Structure of 2-deoxy-scyllo-inosose synthase, a key enzyme in the biosynthesis of 2-deoxystreptamine-containing aminoglycoside antibiotics, in complex with a mechanism-based inhibitor and NAD+.

Structure of 2-deoxy-scyllo-inosose synthase, a key enzyme in the biosynthesis of 2-deoxystreptamine-containing aminoglycoside antibiotics, in complex with a mechanism-based inhibitor and NAD+. Research Abstract Details 

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Structure of 2-deoxy-scyllo-inosose synthase, a key enzyme in the biosynthesis of 2-deoxystreptamine-containing aminoglycoside antibiotics, in complex with a mechanism-based inhibitor and NAD+. Abstract Text:

Eriko Nango,Takashi Kumasaka,Toshifumi Hirayama,Nobuo Tanaka,Tadashi Eguchi,Eriko Nango,Takashi Kumasaka,Toshifumi Hirayama,Nobuo Tanaka,Tadashi Eguchi,Eriko Nango,Takashi Kumasaka,Toshifumi Hirayama,Nobuo Tanaka,Tadashi Eguchi,

A key enzyme in the biosynthesis of clinically important aminoglycoside antibiotics is 2-deoxy-scyllo-inosose synthase (DOIS), which catalyzes carbocycle formation from D-glucose-6-phosphate to 2-deoxy-scyllo-inosose through a multistep reaction. This reaction mechanism is similar to the catalysis by dehydroquinate synthase (DHQS) of the cyclization of 3-deoxy-D-arabino-heputulosonate-7-phosphate to dehydroquinate in the shikimate pathway, but significant dissimilarity between these enzymes is also known, particularly in the stereochemistry of the phosphate elimination reaction and the cyclization. Here, the crystal structures of DOIS from Bacillus circulans and its complex with the substrate analog inhibitor carbaglucose-6-phosphate, NAD+, and Co2+ have been determined to provide structural insights into the reaction mechanism. The complex structure shows that an active site exists between the N-terminal and C-terminal domains and that the inhibitor coordinates a cobalt ion in this site. Two subunits exist as a dimer in the asymmetric unit. The two active sites of the dimer were observed to be different. One contains a dephosphorylated compound derived from the inhibitor and the other includes the inhibitor without change. The present study suggested that phosphate elimination proceeds through syn-elimination assisted by Glu 243 and the aldol condensation proceeds via a boat conformation. Also discussed are significant similarities and dissimilarities between DOIS and DHQS, particularly in terms of the structure at the active site and the reaction mechanism.

Structure of 2-deoxy-scyllo-inosose synthase, a key enzyme in the biosynthesis of 2-deoxystreptamine-containing aminoglycoside antibiotics, in complex with a mechanism-based inhibitor and NAD+. Publishing Authors By Initials

E Nango,T Kumasaka,T Hirayama,N Tanaka,T Eguchi,E Nango,T Kumasaka,T Hirayama,N Tanaka,T Eguchi,E Nango,T Kumasaka,T Hirayama,N Tanaka,T Eguchi,

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Structure of 2-deoxy-scyllo-inosose synthase, a key enzyme in the biosynthesis of 2-deoxystreptamine-containing aminoglycoside antibiotics, in complex with a mechanism-based inhibitor and NAD+. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Proteins

VOLUME: 70

Page Numbers: 517-27

Journal Abbreviation: Proteins

ISSN: 1097-0134

DAY: 1

MONTH: Feb

YEAR: 2008

Structure of 2-deoxy-scyllo-inosose synthase, a key enzyme in the biosynthesis of 2-deoxystreptamine-containing aminoglycoside antibiotics, in complex with a mechanism-based inhibitor and NAD+. Information

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LANGUAGE: eng

NlmUniqueID: 8700181

Structure of 2-deoxy-scyllo-inosose synthase, a key enzyme in the biosynthesis of 2-deoxystreptamine-containing aminoglycoside antibiotics, in complex with a mechanism-based inhibitor and NAD+. Keywords Mesh Terms:

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AFFILIATION: Department of Chemistry, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo 152-8551, Japan.

Country: United States

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