AI Insight
Researchers determined the first cryo-electron microscopy structures of human MBOAT2, an enzyme that protects cells from ferroptosis by adding specific fatty acid chains to lipids. The structures reveal that MBOAT2 retains its product after catalysis and appears to pre-load substrates, capturing the enzyme in multiple states including with endogenous lipids, added substrates, and an inactive mutant form. These structural snapshots define how MBOAT2 performs its catalytic cycle and establish a framework for understanding its mechanism of action.
Why it matters
This structural information could enable the design of drugs targeting MBOAT2 to either enhance its ferroptosis-suppressing activity in degenerative diseases or inhibit it in cancer cells that exploit this pathway for survival. The discovery of product retention and substrate preloading mechanisms also advances fundamental understanding of the MBOAT enzyme family.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
MBOAT2 suppresses ferroptosis independently of GPX4 and FSP1 by transferring monounsaturated acyl chains from acyl-CoA donors to lysophospholipid acceptors, but the structural basis of its catalytic cycle remains unclear. Here, we report the first cryo-EM structures of human MBOAT2, capturing endogenous and substrate-induced ligand-bound states. Unexpectedly, as-purified MBOAT2 contains a co-purified phospholipid-like density consistent with a retained product, together with a second density at a putative acyl-donor entry site. Oleoyl-CoA addition reduces the ordered product-like density and reveals donor density, whereas LPE addition increases local heterogeneity near the archway. The inactive H373A mutant contains endogenous donor- and acceptor-like densities along the two access pathways, consistent with substrate preloading. Together, these structures define the catalytic architecture of MBOAT2, support a product-retained, donor-primed working model, and provide templates for structure-guided ligand discovery.
Source: Structural insights into MBOAT2 catalysis, product retention, and ligand exchange