Structure and Function of a Squalene Cyclase

• Published in: Science (American Association for the Advancement of Science) 1997-09, Vol.277 (5333), p.1811-1815
• Main Authors: Wendt, K. Ulrich, Poralla, Karl, Schulz, Georg E.
• Format: Article
• Language: English
• Subjects: Active sites; Alicyclobacillus acidocaldarius; Amino Acid Sequence; Amino acids; Analytical, structural and metabolic biochemistry; Atoms; Bacillaceae - enzymology; Binding Sites; Biochemistry; Biological and medical sciences; Cell Membrane - enzymology; Chemical bases; Chemistry; Crystal structure; Crystallization; Crystallography; Crystallography, X-Ray; Crystals; Cyclization; Cyclization (Chemistry); Dimerization; Electrons; Enzyme structure-activity relationships; Enzymes; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Humans; Hydrogen Bonding; Intramolecular Transferases; Isomerases - chemistry; Isomerases - metabolism; Lyases; Membrane proteins; Models, Molecular; Molecular Sequence Data; Protein Conformation; Protein Folding; Protein Structure, Secondary; Proteins; Protons; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Ring formation (Chemistry); Scientific Concepts; Sequence Alignment; Squalene; Squalene - metabolism; Structure-activity relationship; Thermodynamics
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.277.5333.1811

The crystal structure of squalene-hopene cyclase from Alicyclobacillus acidocaldarius was determined at 2.9 angstrom resolution. The mechanism and sequence of this cyclase are closely related to those of 2,3-oxidosqualene cyclases that catalyze the cyclization step in cholesterol biosynthesis. The structure reveals a membrane protein with membrane-binding characteristics similar to those of prostaglandin-H$_2$ synthase, the only other reported protein of this type. The active site of the enzyme is located in a large central cavity that is of suitable size to bind squalene in its required conformation and that is lined by aromatic residues. The structure supports a mechanism in which the acid starting the reaction by protonating a carbon-carbon double bond is an aspartate that is coupled to a histidine. Numerous surface α helices are connected by characteristic QW-motifs (Q is glutamine and W is tryptophan) that tighten the protein structure, possibly for absorbing the reaction energy without structural damage.