Phosphoglycerate mutase from Trypanosoma brucei is hyperactivated by cobalt in vitro, but not in vivo
Production of ATP by the glycolytic pathway in the mammalian pathogenic stage of protists from the genus Trypanosoma is required for the survival of the parasites. Cofactor-independent phosphoglycerate mutase (iPGAM) is particularly attractive as a drug target because it shows no similarity to the c...
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| Veröffentlicht in: | Metallomics 2011-12, Vol.3 (12), p.131-1317 |
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| creator | Fuad, Fazia Adyani Ahmad Fothergill-Gilmore, Linda A Nowicki, Matthew W Eades, Lorna J Morgan, Hugh P McNae, Iain W Michels, Paul A. M Walkinshaw, Malcolm D |
| description | Production of ATP by the glycolytic pathway in the mammalian pathogenic stage of protists from the genus
Trypanosoma
is required for the survival of the parasites. Cofactor-independent phosphoglycerate mutase (iPGAM) is particularly attractive as a drug target because it shows no similarity to the corresponding enzyme in humans, and has also been genetically validated as a target by RNAi experiments. It has previously been shown that trypanosomatid iPGAMs require Co
2+
to reach maximal activity, but the biologically relevant metal has remained unclear. In this paper the metal content in the cytosol of procyclic and bloodstream-form
T. brucei
(analysed by inductively coupled plasma-optical emission spectroscopy) shows that Mg
2+
, Zn
2+
and Fe
2+
were the most abundant, whereas Co
2+
was below the limit of detection ( |
| doi_str_mv | 10.1039/c1mt00119a |
| format | Article |
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Trypanosoma
is required for the survival of the parasites. Cofactor-independent phosphoglycerate mutase (iPGAM) is particularly attractive as a drug target because it shows no similarity to the corresponding enzyme in humans, and has also been genetically validated as a target by RNAi experiments. It has previously been shown that trypanosomatid iPGAMs require Co
2+
to reach maximal activity, but the biologically relevant metal has remained unclear. In this paper the metal content in the cytosol of procyclic and bloodstream-form
T. brucei
(analysed by inductively coupled plasma-optical emission spectroscopy) shows that Mg
2+
, Zn
2+
and Fe
2+
were the most abundant, whereas Co
2+
was below the limit of detection (<0.035 μM). The low concentration indicates that Co
2+
is unlikely to be the biologically relevant metal, but that instead, Mg
2+
and/or Zn
2+
may assume this role. Results from metal analysis of purified
Leishmania mexicana
iPGAM by inductively coupled plasma-mass spectrometry also show high concentrations of Mg
2+
and Zn
2+
, and are consistent with this proposal. Our data suggest that
in vivo
cellular conditions lacking Co
2+
are unable to support the maximal activity of iPGAM, but instead maintain its activity at a relatively low level by using Mg
2+
and/or Zn
2+
. The physiological significance of these observations is being pursued by structural, biochemical and biophysical studies.
