Biochemistry and Crystal Structure of Ectoine Synthase: A Metal-Containing Member of the Cupin Superfamily

PLoS One. 2016 Mar 17;11(3):e0151285. doi: 10.1371/journal.pone.0151285. eCollection 2016.

Abstract

Ectoine is a compatible solute and chemical chaperone widely used by members of the Bacteria and a few Archaea to fend-off the detrimental effects of high external osmolarity on cellular physiology and growth. Ectoine synthase (EctC) catalyzes the last step in ectoine production and mediates the ring closure of the substrate N-gamma-acetyl-L-2,4-diaminobutyric acid through a water elimination reaction. However, the crystal structure of ectoine synthase is not known and a clear understanding of how its fold contributes to enzyme activity is thus lacking. Using the ectoine synthase from the cold-adapted marine bacterium Sphingopyxis alaskensis (Sa), we report here both a detailed biochemical characterization of the EctC enzyme and the high-resolution crystal structure of its apo-form. Structural analysis classified the (Sa)EctC protein as a member of the cupin superfamily. EctC forms a dimer with a head-to-tail arrangement, both in solution and in the crystal structure. The interface of the dimer assembly is shaped through backbone-contacts and weak hydrophobic interactions mediated by two beta-sheets within each monomer. We show for the first time that ectoine synthase harbors a catalytically important metal co-factor; metal depletion and reconstitution experiments suggest that EctC is probably an iron-dependent enzyme. We found that EctC not only effectively converts its natural substrate N-gamma-acetyl-L-2,4-diaminobutyric acid into ectoine through a cyclocondensation reaction, but that it can also use the isomer N-alpha-acetyl-L-2,4-diaminobutyric acid as its substrate, albeit with substantially reduced catalytic efficiency. Structure-guided site-directed mutagenesis experiments targeting amino acid residues that are evolutionarily highly conserved among the extended EctC protein family, including those forming the presumptive iron-binding site, were conducted to functionally analyze the properties of the resulting EctC variants. An assessment of enzyme activity and iron content of these mutants give important clues for understanding the architecture of the active site positioned within the core of the EctC cupin barrel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acids, Diamino / chemistry
  • Amino Acids, Diamino / metabolism
  • Aminobutyrates / chemistry
  • Aminobutyrates / metabolism
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Biocatalysis / drug effects
  • Crystallography, X-Ray
  • Hydro-Lyases / chemistry*
  • Hydro-Lyases / genetics
  • Hydro-Lyases / metabolism
  • Hydrogen-Ion Concentration
  • Iron / chemistry
  • Iron / metabolism
  • Kinetics
  • Magnetic Resonance Spectroscopy / methods
  • Metals / chemistry*
  • Metals / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Potassium Chloride / pharmacology
  • Protein Conformation
  • Protein Multimerization
  • Sequence Homology, Amino Acid
  • Sodium Chloride / pharmacology
  • Sphingomonadaceae / enzymology*
  • Sphingomonadaceae / genetics
  • Substrate Specificity
  • Temperature

Substances

  • Amino Acids, Diamino
  • Aminobutyrates
  • Bacterial Proteins
  • Metals
  • 2,4-diaminobutyric acid
  • Sodium Chloride
  • Potassium Chloride
  • ectoine
  • Iron
  • Hydro-Lyases
  • ectoine synthase

Grants and funding

This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (DFG) through the SFB 987 (Philipps-University Marburg; to J.H. and E.B.), by the LOEWE program of the state of Hessen (via the Center for Synthetic Microbiology, Marburg; to J.H. and E.B.), by the Strategischer Forschungs-Fond (SFF) (Heinrich-Heine-University Düsseldorf and its Institute of Biochemistry; to S.H.J.S.) and the DFG-funded Transregio SFB TR41 (Braunschweig/Oldenburg; to J.S.D.). N.W. is the recipient of a Ph.D. fellowship from the International Max Planck Research School for Environmental, Cellular and Molecular Microbiology (IMPRS-Mic, Marburg) and gratefully acknowledges its generous support.