title: Transmitting the allosteric signal in methylglyoxal synthase.
abstract: The homohexameric enzyme methylglyoxal synthase (MGS) converts dihydroxyacetone phosphate (DHAP) to methylglyoxal and phosphate. This enzyme is allosterically inhibited by phosphate. The allosteric signal induced by phosphate in MGS from Thermus sp. GH5 (TMGS) has been tracked by site-directed mutagenesis, from the binding site of phosphate to the pathways that transmit the signal, and finally to the active site which is the receiver of the signal. In TMGS, Ser-55 distinguishes the inhibitory phosphate from the phosphoryl group of the substrate, DHAP, and transmits the allosteric signal through Pro-82, Arg-97 and Val-101 to the active site. Furthermore, the addition of a C-terminal tail to TMGS reinforces the allosteric signal by introducing a new salt bridge between Asp-10 and an Arg in this tail. Lastly, the active site amino acid, Gly-56, is shown to be involved in both allostery and phosphate elimination step from DHAP by TMGS. Interestingly, some of the mutations also trigger homotropic allostery, supporting the hypothesis that allostery is an intrinsic property of all dynamic proteins. The details of the TMGS allosteric network discussed in this study can serve as a model system for understanding the enigmatic allosteric mechanism of other proteins.
authors.affiliation: Department of Quantitative and Computational Biology, Princeton University, Princeton, NJ, USA.
authors.forename: Hanieh
authors.initials: H
authors.lastname: Falahati
authors.forename: Mohammad
authors.initials: M
authors.lastname: Pazhang
authors.forename: Shekufeh
authors.initials: S
authors.lastname: Zareian
authors.forename: Nasser
authors.initials: N
authors.lastname: Ghaemi
authors.forename: Reza
authors.initials: R
authors.lastname: Rofougaran
authors.forename: Anders
authors.initials: A
authors.lastname: Hofer
authors.forename: Alireza R
authors.initials: AR
authors.lastname: Rezaie
authors.forename: Khosro
authors.initials: K
authors.lastname: Khajeh
mesh_terms: D000494:Allosteric Regulation; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D019757:Carbon-Oxygen Lyases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D004099:Dihydroxyacetone Phosphate / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D016297:Mutagenesis, Site-Directed; D012694:Serine / Q000235:genetics / Q000378:metabolism; D013824:Thermus / Q000201:enzymology / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D012694:Serine; D004099:Dihydroxyacetone Phosphate; D019757:Carbon-Oxygen Lyases; C021578:methylglyoxal synthase
keywords: allosteric pathway; inhibition; mechanism of allostery; methylglyoxal synthase from Thermus sp. GH5 (TMGS); triggered allostery