Metal-dependent phosphoglycerate mutase from
Trypanosoma brucei
is 20-fold more active with cobalt than with any biologically relevant metal.</description><identifier>ISSN: 1756-5901</identifier><identifier>EISSN: 1756-591X</identifier><identifier>DOI: 10.1039/c1mt00119a</identifier><identifier>PMID: 21993954</identifier><language>eng</language><publisher>England</publisher><subject>ATP ; Cobalt ; Cobalt - analysis ; Cobalt - metabolism ; Cytosol ; Cytosol - enzymology ; Data processing ; Drugs ; Enzymes ; Glycolysis ; Heavy metals ; Iron ; Iron - analysis ; Iron - metabolism ; Leishmania mexicana ; Magnesium ; Magnesium - analysis ; Magnesium - metabolism ; Mass Spectrometry ; Models, Molecular ; Parasites ; Phosphoglycerate mutase ; Phosphoglycerate Mutase - chemistry ; Phosphoglycerate Mutase - isolation & purification ; Phosphoglycerate Mutase - metabolism ; RNA-mediated interference ; Spectrometry ; Spectroscopy ; Survival ; Trypanosoma brucei ; Trypanosoma brucei brucei - chemistry ; Trypanosoma brucei brucei - enzymology ; Zinc ; Zinc - analysis ; Zinc - metabolism</subject><ispartof>Metallomics, 2011-12, Vol.3 (12), p.131-1317</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c403t-27e9fd4a83ab38d0d86c2d6dfcebe474a80f207c0ffa0d4e803be7fbbb4bdb573</citedby><cites>FETCH-LOGICAL-c403t-27e9fd4a83ab38d0d86c2d6dfcebe474a80f207c0ffa0d4e803be7fbbb4bdb573</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21993954$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fuad, Fazia Adyani Ahmad</creatorcontrib><creatorcontrib>Fothergill-Gilmore, Linda A</creatorcontrib><creatorcontrib>Nowicki, Matthew W</creatorcontrib><creatorcontrib>Eades, Lorna J</creatorcontrib><creatorcontrib>Morgan, Hugh P</creatorcontrib><creatorcontrib>McNae, Iain W</creatorcontrib><creatorcontrib>Michels, Paul A. M</creatorcontrib><creatorcontrib>Walkinshaw, Malcolm D</creatorcontrib><title>Phosphoglycerate mutase from Trypanosoma brucei is hyperactivated by cobalt in vitro, but not in vivo</title><title>Metallomics</title><addtitle>Metallomics</addtitle><description>Production of ATP by the glycolytic pathway in the mammalian pathogenic stage of protists from the genus
Trypanosoma
is required for the survival of the parasites. Cofactor-independent phosphoglycerate mutase (iPGAM) is particularly attractive as a drug target because it shows no similarity to the corresponding enzyme in humans, and has also been genetically validated as a target by RNAi experiments. It has previously been shown that trypanosomatid iPGAMs require Co
2+
to reach maximal activity, but the biologically relevant metal has remained unclear. In this paper the metal content in the cytosol of procyclic and bloodstream-form
T. brucei
(analysed by inductively coupled plasma-optical emission spectroscopy) shows that Mg
2+
, Zn
2+
and Fe
2+
were the most abundant, whereas Co
2+
was below the limit of detection (<0.035 μM). The low concentration indicates that Co
2+
is unlikely to be the biologically relevant metal, but that instead, Mg
2+
and/or Zn
2+
may assume this role. Results from metal analysis of purified
Leishmania mexicana
iPGAM by inductively coupled plasma-mass spectrometry also show high concentrations of Mg
2+
and Zn
2+
, and are consistent with this proposal. Our data suggest that
in vivo
cellular conditions lacking Co
2+
are unable to support the maximal activity of iPGAM, but instead maintain its activity at a relatively low level by using Mg
2+
and/or Zn
2+
. The physiological significance of these observations is being pursued by structural, biochemical and biophysical studies.
