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Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882
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| Zeitschriftentitel: | Applied and Environmental Microbiology |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , |
| In: | Applied and Environmental Microbiology, 84, 2018, 12 |
| Format: | E-Article |
| Sprache: | Englisch |
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American Society for Microbiology
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| author_facet |
Wu, Hao Liang, Jingdan Wang, Jialiang Liang, Wei-Jun Gou, Lixia Wu, Qiulin Zhou, Xiufen Bruce, Ian J. Deng, Zixin Wang, Zhijun Wu, Hao Liang, Jingdan Wang, Jialiang Liang, Wei-Jun Gou, Lixia Wu, Qiulin Zhou, Xiufen Bruce, Ian J. Deng, Zixin Wang, Zhijun |
|---|---|
| author |
Wu, Hao Liang, Jingdan Wang, Jialiang Liang, Wei-Jun Gou, Lixia Wu, Qiulin Zhou, Xiufen Bruce, Ian J. Deng, Zixin Wang, Zhijun |
| spellingShingle |
Wu, Hao Liang, Jingdan Wang, Jialiang Liang, Wei-Jun Gou, Lixia Wu, Qiulin Zhou, Xiufen Bruce, Ian J. Deng, Zixin Wang, Zhijun Applied and Environmental Microbiology Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882 Ecology Applied Microbiology and Biotechnology Food Science Biotechnology |
| author_sort |
wu, hao |
| spelling |
Wu, Hao Liang, Jingdan Wang, Jialiang Liang, Wei-Jun Gou, Lixia Wu, Qiulin Zhou, Xiufen Bruce, Ian J. Deng, Zixin Wang, Zhijun 0099-2240 1098-5336 American Society for Microbiology Ecology Applied Microbiology and Biotechnology Food Science Biotechnology http://dx.doi.org/10.1128/aem.00586-18 <jats:title>ABSTRACT</jats:title> <jats:p> Calcimycin, N-demethyl calcimycin, and cezomycin are polyether divalent cation ionophore secondary metabolites produced by <jats:named-content content-type="genus-species">Streptomyces chartreusis</jats:named-content> . A thorough understanding of the organization of their encoding genes, biosynthetic pathway(s), and cation specificities is vitally important for their efficient future production and therapeutic use. So far, this has been lacking, as has information concerning any biosynthetic relationships that may exist between calcimycin and cezomycin. In this study, we observed that when a Cal <jats:sup>−</jats:sup> ( <jats:italic>calB1</jats:italic> mutant) derivative of a calcimycin-producing strain of <jats:named-content content-type="genus-species">S. chartreusis</jats:named-content> (NRRL 3882) was grown on cezomycin, calcimycin production was restored. This suggested that calcimycin synthesis may have resulted from postsynthetic modification of cezomycin rather than from a <jats:italic>de novo</jats:italic> process through a novel and independent biosynthetic mechanism. Systematic screening of a number of Cal <jats:sup>−</jats:sup> <jats:named-content content-type="genus-species">S. chartreusis</jats:named-content> mutants lacking the ability to convert cezomycin to calcimycin allowed the identification of a gene, provisionally named <jats:italic>calC</jats:italic> , which was involved in the conversion step. Molecular cloning and heterologous expression of the CalC protein along with its purification to homogeneity and negative-staining electron microscopy allowed the determination of its apparent molecular weight, oligomeric forms in solution, and activity. These experiments allowed us to confirm that the protein possessed ATP pyrophosphatase activity and was capable of ligating coenzyme A (CoA) with cezomycin but not 3-hydroxyanthranilic acid. The CalC protein's apparent <jats:italic> K <jats:sub>m</jats:sub> </jats:italic> and <jats:italic>k</jats:italic> <jats:sub>cat</jats:sub> for cezomycin were observed to be 190 μM and 3.98 min <jats:sup>−1</jats:sup> , respectively, and it possessed the oligomeric form in solution. Our results unequivocally show that cezomycin is postsynthetically modified to calcimycin by the CalC protein through its activation of cezomycin to a CoA ester form. </jats:p> <jats:p> <jats:bold>IMPORTANCE</jats:bold> Calcimycin is a secondary metabolite divalent cation-ionophore that has been studied in the context of human health. However, detail is lacking with respect to both calcimycin's biosynthesis and its biochemical/biophysical properties as well as information regarding its, and its analogues', divalent cation binding