The sedoheptulose 7-phosphate cyclases and their emerging roles in biology and ecology

Abstract

Covering up to: 1999-2016This highlight covers a family of enzymes of growing importance, the sedoheptulose 7-phosphate cyclases, initially of interest due to their involvement in the biosynthesis of pharmaceutically relevant secondary metabolites. More recently, these enzymes have been found throughout Prokarya and Eukarya, suggesting their broad potential biological roles in nature.

Figure 1

Sugar phosphate cyclases (SPCs), their products, and representative natural products resulting from their pathways. Glc6P, glucose 6-phosphate; SH7P, sedoheptulose 7-phosphate; E4P, erythrose 4-phosphate; iminoE4P, imino-erythrose 4-phosphate; EEV, 2-epi-5-epi-valiolone, EV, 2-epi-valiolone, DDG, desmethyl-4-deoxygadusol; DHQ, 3-dehydroquinate; aDHQ, 3-aminodehydroquinate; DOI, 2-deoxy-scyllo-inosose.

Figure 2

Proposed catalytic mechanisms for EEVS and DDGS. (A) Proposed mechanism for EEVS. (B) Proposed mechanism for DDGS.

Figure 3

Overall structure and topology of known SH7PCs, EEVS and DDGS. (A) Overlay of the dimers of the Ava_3858 (teal and orange; PDB code 5TPR) and ValA (purple and green; PDB code 4P53) are shown with the N-terminal NAD⁺-binding domains in light hues and C-terminal metal-binding domains in dark hues. The NAD⁺ and Zn²⁺ with its coordinating ligands are shown for each. Secondary structural elements in each domain of one monomer are labeled. (B) Topology diagram showing α-helices (cylinders), β-strands (arrows), 3₁₀ helices (triangular prisms) and π-helices (wider cylinder) common to EEVS and DDGS. The domains are colored light and dark teal as indicated, and helices (H) and strands (β) common to the SPCs are named within each domain. The domain swapped β-strand β1 from the other subunit of the dimer but contributing to the NAD⁺-binding domain of the teal subunit is colored in light orange. The three Zn²⁺-binding residues (red asterisks) and glycine-rich turn and conserved aspartic acids (green asterisks) important for NAD⁺ binding are indicated.

Figure 4

Proposed enzyme-specific selection of forms of sedoheptulose 7-phosphate (SH7P). EEV, 2-epi-5-epi-valiolone; DDG, desmethyl-4-deoxygadusol; EV, 2-epi-valiolone.

Figure 5

Substrate recognition by SH7PCs. (A) The boat conformation of DAHP as it coordinates Zn²⁺ in the DHQS active site has both Zn-ligating hydroxyls equatorial, yet in SH7P one putative Zn-ligating hydroxyl is equatorial while the other Zn-ligating hydroxyl is axial. (B) Speculative binding mode of SH7P in EEVS and DDGS. The α-pyranose anomer of SH7P (magenta) manually docked into the active site of Ava_3858 (teal) with bound zinc (silver sphere). The electron density (grey, contoured at 1.3ρ_rms) evidence for the bound waters (red spheres) and sulfate (yellow) is shown along with proposed interactions of the docked SH7P with the active site (dashed lines). While Lys156 and Arg265 have short approach distances in this model, we expect these sidechains will move due to an anticipated conformation change upon substrate binding. The coordination of Zn with its three ligating residues are also shown (solid black lines). The carbons of SH7P the protein side chains and NAD⁺ are labeled, with a prime symbol meaning the side chain comes from the other subunit of the dimer.

Figure 6

Chemical structures of kirkamide, gadusol, and representatives of mycosporines and MAAs. Some stereoconfigurations were not assigned.

Figure 7

Distribution of gadusol and MAAs through different tropic levels of the marine environment. Some microorganisms, algae, and corals can produce MAA de novo, where as gadusol is mostly produced by non-mammalian vertebrates, such as fish.