavfvkitpagvkeshphdiiitkespnywvqa", method:"XRAY", numchains:"2", resolution:"2.18", rfree:"0.25759", mattcoeff:"3.80", rfactor:"0.21653", waters:"206", solcontent:"67.42", ligands:"", metals:"", model:"False", uniprot:"Q9X168", pubmed:"" } }}

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    Inosine monophosphate dehydrogenase activity of TM1347 (1VRD)

    ...

    The Thermotoga maritima TM1347 ORF (1VRD) was annotated as a putative inosine 5’-monophosphate dehydrogenase (IMPDH; 1.1.1.205) based on structure and sequence comparisons. TM1347 sequence is similar to IMPDH from Streptococcus pyogenes (1ZFJ; 58% identity, 74% similarity) and Borrelia burgdorferi (1EEP; 58% identity, 76% similarity), both of which have been functionally characterized1-5.TM1347 also contains the TIM barrel catalytic domain and CBS subdomain commonly found in conjunction with the IMPDH domain of IMPDH proteins3. The catalytic domain contains an active site loop with a trio of catalytic residues essential to enzymatic activity: C301, D334 and E409.

    ...

    Michaelis-Menten kinetics data demonstrate TM1347 has IMPDH activity. TM1347 catalyzes the conversion of inosine 5’-monophosphate (IMP) to xanthosine 5’-monophosphate (KM = 31 µM and kcat= 0.028 s-1at 37 °C) (Figure 1). Because TM1347 may exhibit positive cooperativity with inosine 5’-monophosphate (n=1.8) (Figure 1B; different from the positive cooperativity observed with monovalent cations4,6), kinetic parameters are based on curve-fitting to the data using the Hill equation. TM1347 showed an increased kcat (0.10 s-1) and KM (71 µM) when tested at 70 °C (T. maritima optimal growth temperature). The KM for TM1347 is comparable to that of IMPDH from B. burgdorferi (29 ± 8 µM) and similar to that of IMPDH from S. pyogenes (62 ± 19 µM), though the activity (kcat) is much lower compared to both (S. pyogenes, 24.3 ± 3 s-1; B. burgdorferi, 2.6 ±0.3 s-1)2,3.

    ...

    The dependence on and specificity of TM1347 for monocovalent cations was determined at 70 °C, pH 8.0, by substitution of K+ in the standard assay (50 mMTris [pH 8.5], 1 mM β-mercaptoethanol, 3 mM EDTA, and 1 mM NAD+) with either Li+, Na+, or no cation. There was an approximately 50% decrease in reaction rate when K+ was substituted or removed (Figure 2). These data support the observation that IMPDHs are activated ~100 fold by K+ and similar monovalent cations4.TM1347 activity decreased as the size of the monovalent cation decreases in size (K+>Na+>Li+) and was lowest in the absence of monovalent cation.

    ...

    BioLEd Contributors: Jacqueline Stevens ,Evans Wralstad, Alice Yeh, Vernon Forrester, Bridget Bailey, Ahmed Ragab, Tomasz Kabzinski, Kaitlin Bailey, Cameron Mura, Carol Price, Linda Columbus. Funded by NSF DUE 1044858.

    ...

    References

    1.      Shu, Q., and Nair, V. 2008. Inosine Monophosphate Dehydrogenase (IMPDH) as a Target in Drug Discovery. Med. Res. Rev. 28:219-232.

    2.      Zhang, R. G., Evans, GRotella, F. J., Westbrook, E. M., Beno, D., Huberman, E., Joachimiak, A., and Collart, F. R. 1999 Characteristics and Crystal Structure of Bacterial inosine-5'-monophosphate dehydrogenase. Biochemistry. 38(15):4691-4700.

    3.      Zhou, X., Cahoon, M., Rosa, P., and Hedstrom, L. 1997. Expression, Purification, and Characterization of Inosine 5'-Monophosphate Dehydrogenase from Borreliaburgdorferi. J. Biol. Chem. 272(35):21977-21981.

    4.      Hedstrom, L. 2009. IMP Dehydrogenase: Structure, Mechanism, and Inhibition. Chem. Rev. 109:2903-2928.

    5.      Pimkin, M., and Markham, G. D. 2008. The CBS Subdomain of Inosine 5'-Monophosphate Dehydrogenase Regulates Purine Nucleotide Turnover. Mol. Microbiol. 68:342-359.

    6.      Riera, T. V., Zheng, L., Josephine, H. R., Min, D., Yang, W., and Hedstrom, L. 2011. Allosteric Activation via Kinetic Control: Potassium Accelerates a Conformational Change in IMP Dehydrogenase. Biochemistry. 50:8508-8518.

    ...



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