Structural insights into the inhibition properties of archaeon citrate synthase from Metallosphaera sedula

Metallosphaera sedula is a thermoacidophilic archaeon and has an incomplete TCA/glyoxylate cycle that is used for production of biosynthetic precursors of essential metabolites. Citrate synthase from M. sedula (MsCS) is an enzyme involved in the first step of the incomplete TCA/glyoxylate cycle by c...

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Bibliographic Details
Published in:PloS one 2019-02, Vol.14 (2), p.e0212807-e0212807
Main Authors: Lee, Seul Hoo, Son, Hyeoncheol Francis, Kim, Kyung-Jin
Format: Article
Language:English
Subjects:
Amino acids
Archaeal Proteins - antagonists & inhibitors
Archaeal Proteins - chemistry
Binding Sites
Biochemistry
Biology and Life Sciences
Citrate (si)-Synthase - antagonists & inhibitors
Citrate (si)-Synthase - chemistry
Citrate synthase
Citric acid
Coenzyme A
Crenarchaeota
Crystal structure
Crystallography, X-Ray
Dimers
Domains
Enzyme Inhibitors - chemistry
Enzymes
Glyoxylate cycle
Gram-positive bacteria
Inhibition
Metabolites
Metallosphaera sedula
Microorganisms
Mutation
NADH
Nicotinamide adenine dinucleotide
Physical Sciences
Physiological aspects
Polymerase chain reaction
Protein Multimerization
Protein Structure, Quaternary
Proteins
Substrate Specificity
Substrates
Sulfolobaceae - enzymology
Thiols
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Summary:Metallosphaera sedula is a thermoacidophilic archaeon and has an incomplete TCA/glyoxylate cycle that is used for production of biosynthetic precursors of essential metabolites. Citrate synthase from M. sedula (MsCS) is an enzyme involved in the first step of the incomplete TCA/glyoxylate cycle by converting oxaloacetate and acetyl-CoA into citrate and coenzyme A. To elucidate the inhibition properties of MsCS, we determined its crystal structure at 1.7 Å resolution. Like other Type-I CS, MsCS functions as a dimer and each monomer consists of two distinct domains, a large domain and a small domain. The oxaloacetate binding site locates at the cleft between the two domains, and the active site was more closed upon binding of the oxaloacetate substrate than binding of the citrate product. Interestingly, the inhibition kinetic analysis showed that, unlike other Type-I CSs, MsCS is non-competitively inhibited by NADH. Finally, amino acids and structural comparison of MsCS with other Type-II CSs, which were reported to be non-competitively inhibited by NADH, revealed that MsCS has quite unique NADH binding mode for non-competitive inhibition.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0212807