Insights into the structure-function relationship of Brugia malayi thymidylate kinase (BmTMK).
Identifieur interne : 000898 ( PubMed/Corpus ); précédent : 000897; suivant : 000899Insights into the structure-function relationship of Brugia malayi thymidylate kinase (BmTMK).
Auteurs : Pawan Kumar Doharey ; Sudhir Kumar Singh ; Pravesh Verma ; Anita Verma ; Sushma Rathaur ; Jitendra Kumar SaxenaSource :
- International journal of biological macromolecules [ 1879-0003 ] ; 2016.
English descriptors
- KwdEn :
- Animals, Brugia malayi (enzymology), Brugia malayi (pathogenicity), Catalytic Domain, Dimerization, Elephantiasis, Filarial (drug therapy), Elephantiasis, Filarial (enzymology), Elephantiasis, Filarial (parasitology), Humans, Nucleoside-Phosphate Kinase (chemistry), Nucleoside-Phosphate Kinase (genetics), Nucleoside-Phosphate Kinase (isolation & purification), Protein Conformation, Recombinant Proteins (chemistry), Recombinant Proteins (genetics), Structure-Activity Relationship, Thymine Nucleotides (chemistry).
- MESH :
- chemical , chemistry : Nucleoside-Phosphate Kinase, Recombinant Proteins, Thymine Nucleotides.
- drug therapy : Elephantiasis, Filarial.
- enzymology : Brugia malayi, Elephantiasis, Filarial.
- chemical , genetics : Nucleoside-Phosphate Kinase, Recombinant Proteins.
- chemical , isolation & purification : Nucleoside-Phosphate Kinase.
- parasitology : Elephantiasis, Filarial.
- pathogenicity : Brugia malayi.
- Animals, Catalytic Domain, Dimerization, Humans, Protein Conformation, Structure-Activity Relationship.
Abstract
Lymphatic filariasis is a debilitating disease caused by lymph dwelling nematodal parasites like Wuchereria bancrofti, Brugia malayi and Brugia timori. Thymidylate kinase of B. malayi is a key enzyme in the de novo and salvage pathways for thymidine 5'-triphosphate (dTTP) synthesis. Therefore, B. malayi thymidylate kinase (BmTMK) is an essential enzyme for DNA biosynthesis and an important drug target to rein in filariasis. In the present study, the structural and functional changes associated with recombinant BmTMK, in the presence of protein denaturant GdnHCl, urea and pH were studied. GdnHCl and urea induced unfolding of BmTMK is non-cooperative and influence the functional property of the enzyme much lower than their Cm values. The study delineate that BmTMK is more prone to ionic perturbation. The dimeric assembly of BmTMK is an absolute requirement for enzymatic acitivity and any subtle change in dimeric conformation due to denaturation leads to loss of enzymatic activity. The pH induced changes on structure and activity suggests that selective modification of active site microenvironment pertains to difference in activity profile. This study also envisages that chemical moieties which acts by modulating oligomeric assembly, could be used for better designing of inhibitors against BmTMK enzyme.
DOI: 10.1016/j.ijbiomac.2016.04.004
PubMed: 27044348
Links to Exploration step
pubmed:27044348Le document en format XML
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Box 173, Lucknow 226031, India.</nlm:affiliation></affiliation></author><author><name sortKey="Verma, Pravesh" sort="Verma, Pravesh" uniqKey="Verma P" first="Pravesh" last="Verma">Pravesh Verma</name><affiliation><nlm:affiliation>Biochemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226031, India.</nlm:affiliation></affiliation></author><author><name sortKey="Verma, Anita" sort="Verma, Anita" uniqKey="Verma A" first="Anita" last="Verma">Anita Verma</name><affiliation><nlm:affiliation>Biochemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226031, India.</nlm:affiliation></affiliation></author><author><name sortKey="Rathaur, Sushma" sort="Rathaur, Sushma" uniqKey="Rathaur S" first="Sushma" last="Rathaur">Sushma Rathaur</name><affiliation><nlm:affiliation>Department of Biochemistry, Banaras Hindu University, Varanasi 221005, India.</nlm:affiliation></affiliation></author><author><name sortKey="Saxena, Jitendra Kumar" sort="Saxena, Jitendra Kumar" uniqKey="Saxena J" first="Jitendra Kumar" last="Saxena">Jitendra Kumar Saxena</name><affiliation><nlm:affiliation>Biochemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226031, India. 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Box 173, Lucknow 226031, India.</nlm:affiliation></affiliation></author><author><name sortKey="Singh, Sudhir Kumar" sort="Singh, Sudhir Kumar" uniqKey="Singh S" first="Sudhir Kumar" last="Singh">Sudhir Kumar Singh</name><affiliation><nlm:affiliation>Molecular & Structural Biology Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226031, India.</nlm:affiliation></affiliation></author><author><name sortKey="Verma, Pravesh" sort="Verma, Pravesh" uniqKey="Verma P" first="Pravesh" last="Verma">Pravesh Verma</name><affiliation><nlm:affiliation>Biochemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226031, India.</nlm:affiliation></affiliation></author><author><name sortKey="Verma, Anita" sort="Verma, Anita" uniqKey="Verma A" first="Anita" last="Verma">Anita Verma</name><affiliation><nlm:affiliation>Biochemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226031, India.</nlm:affiliation></affiliation></author><author><name sortKey="Rathaur, Sushma" sort="Rathaur, Sushma" uniqKey="Rathaur S" first="Sushma" last="Rathaur">Sushma Rathaur</name><affiliation><nlm:affiliation>Department of Biochemistry, Banaras Hindu University, Varanasi 221005, India.