Structural Insight into MtmC, a Bifunctional Ketoreductase-Methyltransferase Involved in the Assembly of the Mithramycin Trisaccharide Chain.
| Title: | Structural Insight into MtmC, a Bifunctional Ketoreductase-Methyltransferase Involved in the Assembly of the Mithramycin Trisaccharide Chain. |
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| Authors: | Jhong-Min Chen1, Caixia Hou1, Guojun Wang1, Tsodikov, Oleg V.1 ovts222@uky.edu, Rohr, Jürgen1 jrohr2@email.uky.edu |
| Source: | Biochemistry. 4/21/2015, Vol. 54 Issue 15, p2481-2489. 9p. |
| Subject Terms: | *METHYLTRANSFERASES, *TRISACCHARIDES, *ANTINEOPLASTIC antibiotics, *STREPTOMYCES, *CRYSTAL structure, *NICOTINAMIDE adenine dinucleotide phosphate |
| Abstract: | More and more post-PKS tailoring enzymes are recognized as being multifunctional and codependent on other tailoring enzymes. One of the recently discovered intriguing examples is MtmC, a bifunctional TDP-4-keto-d-olivose ketoreductase-methyltransferase, which—in codependence with glycosyltransferase MtmGIV—is a key contributor to the biosynthesis of the critical trisaccharide chain of the antitumor antibiotic mithramycin (MTM), produced by Streptomyces argillaceus. We report crystal structures of three binary complexes of MtmC with its methylation cosubstrate SAM, its coproduct SAH, and a nucleotide TDP as well as crystal structures of two ternary complexes, MtmC-SAH-TDP-4-keto-d-olivose and MtmC-SAM-TDP, in the range of 2.2-2.7 Å resolution. The structures reveal general and sugar-specific recognition and catalytic structural features of MtmC. Depending on the catalytic function that is conducted by MtmC, it must bind either NADPH or SAM in the same cofactor binding pocket. A tyrosine residue (Tyr79) appears as a lid covering the sugar moiety of the substrate during the methyl transfer reaction. This residue swings out of the active site by ~180° in the absence of the substrate. This unique conformational change likely serves to release the methylated product and, possibly, to open the active site for binding the bulkier cosubstrate NADPH prior to the reduction reaction. [ABSTRACT FROM AUTHOR] |
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| Items | – Name: Title Label: Title Group: Ti Data: Structural Insight into MtmC, a Bifunctional Ketoreductase-Methyltransferase Involved in the Assembly of the Mithramycin Trisaccharide Chain. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Jhong-Min+Chen%22">Jhong-Min Chen</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Caixia+Hou%22">Caixia Hou</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Guojun+Wang%22">Guojun Wang</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Tsodikov%2C+Oleg+V%2E%22">Tsodikov, Oleg V.</searchLink><relatesTo>1</relatesTo><i> ovts222@uky.edu</i><br /><searchLink fieldCode="AR" term="%22Rohr%2C+Jürgen%22">Rohr, Jürgen</searchLink><relatesTo>1</relatesTo><i> jrohr2@email.uky.edu</i> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Biochemistry%22">Biochemistry</searchLink>. 4/21/2015, Vol. 54 Issue 15, p2481-2489. 9p. – Name: Subject Label: Subject Terms Group: Su Data: *<searchLink fieldCode="DE" term="%22METHYLTRANSFERASES%22">METHYLTRANSFERASES</searchLink><br />*<searchLink fieldCode="DE" term="%22TRISACCHARIDES%22">TRISACCHARIDES</searchLink><br />*<searchLink fieldCode="DE" term="%22ANTINEOPLASTIC+antibiotics%22">ANTINEOPLASTIC antibiotics</searchLink><br />*<searchLink fieldCode="DE" term="%22STREPTOMYCES%22">STREPTOMYCES</searchLink><br />*<searchLink fieldCode="DE" term="%22CRYSTAL+structure%22">CRYSTAL structure</searchLink><br />*<searchLink fieldCode="DE" term="%22NICOTINAMIDE+adenine+dinucleotide+phosphate%22">NICOTINAMIDE adenine dinucleotide phosphate</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: More and more post-PKS tailoring enzymes are recognized as being multifunctional and codependent on other tailoring enzymes. One of the recently discovered intriguing examples is MtmC, a bifunctional TDP-4-keto-d-olivose ketoreductase-methyltransferase, which—in codependence with glycosyltransferase MtmGIV—is a key contributor to the biosynthesis of the critical trisaccharide chain of the antitumor antibiotic mithramycin (MTM), produced by Streptomyces argillaceus. We report crystal structures of three binary complexes of MtmC with its methylation cosubstrate SAM, its coproduct SAH, and a nucleotide TDP as well as crystal structures of two ternary complexes, MtmC-SAH-TDP-4-keto-d-olivose and MtmC-SAM-TDP, in the range of 2.2-2.7 Å resolution. The structures reveal general and sugar-specific recognition and catalytic structural features of MtmC. Depending on the catalytic function that is conducted by MtmC, it must bind either NADPH or SAM in the same cofactor binding pocket. A tyrosine residue (Tyr79) appears as a lid covering the sugar moiety of the substrate during the methyl transfer reaction. This residue swings out of the active site by ~180° in the absence of the substrate. This unique conformational change likely serves to release the methylated product and, possibly, to open the active site for binding the bulkier cosubstrate NADPH prior to the reduction reaction. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Biochemistry is the property of American Chemical Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1021/bi501462g Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 9 StartPage: 2481 Subjects: – SubjectFull: METHYLTRANSFERASES Type: general – SubjectFull: TRISACCHARIDES Type: general – SubjectFull: ANTINEOPLASTIC antibiotics Type: general – SubjectFull: STREPTOMYCES Type: general – SubjectFull: CRYSTAL structure Type: general – SubjectFull: NICOTINAMIDE adenine dinucleotide phosphate Type: general Titles: – TitleFull: Structural Insight into MtmC, a Bifunctional Ketoreductase-Methyltransferase Involved in the Assembly of the Mithramycin Trisaccharide Chain. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Jhong-Min Chen – PersonEntity: Name: NameFull: Caixia Hou – PersonEntity: Name: NameFull: Guojun Wang – PersonEntity: Name: NameFull: Tsodikov, Oleg V. – PersonEntity: Name: NameFull: Rohr, Jürgen IsPartOfRelationships: – BibEntity: Dates: – D: 21 M: 04 Text: 4/21/2015 Type: published Y: 2015 Identifiers: – Type: issn-print Value: 00062960 Numbering: – Type: volume Value: 54 – Type: issue Value: 15 Titles: – TitleFull: Biochemistry Type: main |
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