Metal-dependent phosphoglycerate mutase from
Trypanosoma brucei
is 20-fold more active with cobalt than with any biologically relevant metal.</description><subject>ATP</subject><subject>Cobalt</subject><subject>Cobalt - analysis</subject><subject>Cobalt - metabolism</subject><subject>Cytosol</subject><subject>Cytosol - enzymology</subject><subject>Data processing</subject><subject>Drugs</subject><subject>Enzymes</subject><subject>Glycolysis</subject><subject>Heavy metals</subject><subject>Iron</subject><subject>Iron - analysis</subject><subject>Iron - metabolism</subject><subject>Leishmania mexicana</subject><subject>Magnesium</subject><subject>Magnesium - analysis</subject><subject>Magnesium - metabolism</subject><subject>Mass Spectrometry</subject><subject>Models, Molecular</subject><subject>Parasites</subject><subject>Phosphoglycerate mutase</subject><subject>Phosphoglycerate Mutase - chemistry</subject><subject>Phosphoglycerate Mutase - isolation & purification</subject><subject>Phosphoglycerate Mutase - metabolism</subject><subject>RNA-mediated interference</subject><subject>Spectrometry</subject><subject>Spectroscopy</subject><subject>Survival</subject><subject>Trypanosoma brucei</subject><subject>Trypanosoma brucei brucei - chemistry</subject><subject>Trypanosoma brucei brucei - enzymology</subject><subject>Zinc</subject><subject>Zinc - analysis</subject><subject>Zinc - metabolism</subject><issn>1756-5901</issn><issn>1756-591X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90UtLxDAQB_Agio_Vi3clnhRxddKk2-Yoiy9Y0IOCt5KnW2k3NUkX-u2N7LrePM0w8-N_mEHomMA1AcpvFGkjACFcbKF9UuSTcc7J-_amB7KHDkL4BJgwgHwX7WWEc8pzto_My9yFbu4-mkEZL6LBbR9FMNh61-JXP3Ri4YJrBZa-V6bGdcDzoUtUxXqZvMZywMpJ0URcL_Cyjt5dYdlHvHDrydIdoh0rmmCO1nWE3u7vXqeP49nzw9P0djZWDGgcZ4XhVjNRUiFpqUGXE5XpibbKSMOKtACbQaHAWgGamRKoNIWVUjKpZV7QETpf5XbeffUmxKqtgzJNIxbG9aHiUBCWQ8aSvPhXEshKKDgtaaKXK6q8C8EbW3W-boUfEqp-HlD9PSDh03VuL1ujN_T34gmcrYAParP9C6g6bZM5-c_Qb1YLmO8</recordid><startdate>201112</startdate><enddate>201112</enddate><creator>Fuad, Fazia Adyani Ahmad</creator><creator>Fothergill-Gilmore, Linda A</creator><creator>Nowicki, Matthew W</creator><creator>Eades, Lorna J</creator><creator>Morgan, Hugh P</creator><creator>McNae, Iain W</creator><creator>Michels, Paul A. M</creator><creator>Walkinshaw, Malcolm D</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>M7N</scope><scope>7X8</scope></search><sort><creationdate>201112</creationdate><title>Phosphoglycerate mutase from Trypanosoma brucei is hyperactivated by cobalt in vitro, but not in vivo</title><author>Fuad, Fazia Adyani Ahmad ; Fothergill-Gilmore, Linda A ; Nowicki, Matthew W ; Eades, Lorna J ; Morgan, Hugh P ; McNae, Iain W ; Michels, Paul A. M ; Walkinshaw, Malcolm D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c403t-27e9fd4a83ab38d0d86c2d6dfcebe474a80f207c0ffa0d4e803be7fbbb4bdb573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>ATP</topic><topic>Cobalt</topic><topic>Cobalt - analysis</topic><topic>Cobalt - metabolism</topic><topic>Cytosol</topic><topic>Cytosol - enzymology</topic><topic>Data processing</topic><topic>Drugs</topic><topic>Enzymes</topic><topic>Glycolysis</topic><topic>Heavy metals</topic><topic>Iron</topic><topic>Iron - analysis</topic><topic>Iron - metabolism</topic><topic>Leishmania mexicana</topic><topic>Magnesium</topic><topic>Magnesium - analysis</topic><topic>Magnesium - metabolism</topic><topic>Mass Spectrometry</topic><topic>Models, Molecular</topic><topic>Parasites</topic><topic>Phosphoglycerate mutase</topic><topic>Phosphoglycerate Mutase - chemistry</topic><topic>Phosphoglycerate Mutase - isolation & purification</topic><topic>Phosphoglycerate Mutase - metabolism</topic><topic>RNA-mediated interference</topic><topic>Spectrometry</topic><topic>Spectroscopy</topic><topic>Survival</topic><topic>Trypanosoma brucei</topic><topic>Trypanosoma brucei brucei - chemistry</topic><topic>Trypanosoma brucei brucei - enzymology</topic><topic>Zinc</topic><topic>Zinc - analysis</topic><topic>Zinc - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fuad, Fazia