specificities and other activities. Such knowledge would be useful in understanding how calcimycin and related compounds may be effective in modifying the calcium channel ion flux and might be useful in influencing the homeostasis of magnesium and manganese ions for the cure or control of human and bacterial infectious diseases. The results presented here unequivocally show that CalC protein is essential for the production of calcimycin, which is essentially a derivative of cezomycin, and allow us to propose a biosynthetic mechanism for calcimycin's production. </jats:p> Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882 Applied and Environmental Microbiology |
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10.1128/aem.00586-18 |
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American Society for Microbiology, 2018 |
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American Society for Microbiology, 2018 |
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American Society for Microbiology |
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Applied and Environmental Microbiology |
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| title |
Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882 |
| title_unstemmed |
Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882 |
| title_full |
Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882 |
| title_fullStr |
Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882 |
| title_full_unstemmed |
Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882 |
| title_short |
Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882 |
| title_sort |
cezomycin is activated by calc to its ester form for further biosynthesis steps in the production of calcimycin in streptomyces chartreusis nrrl 3882 |
| topic |
Ecology Applied Microbiology and Biotechnology Food Science Biotechnology |
| url |
http://dx.doi.org/10.1128/aem.00586-18 |
| publishDate |
2018 |
| physical |
|
| description |
<jats:title>ABSTRACT</jats:title>
<jats:p>
Calcimycin, N-demethyl calcimycin, and cezomycin are polyether divalent cation ionophore secondary metabolites produced by
<jats:named-content content-type="genus-species">Streptomyces chartreusis</jats:named-content>
. A thorough understanding of the organization of their encoding genes, biosynthetic pathway(s), and cation specificities is vitally important for their efficient future production and therapeutic use. So far, this has been lacking, as has information concerning any biosynthetic relationships that may exist between calcimycin and cezomycin. In this study, we observed that when a Cal
<jats:sup>−</jats:sup>
(
<jats:italic>calB1</jats:italic>
mutant) derivative of a calcimycin-producing strain of
<jats:named-content content-type="genus-species">S. chartreusis</jats:named-content>
(NRRL 3882) was grown on cezomycin, calcimycin production was restored. This suggested that calcimycin synthesis may have resulted from postsynthetic modification of cezomycin rather than from a
<jats:italic>de novo</jats:italic>
process through a novel and independent biosynthetic mechanism. Systematic screening of a number of Cal
<jats:sup>−</jats:sup>
<jats:named-content content-type="genus-species">S. chartreusis</jats:named-content>
mutants lacking the ability to convert cezomycin to calcimycin allowed the identification of a gene, provisionally named
<jats:italic>calC</jats:italic>
, which was involved in the conversion step. Molecular cloning and heterologous expression of the CalC protein along with its purification to homogeneity and negative-staining electron microscopy allowed the determination of its apparent molecular weight, oligomeric forms in solution, and activity. These experiments allowed us to confirm that the protein possessed ATP pyrophosphatase activity and was capable of ligating coenzyme A (CoA) with cezomycin but not 3-hydroxyanthranilic acid. The CalC protein's apparent
<jats:italic>
K
<jats:sub>m</jats:sub>
</jats:italic>
and
<jats:italic>k</jats:italic>
<jats:sub>cat</jats:sub>
for cezomycin were observed to be 190 μM and 3.98 min
<jats:sup>−1</jats:sup>
, respectively, and it possessed the oligomeric form in solution. Our results unequivocally show that cezomycin is postsynthetically modified to calcimycin by the CalC protein through its activation of cezomycin to a CoA ester form.
