Insights into the structure-function relationship of Brugia malayi thymidylate kinase (BmTMK).
Identifieur interne : 000F56 ( Main/Exploration ); précédent : 000F55; suivant : 000F57Insights into the structure-function relationship of Brugia malayi thymidylate kinase (BmTMK).
Auteurs : Pawan Kumar Doharey [Inde] ; Sudhir Kumar Singh [Inde] ; Pravesh Verma [Inde] ; Anita Verma [Inde] ; Sushma Rathaur [Inde] ; Jitendra Kumar Saxena [Inde]Source :
- International journal of biological macromolecules [ 1879-0003 ] ; 2016.
Descripteurs français
- KwdFr :
- Animaux, Brugia malayi (enzymologie), Brugia malayi (pathogénicité), Conformation des protéines, Dimérisation, Domaine catalytique, Filariose lymphatique (enzymologie), Filariose lymphatique (parasitologie), Filariose lymphatique (traitement médicamenteux), Humains, Nucleoside phosphate kinase (), Nucleoside phosphate kinase (génétique), Nucleoside phosphate kinase (isolement et purification), Nucléotides thymidyliques (), Protéines recombinantes (), Protéines recombinantes (génétique), Relation structure-activité.
- MESH :
- enzymologie : Brugia malayi, Filariose lymphatique.
- génétique : Nucleoside phosphate kinase, Protéines recombinantes.
- isolement et purification : Nucleoside phosphate kinase.
- parasitologie : Filariose lymphatique.
- pathogénicité : Brugia malayi.
- traitement médicamenteux : Filariose lymphatique.
- Animaux, Conformation des protéines, Dimérisation, Domaine catalytique, Humains, Nucleoside phosphate kinase, Nucléotides thymidyliques, Protéines recombinantes, Relation structure-activité.
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
Affiliations:
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O. Box 173, Lucknow 226031, India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Biochemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226031</wicri:regionArea><wicri:noRegion>Lucknow 226031</wicri:noRegion></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 wicri:level="1"><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><country xml:lang="fr">Inde</country><wicri:regionArea>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</wicri:regionArea><wicri:noRegion>Lucknow 226031</wicri:noRegion></affiliation></author><author><name sortKey="Verma, Pravesh" sort="Verma, Pravesh" uniqKey="Verma P" first="Pravesh" last="Verma">Pravesh Verma</name><affiliation wicri:level="1"><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><country xml:lang="fr">Inde</country><wicri:regionArea>Biochemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226031</wicri:regionArea><wicri:noRegion>Lucknow 226031</wicri:noRegion></affiliation></author><author><name sortKey="Verma, Anita" sort="Verma, Anita" uniqKey="Verma A" first="Anita" last="Verma">Anita Verma</name><affiliation wicri:level="1"><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><country xml:lang="fr">Inde</country><wicri:regionArea>Biochemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226031</wicri:regionArea><wicri:noRegion>Lucknow 226031</wicri:noRegion></affiliation></author><author><name sortKey="Rathaur, Sushma" sort="Rathaur, Sushma" uniqKey="Rathaur S" first="Sushma" last="Rathaur">Sushma Rathaur</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry, Banaras Hindu University, Varanasi 221005, India.</nlm:affiliation><country xml:lang="fr">Inde</country><wicri:regionArea>Department of Biochemistry, Banaras Hindu University, Varanasi 221005</wicri:regionArea><wicri:noRegion>Varanasi 221005</wicri:noRegion></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 wicri:level="1"><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><country xml:lang="fr">Inde</country><wicri:regionArea>Biochemistry Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, P. O. Box 173, Lucknow 226031</wicri:regionArea><wicri:noRegion>Lucknow 226031</wicri:noRegion></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="KwdFr" xml:lang="fr"><term>Animaux</term><term>Brugia malayi (enzymologie)</term><term>Brugia malayi (pathogénicité)</term><term>Conformation des protéines</term><term>Dimérisation</term><term>Domaine catalytique</term><term>Filariose lymphatique (enzymologie)</term><term>Filariose lymphatique (parasitologie)</term><term>Filariose lymphatique (traitement médicamenteux)</term><term>Humains</term><term>Nucleoside phosphate kinase ()</term><term>Nucleoside phosphate kinase (génétique)</term><term>Nucleoside phosphate kinase (isolement et purification)</term><term>Nucléotides thymidyliques ()</term><term>Protéines recombinantes ()</term><term>Protéines recombinantes (génétique)</term><term>Relation structure-activité</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="enzymologie" xml:lang="fr"><term>Brugia malayi</term><term>Filariose lymphatique</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" qualifier="génétique" xml:lang="fr"><term>Nucleoside phosphate kinase</term><term>Protéines recombinantes</term></keywords><keywords scheme="MESH" type="chemical" qualifier="isolation & purification" xml:lang="en"><term>Nucleoside-Phosphate Kinase</term></keywords><keywords scheme="MESH" qualifier="isolement et purification" xml:lang="fr"><term>Nucleoside phosphate kinase</term></keywords><keywords scheme="MESH" qualifier="parasitologie" xml:lang="fr"><term>Filariose lymphatique</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" qualifier="pathogénicité" xml:lang="fr"><term>Brugia malayi</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Filariose lymphatique</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><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Conformation des protéines</term><term>Dimérisation</term><term>Domaine catalytique</term><term>Humains</term><term>Nucleoside phosphate kinase</term><term>Nucléotides thymidyliques</term><term>Protéines recombinantes</term><term>Relation structure-activité</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><affiliations><list><country><li>Inde</li></country></list><tree><country name="Inde"><noRegion><name sortKey="Doharey, Pawan Kumar" sort="Doharey, Pawan Kumar" uniqKey="Doharey P" first="Pawan Kumar" last="Doharey">Pawan Kumar Doharey</name></noRegion><name sortKey="Rathaur, Sushma" sort="Rathaur, Sushma" uniqKey="Rathaur S" first="Sushma" last="Rathaur">Sushma Rathaur</name><name sortKey="Saxena, Jitendra Kumar" sort="Saxena, Jitendra Kumar" uniqKey="Saxena J" first="Jitendra Kumar" last="Saxena">Jitendra Kumar Saxena</name><name sortKey="Singh, Sudhir Kumar" sort="Singh, Sudhir Kumar" uniqKey="Singh S" first="Sudhir Kumar" last="Singh">Sudhir Kumar Singh</name><name sortKey="Verma, Anita" sort="Verma, Anita" uniqKey="Verma A" first="Anita" last="Verma">Anita Verma</name><name sortKey="Verma, Pravesh" sort="Verma, Pravesh" uniqKey="Verma P" first="Pravesh" last="Verma">Pravesh Verma</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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