4YWU

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

Summary for 4YWU

• Entry DOI: 10.2210/pdb4ywu/pdb
• Related: 4OGD 4OHT 4YWV
• Descriptor: Succinic semialdehyde dehydrogenase, 4-oxobutanoic acid, SULFATE ION, ... (4 entities in total)
• Functional Keywords: succinic semialdehyde dehydrogenase, streptococcus pyogenes, substrate inhibition, es-complex structure, oxidoreductase
• Biological source: Streptococcus pyogenes MGAS1882
• Total number of polymer chains: 2
• Total formula weight: 104310.88

Authors

Jang, E.H.,Park, S.A.,Chi, Y.M.,Lee, K.S. (deposition date: 2015-03-21, release date: 2015-05-06, Last modification date: 2023-11-08)

Primary citation

Jang, E.H.,Park, S.A.,Chi, Y.M.,Lee, K.S.
Structural insight into the substrate inhibition mechanism of NADP(+)-dependent succinic semialdehyde dehydrogenase from Streptococcus pyogenes.
Biochem.Biophys.Res.Commun., 461:487-493, 2015

PubMed 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 Å 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 (Ki) 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.

PubMed: 25888791
DOI: 10.1016/j.bbrc.2015.04.047

Experimental method

X-RAY DIFFRACTION (2.4 Å)