</jats:p>
<jats:p>
<jats:bold>IMPORTANCE</jats:bold>
Calcimycin is a secondary metabolite divalent cation-ionophore that has been studied in the context of human health. However, detail is lacking with respect to both calcimycin's biosynthesis and its biochemical/biophysical properties as well as information regarding its, and its analogues', divalent cation binding specificities and other activities. Such knowledge would be useful in understanding how calcimycin and related compounds may be effective in modifying the calcium channel ion flux and might be useful in influencing the homeostasis of magnesium and manganese ions for the cure or control of human and bacterial infectious diseases. The results presented here unequivocally show that CalC protein is essential for the production of calcimycin, which is essentially a derivative of cezomycin, and allow us to propose a biosynthetic mechanism for calcimycin's production.
</jats:p> |
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| description | <jats:title>ABSTRACT</jats:title> <jats:p> Calcimycin, N-demethyl calcimycin, and cezomycin are polyether divalent cation ionophore secondary metabolites produced by <jats:named-content content-type="genus-species">Streptomyces chartreusis</jats:named-content> . A thorough understanding of the organization of their encoding genes, biosynthetic pathway(s), and cation specificities is vitally important for their efficient future production and therapeutic use. So far, this has been lacking, as has information concerning any biosynthetic relationships that may exist between calcimycin and cezomycin. In this study, we observed that when a Cal <jats:sup>−</jats:sup> ( <jats:italic>calB1</jats:italic> mutant) derivative of a calcimycin-producing strain of <jats:named-content content-type="genus-species">S. chartreusis</jats:named-content> (NRRL 3882) was grown on cezomycin, calcimycin production was restored. This suggested that calcimycin synthesis may have resulted from postsynthetic modification of cezomycin rather than from a <jats:italic>de novo</jats:italic> process through a novel and independent biosynthetic mechanism. Systematic screening of a number of Cal <jats:sup>−</jats:sup> <jats:named-content content-type="genus-species">S. chartreusis</jats:named-content> mutants lacking the ability to convert cezomycin to calcimycin allowed the identification of a gene, provisionally named <jats:italic>calC</jats:italic> , which was involved in the conversion step. Molecular cloning and heterologous expression of the CalC protein along with its purification to homogeneity and negative-staining electron microscopy allowed the determination of its apparent molecular weight, oligomeric forms in solution, and activity. These experiments allowed us to confirm that the protein possessed ATP pyrophosphatase activity and was capable of ligating coenzyme A (CoA) with cezomycin but not 3-hydroxyanthranilic acid. The CalC protein's apparent <jats:italic> K <jats:sub>m</jats:sub> </jats:italic> and <jats:italic>k</jats:italic> <jats:sub>cat</jats:sub> for cezomycin were observed to be 190 μM and 3.98 min <jats:sup>−1</jats:sup> , respectively, and it possessed the oligomeric form in solution. Our results unequivocally show that cezomycin is postsynthetically modified to calcimycin by the CalC protein through its activation of cezomycin to a CoA ester form. </jats:p> <jats:p> <jats:bold>IMPORTANCE</jats:bold> Calcimycin is a secondary metabolite divalent cation-ionophore that has been studied in the context of human health. However, detail is lacking with respect to both calcimycin's biosynthesis and its biochemical/biophysical properties as well as information regarding its, and its analogues', divalent cation binding specificities and other activities. Such knowledge would be useful in understanding how calcimycin and related compounds may be effective in modifying the calcium channel ion flux and might be useful in influencing the homeostasis of magnesium and manganese ions for the cure or control of human and bacterial infectious diseases. The results presented here unequivocally show that CalC protein is essential for the production of calcimycin, which is essentially a derivative of cezomycin, and allow us to propose a biosynthetic mechanism for calcimycin's production. </jats:p> |