Adyani Ahmad</creatorcontrib><creatorcontrib>Fothergill-Gilmore, Linda A</creatorcontrib><creatorcontrib>Nowicki, Matthew W</creatorcontrib><creatorcontrib>Eades, Lorna J</creatorcontrib><creatorcontrib>Morgan, Hugh P</creatorcontrib><creatorcontrib>McNae, Iain W</creatorcontrib><creatorcontrib>Michels, Paul A. M</creatorcontrib><creatorcontrib>Walkinshaw, Malcolm D</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>MEDLINE - Academic</collection><jtitle>Metallomics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fuad, Fazia Adyani Ahmad</au><au>Fothergill-Gilmore, Linda A</au><au>Nowicki, Matthew W</au><au>Eades, Lorna J</au><au>Morgan, Hugh P</au><au>McNae, Iain W</au><au>Michels, Paul A. M</au><au>Walkinshaw, Malcolm D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phosphoglycerate mutase from Trypanosoma brucei is hyperactivated by cobalt in vitro, but not in vivo</atitle><jtitle>Metallomics</jtitle><addtitle>Metallomics</addtitle><date>2011-12</date><risdate>2011</risdate><volume>3</volume><issue>12</issue><spage>131</spage><epage>1317</epage><pages>131-1317</pages><issn>1756-5901</issn><eissn>1756-591X</eissn><abstract>Production of ATP by the glycolytic pathway in the mammalian pathogenic stage of protists from the genus
Trypanosoma
is required for the survival of the parasites. Cofactor-independent phosphoglycerate mutase (iPGAM) is particularly attractive as a drug target because it shows no similarity to the corresponding enzyme in humans, and has also been genetically validated as a target by RNAi experiments. It has previously been shown that trypanosomatid iPGAMs require Co
2+
to reach maximal activity, but the biologically relevant metal has remained unclear. In this paper the metal content in the cytosol of procyclic and bloodstream-form
T. brucei
(analysed by inductively coupled plasma-optical emission spectroscopy) shows that Mg
2+
, Zn
2+
and Fe
2+
were the most abundant, whereas Co
2+
was below the limit of detection (<0.035 μM). The low concentration indicates that Co
2+
is unlikely to be the biologically relevant metal, but that instead, Mg
2+
and/or Zn
2+
may assume this role. Results from metal analysis of purified
Leishmania mexicana
iPGAM by inductively coupled plasma-mass spectrometry also show high concentrations of Mg
2+
and Zn
2+
, and are consistent with this proposal. Our data suggest that
in vivo
cellular conditions lacking Co
2+
are unable to support the maximal activity of iPGAM, but instead maintain its activity at a relatively low level by using Mg
2+
and/or Zn
2+
. The physiological significance of these observations is being pursued by structural, biochemical and biophysical studies.
Metal-dependent phosphoglycerate mutase from
Trypanosoma brucei
is 20-fold more active with cobalt than with any biologically relevant metal.</abstract><cop>England</cop><pmid>21993954</pmid><doi>10.1039/c1mt00119a</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Metallomics, 2011-12, Vol.3 (12), p.131-1317 |
| issn | 1756-5901 1756-591X |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1028079383 |
| source | MEDLINE; Royal Society Of Chemistry Journals; Oxford University Press Journals All Titles (1996-Current) |
| subjects | ATP Cobalt Cobalt - analysis Cobalt - metabolism Cytosol Cytosol - enzymology Data processing Drugs Enzymes Glycolysis Heavy metals Iron Iron - analysis Iron - metabolism Leishmania mexicana Magnesium Magnesium - analysis Magnesium - metabolism Mass Spectrometry Models, Molecular Parasites Phosphoglycerate mutase Phosphoglycerate Mutase - chemistry Phosphoglycerate Mutase - isolation & purification Phosphoglycerate Mutase - metabolism RNA-mediated interference Spectrometry Spectroscopy Survival Trypanosoma brucei Trypanosoma brucei brucei - chemistry Trypanosoma brucei brucei - enzymology Zinc Zinc - analysis Zinc - metabolism |
| title | Phosphoglycerate mutase from Trypanosoma brucei is hyperactivated by cobalt in vitro, but not in vivo |
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