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Structural insight into the substrate inhibition mechanism of NADP(+)-dependent succinic semialdehyde dehydrogenase from Streptococcus pyogenes

Authors
Jang, Eun HyukPark, Seong AhChi, Young MinLee, Ki Seog
Issue Date
5-6월-2015
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
Keywords
Succinic semialdehyde dehydrogenase; Streptococcus pyogenes; Substrate inhibition; ESS-complex structure
Citation
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, v.461, no.3, pp.487 - 493
Indexed
SCIE
SCOPUS
Journal Title
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume
461
Number
3
Start Page
487
End Page
493
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/93281
DOI
10.1016/j.bbrc.2015.04.047
ISSN
0006-291X
Abstract
Succinic semialdehyde dehydrogenases (SSADHs) are ubiquitous enzymes that catalyze the oxidation of succinic semialdehyde (SSA) to succinic acid in the presence of NAD(P)(+), and play an important role in the cellular mechanisms including the detoxification of accumulated SSA or the survival in conditions of limited nutrients. Here, we report the inhibitory properties and two crystal structures of SSADH from Streptococcus pyogenes (SpSSADH) in a binary (ES) complex with SSA as the substrate and a ternary (ESS) complex with the substrate SSA and the inhibitory SSA, at 2.4 angstrom resolution for both structures. Analysis of the kinetic inhibitory parameters revealed significant substrate inhibition in the presence of NADP at concentrations of SSA higher than 0.02 mM, which exhibited complete uncompetitive substrate inhibition with the inhibition constant (K-i) value of 0.10 +/- 0.02 mM. In ES-complex of SpSSADH, the SSA showed a tightly bound bent form nearby the catalytic residues, which may be caused by reduction of the cavity volume for substrate binding, compared with other SSADHs. Moreover, structural comparison of ESS-complex with a binary complex with NADP(+) of SpSSADH indicated that the substrate inhibition was induced by the binding of inhibitory SSA in the cofactor-binding site, instead of NADP(+). Our results provide first structure-based molecular insights into the substrate inhibition mechanism of SpSSADH as the Gram-positive bacterial SSADH. (C) 2015 Elsevier Inc. All rights reserved.
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생명과학대학 (생명공학부)
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