27JX

Crystal structure of the HVM1 in complex with oxovanadium, succinic acid and helvamide.

This is a non-PDB format compatible entry.

Summary for 27JX

• Entry DOI: 10.2210/pdb27jx/pdb
• Descriptor: oxidoreductase, SUCCINIC ACID, oxovanadium(2+), ... (5 entities in total)
• Functional Keywords: akg, sin, vvo, oxidoreductase
• Biological source: Aspergillus rugulosus
• Total number of polymer chains: 2
• Total formula weight: 65062.27

Authors

Zuo, J.Y.,Zhang, Z.M. (deposition date: 2026-06-03, release date: 2026-09-30)

Primary citation

Zhou, S.,Zhang, J.,Zuo, J.Y.,Yu, J.,Du, Y.F.,Wang, R.,Wu, C.,Zhang, G.,Shang, A.,Zhou, P.,Wang, Y.,Zhang, Z.M.,Li, H.,Liu, H.
Radical Mechanism and Stereochemical Control in Consecutive C-C Bond Formation by the Nonheme Iron Enzyme Hvm1.
J.Am.Chem.Soc., 148:35399-35410, 2026

PubMed Abstract: Iron(II)/2-oxoglutarate-dependent (Fe/2OG) enzymes catalyze consecutive C-C bond formations to assemble complex heterobicyclic ring systems and generate three new stereocenters in piperazine alkaloids helvamide B and the arizonamides through C(sp3)-H activation─a transformation that remains challenging in synthetic chemistry. Here, we report a comprehensive mechanistic study of this unique transformation catalyzed by the Fe/2OG enzyme Hvm1, using a combination of deuterated substrates, substrate analogs bearing electron-withdrawing substituents, and multiple spectroscopic methods (LC-MS, X-ray crystallography, CD spectroscopy, and NMR). The reaction proceeds via consecutive radicaloid C-C (C3'-C2 and C3-C3″) couplings, involving sequential radical attack on the olefin and benzoyl group (Minisci variant), initiated by a C3' radical generated through C3' pro-S hydrogen atom transfer (HAT). The first C-C bond (C3'-C2) is formed on the Si-face of C2 with retention of C3' configuration. The second C-C bond (C3-C3″) formation can proceed with either of two stereochemical senses─antarafacial or suprafacial─relative to the first newly formed C3'-C2 bond: the antarafacial pathway leads to helvamide B, while the suprafacial pathway affords the previously unreported epimer, helvamide A. Crystal structure analysis identifies Y67 as a key residue governing the partitioning of stereochemical outcomes in the second C-C bond formation. Furthermore, the conclusive stereochemical assignment of helvamide B corrects the prior misassignment of the C3' configuration in the arizonamides.

PubMed: 42677573
DOI: 10.1021/jacs.6c05166

Experimental method

X-RAY DIFFRACTION (1.96001018958 Å)