</nlm:affiliation></affiliation></author><author><name sortKey="Saxena, Jitendra Kumar" sort="Saxena, Jitendra Kumar" uniqKey="Saxena J" first="Jitendra Kumar" last="Saxena">Jitendra Kumar Saxena</name><affiliation><nlm:affiliation>Biochemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226031, India. Electronic address: jkscdri@yahoo.com.</nlm:affiliation></affiliation></author></analytic><series><title level="j">International journal of biological macromolecules</title><idno type="eISSN">1879-0003</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Brugia malayi (enzymology)</term><term>Brugia malayi (pathogenicity)</term><term>Catalytic Domain</term><term>Dimerization</term><term>Elephantiasis, Filarial (drug therapy)</term><term>Elephantiasis, Filarial (enzymology)</term><term>Elephantiasis, Filarial (parasitology)</term><term>Humans</term><term>Nucleoside-Phosphate Kinase (chemistry)</term><term>Nucleoside-Phosphate Kinase (genetics)</term><term>Nucleoside-Phosphate Kinase (isolation & purification)</term><term>Protein Conformation</term><term>Recombinant Proteins (chemistry)</term><term>Recombinant Proteins (genetics)</term><term>Structure-Activity Relationship</term><term>Thymine Nucleotides (chemistry)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Nucleoside-Phosphate Kinase</term><term>Recombinant Proteins</term><term>Thymine Nucleotides</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Elephantiasis, Filarial</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Brugia malayi</term><term>Elephantiasis, Filarial</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Nucleoside-Phosphate Kinase</term><term>Recombinant Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="isolation & purification" xml:lang="en"><term>Nucleoside-Phosphate Kinase</term></keywords><keywords scheme="MESH" qualifier="parasitology" xml:lang="en"><term>Elephantiasis, Filarial</term></keywords><keywords scheme="MESH" qualifier="pathogenicity" xml:lang="en"><term>Brugia malayi</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Catalytic Domain</term><term>Dimerization</term><term>Humans</term><term>Protein Conformation</term><term>Structure-Activity Relationship</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Lymphatic filariasis is a debilitating disease caused by lymph dwelling nematodal parasites like Wuchereria bancrofti, Brugia malayi and Brugia timori. Thymidylate kinase of B. malayi is a key enzyme in the de novo and salvage pathways for thymidine 5'-triphosphate (dTTP) synthesis. Therefore, B. malayi thymidylate kinase (BmTMK) is an essential enzyme for DNA biosynthesis and an important drug target to rein in filariasis. In the present study, the structural and functional changes associated with recombinant BmTMK, in the presence of protein denaturant GdnHCl, urea and pH were studied. GdnHCl and urea induced unfolding of BmTMK is non-cooperative and influence the functional property of the enzyme much lower than their Cm values. The study delineate that BmTMK is more prone to ionic perturbation. The dimeric assembly of BmTMK is an absolute requirement for enzymatic acitivity and any subtle change in dimeric conformation due to denaturation leads to loss of enzymatic activity. The pH induced changes on structure and activity suggests that selective modification of active site microenvironment pertains to difference in activity profile. This study also envisages that chemical moieties which acts by modulating oligomeric assembly, could be used for better designing of inhibitors against BmTMK enzyme.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">27044348</PMID><DateCreated><Year>2016</Year><Month>05</Month><Day>17</Day></DateCreated><DateCompleted><Year>2017</Year><Month>03</Month><Day>07</Day></DateCompleted><DateRevised><Year>2017</Year><Month>03</Month><Day>07</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1879-0003</ISSN><JournalIssue CitedMedium="Internet"><Volume>88</Volume><PubDate><Year>2016</Year><Month>Jul</Month></PubDate></JournalIssue><Title>International journal of biological macromolecules</Title><ISOAbbreviation>Int. J. Biol. Macromol.</ISOAbbreviation></Journal><ArticleTitle>Insights into the structure-function relationship of Brugia malayi thymidylate kinase (BmTMK).</ArticleTitle><Pagination><MedlinePgn>565-71</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.ijbiomac.2016.04.004</ELocationID><ELocationID EIdType="pii" ValidYN="Y">S0141-8130(16)30312-9</ELocationID><Abstract><AbstractText>Lymphatic filariasis is a debilitating disease caused by lymph dwelling nematodal parasites like Wuchereria bancrofti, Brugia malayi and Brugia timori. Thymidylate kinase of B. malayi is a key enzyme in the de novo and salvage pathways for thymidine 5'-triphosphate (dTTP) synthesis. Therefore, B. malayi thymidylate kinase (BmTMK) is an essential enzyme for DNA biosynthesis and an important drug target to rein in filariasis. In the present study, the structural and functional changes associated with recombinant BmTMK, in the presence of protein denaturant GdnHCl, urea and pH were studied. GdnHCl and urea induced unfolding of BmTMK is non-cooperative and influence the functional property of the enzyme much lower than their Cm values. The study delineate that BmTMK is more prone to ionic perturbation. The dimeric assembly of BmTMK is an absolute requirement for enzymatic acitivity and any subtle change in dimeric conformation due to denaturation leads to loss of enzymatic activity. The pH induced changes on structure and activity suggests that selective modification of active site microenvironment pertains to difference in activity profile. This study also envisages that chemical moieties which acts by modulating oligomeric assembly, could be used for better designing of inhibitors against BmTMK enzyme.