Saccharomyces cerevisiae oxidosqualene‐lanosterol cyclase: A chemistry–biology interdisciplinary study of the protein's structure–function–reaction mechanism relationships

Abstract

The oxidosqualene cyclases (EC 5.4.99-) constitute a family of enzymes that catalyze diverse cyclization/rearrangement reactions of (3S)-2,3-oxidosqualene into a distinct array of sterols and triterpenes. The relationship between the cyclization mechanism and the enzymatic structure is extremely complex and compelling. This review covers the historical achievements of biomimetic studies and current progress in structural biology, molecular genetics, and bioinformatics studies to elucidate the mechanistic and structure-function relationships of the Saccharomyces cerevisiae oxidosqualene-lanosterol cyclase-catalyzed cyclization/rearrangement reaction.

Biosynthesis of Cholesterol and Other Sterols

“…65,84−86 The cloned and purified human oxidosqualene cyclase is active as a monomer, whereas the corresponding purified enzyme from bovine liver exhibited active forms of 70 and 140 kDa, suggesting dimer organization. 87,88 Insight into lanosterol scaffold formation from the recently determined structure of human oxidosqualene synthase reveals the presence of a cavity, shaped so as to accept the substrate prefolded product-like conformation.…”

“…A final elimination reaction takes place at C9α to produce lanosterol. 65,66 In contrast to formation of a “flat” Δ 8(9) -sterol, formation of “bent” cycloartenol requires the product bend through almost 90° to accommodate the 9β,19-cyclopropane-8β-H bridgehead in which the 19-CH 3 and 8H-atom are cis to one another. 5,14,24,67,68 For “bent” cycloartenol formation, a distinct enzyme–substrate interaction from the one involved at C20 is considered to intercept the positive charge generated at C9α (Figure 8).…”

“…Examination of yeast ERG 7 homology structure and human OSC structure suggest that Tyr 707 and Tyr 99 residues in the Saccharomyces cerevisiae ScERG 7 might play an important role in stabilizing the C8 cation during the formation of the second cyclohexyl ring and the final lanosterol C9 cation. (65) On the other hand, Thomas and colleagues suggest the relevant active site amino acid in the human synthase occurs at His 232 , which is a strictly conserved residue among the oxidosqualene cyclases,(89) whereas Christianson noted that Tyr 503 could possibly accept this proton because it is closer and better-oriented with regard to the C9 proton that is ultimately eliminated to form lanosterol. (92)…”

Identification of genes related to nitrogen uptake in wine strains of Saccharomyces cerevisiae

“…Gene RDL1 showed a high expression in strains AC114 and AC115, which were characterized by showing a low consumption of total nitrogen and nitrogen from ammonium, respectively. Although this gene encodes for a protein of unknown function induced by the lack of zinc (Wu et al 2008), it has a cystiol domain which would participate in its regulation by nitrosylation. In the case of ICY1, its upregulation has been described in amino acid starvation (Dunn and Jensen 2003;Kleinschmidt et al 2005;Suzuki et al 2003).…”

Friedelin Synthase from Maytenus ilicifolia: Leucine 482 Plays an Essential Role in the Production of the Most Rearranged Pentacyclic Triterpene

“…Among the oxidosqualene cyclases (OSCs), the tetracyclic triterpene synthases lanosterol synthase and cycloartenol synthase are the most studied and have several structural features involved in the cyclization rearrangement specificity of their products28293031. Nevertheless, there is only one representative oxidosqualene cyclase (OSC) structure available in the protein data bank from Homo sapiens 32 and one squalene cyclase from Alicyclobacillus acidocaldarius 33.…”