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| spelling | Wu, Hao Liang, Jingdan Wang, Jialiang Liang, Wei-Jun Gou, Lixia Wu, Qiulin Zhou, Xiufen Bruce, Ian J. Deng, Zixin Wang, Zhijun 0099-2240 1098-5336 American Society for Microbiology Ecology Applied Microbiology and Biotechnology Food Science Biotechnology http://dx.doi.org/10.1128/aem.00586-18 <jats:title>ABSTRACT</jats:title> <jats:p> Calcimycin, N-demethyl calcimycin, and cezomycin are polyether divalent cation ionophore secondary metabolites produced by <jats:named-content content-type="genus-species">Streptomyces chartreusis</jats:named-content> . A thorough understanding of the organization of their encoding genes, biosynthetic pathway(s), and cation specificities is vitally important for their efficient future production and therapeutic use. So far, this has been lacking, as has information concerning any biosynthetic relationships that may exist between calcimycin and cezomycin. In this study, we observed that when a Cal <jats:sup>−</jats:sup> ( <jats:italic>calB1</jats:italic> mutant) derivative of a calcimycin-producing strain of <jats:named-content content-type="genus-species">S. chartreusis</jats:named-content> (NRRL 3882) was grown on cezomycin, calcimycin production was restored. This suggested that calcimycin synthesis may have resulted from postsynthetic modification of cezomycin rather than from a <jats:italic>de novo</jats:italic> process through a novel and independent biosynthetic mechanism. Systematic screening of a number of Cal <jats:sup>−</jats:sup> <jats:named-content content-type="genus-species">S. chartreusis</jats:named-content> mutants lacking the ability to convert cezomycin to calcimycin allowed the identification of a gene, provisionally named <jats:italic>calC</jats:italic> , which was involved in the conversion step. Molecular cloning and heterologous expression of the CalC protein along with its purification to homogeneity and negative-staining electron microscopy allowed the determination of its apparent molecular weight, oligomeric forms in solution, and activity. These experiments allowed us to confirm that the protein possessed ATP pyrophosphatase activity and was capable of ligating coenzyme A (CoA) with cezomycin but not 3-hydroxyanthranilic acid. The CalC protein's apparent <jats:italic> K <jats:sub>m</jats:sub> </jats:italic> and <jats:italic>k</jats:italic> <jats:sub>cat</jats:sub> for cezomycin were observed to be 190 μM and 3.98 min <jats:sup>−1</jats:sup> , respectively, and it possessed the oligomeric form in solution. Our results unequivocally show that cezomycin is postsynthetically modified to calcimycin by the CalC protein through its activation of cezomycin to a CoA ester form. </jats:p> <jats:p> <jats:bold>IMPORTANCE</jats:bold> Calcimycin is a secondary metabolite divalent cation-ionophore that has been studied in the context of human health. However, detail is lacking with respect to both calcimycin's biosynthesis and its biochemical/biophysical properties as well as information regarding its, and its analogues', divalent cation binding specificities and other activities. Such knowledge would be useful in understanding how calcimycin and related compounds may be effective in modifying the calcium channel ion flux and might be useful in influencing the homeostasis of magnesium and manganese ions for the cure or control of human and bacterial infectious diseases. The results presented here unequivocally show that CalC protein is essential for the production of calcimycin, which is essentially a derivative of cezomycin, and allow us to propose a biosynthetic mechanism for calcimycin's production. </jats:p> Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882 Applied and Environmental Microbiology |
| spellingShingle | Wu, Hao, Liang, Jingdan, Wang, Jialiang, Liang, Wei-Jun, Gou, Lixia, Wu, Qiulin, Zhou, Xiufen, Bruce, Ian J., Deng, Zixin, Wang, Zhijun, Applied and Environmental Microbiology, Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882, Ecology, Applied Microbiology and Biotechnology, Food Science, Biotechnology |
| title | Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882 |
| title_full | Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882 |
| title_fullStr | Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882 |
| title_full_unstemmed | Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882 |
| title_short | Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882 |
| title_sort | cezomycin is activated by calc to its ester form for further biosynthesis steps in the production of calcimycin in streptomyces chartreusis nrrl 3882 |
| title_unstemmed | Cezomycin Is Activated by CalC to Its Ester Form for Further Biosynthesis Steps in the Production of Calcimycin in Streptomyces chartreusis NRRL 3882 |
| topic | Ecology, Applied Microbiology and Biotechnology, Food Science, Biotechnology |
| url | http://dx.doi.org/10.1128/aem.00586-18 |