</AbstractText><CopyrightInformation>Copyright © 2016 Elsevier B.V. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Doharey</LastName><ForeName>Pawan Kumar</ForeName><Initials>PK</Initials><AffiliationInfo><Affiliation>Biochemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226031, India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Singh</LastName><ForeName>Sudhir Kumar</ForeName><Initials>SK</Initials><AffiliationInfo><Affiliation>Molecular & Structural Biology Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226031, India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Verma</LastName><ForeName>Pravesh</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Biochemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226031, India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Verma</LastName><ForeName>Anita</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Biochemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226031, India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rathaur</LastName><ForeName>Sushma</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Biochemistry, Banaras Hindu University, Varanasi 221005, India.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Saxena</LastName><ForeName>Jitendra Kumar</ForeName><Initials>JK</Initials><AffiliationInfo><Affiliation>Biochemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226031, India. Electronic address: jkscdri@yahoo.com.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2016</Year><Month>04</Month><Day>01</Day></ArticleDate></Article><MedlineJournalInfo><Country>Netherlands</Country><MedlineTA>Int J Biol Macromol</MedlineTA><NlmUniqueID>7909578</NlmUniqueID><ISSNLinking>0141-8130</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011994">Recombinant Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D013942">Thymine Nucleotides</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.4.4</RegistryNumber><NameOfSubstance UI="D009703">Nucleoside-Phosphate Kinase</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.4.9</RegistryNumber><NameOfSubstance UI="C020093">dTMP kinase</NameOfSubstance></Chemical><Chemical><RegistryNumber>QOP4K539MU</RegistryNumber><NameOfSubstance UI="C024157">thymidine 5'-triphosphate</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017178" MajorTopicYN="N">Brugia malayi</DescriptorName><QualifierName UI="Q000201" MajorTopicYN="Y">enzymology</QualifierName><QualifierName UI="Q000472" MajorTopicYN="N">pathogenicity</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020134" MajorTopicYN="N">Catalytic Domain</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019281" MajorTopicYN="N">Dimerization</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004605" MajorTopicYN="N">Elephantiasis, Filarial</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName><QualifierName UI="Q000201" MajorTopicYN="Y">enzymology</QualifierName><QualifierName UI="Q000469" MajorTopicYN="N">parasitology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009703" MajorTopicYN="N">Nucleoside-Phosphate Kinase</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000302" MajorTopicYN="N">isolation & purification</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011487" MajorTopicYN="N">Protein Conformation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011994" MajorTopicYN="N">Recombinant Proteins</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013329" MajorTopicYN="N">Structure-Activity Relationship</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013942" MajorTopicYN="N">Thymine Nucleotides</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Brugia malayi</Keyword><Keyword MajorTopicYN="N">Drug target</Keyword><Keyword MajorTopicYN="N">Inhibition</Keyword><Keyword MajorTopicYN="N">Refolding</Keyword><Keyword MajorTopicYN="N">Thymidylate kinase</Keyword><Keyword MajorTopicYN="N">Unfolding</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2015</Year><Month>12</Month><Day>01</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2016</Year><Month>03</Month><Day>30</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2016</Year><Month>04</Month><Day>01</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2016</Year><Month>4</Month><Day>6</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2016</Year><Month>4</Month><Day>6</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2017</Year><Month>3</Month><Day>8</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">27044348</ArticleId><ArticleId IdType="pii">S0141-8130(16)30312-9</ArticleId><ArticleId IdType="doi">10.1016/j.ijbiomac.2016.04.004</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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