Abstract
Hinokitiol, a natural lipophilic chelator, appears capable of replacing several iron transporters after they have been genetically ablated. Divalent metal-ion transporter (DMT1) is the major iron importer in enterocytes and erythroblasts. We have compared DMT1 and hinokitiol in multiple fashions to learn if the smaller molecule is a suitable substitute using two HEK293 cell lines engineered to overexpress different isoforms of DMT1. Both the macromolecule and the lipophilic chelator enable import of ferrous ions into HEK293 cells. Hinokitiol also mediates ferric ion import but DMT1 cannot do so. While DMT1 can also import Mn2+ ions, hinokitiol lacks this ability. The Michaelis–Menten analysis for kinetics of macromolecular catalysis is also suitable for hinokitiol-supported iron import. To compare hinokitiol to DMT1 relative to other metal ions that DMT1 can transport, we employed an organic extraction procedure with which we initially matched the results obtained for Fe2+, Fe3+ and Mn2+, and then showed that multiple other cations were unlikely to enter via hinokitiol. The small chelator thus shares some functional properties with DMT1, but distinct difference were also noted.
Highlights
Hinokitiol, a natural lipophilic chelator, appears capable of replacing several iron transporters after they have been genetically ablated
Similar results were obtained with HEK293 cells capable of expressing rat 1A/? iron responsive element (IRE) DMT1
The results with hinokitiol confirm and extend those obtained by Grillo and colleagues (Grillo et al 2017) to indicate that hinokitiol can enable the import of iron in its ferric form whereas DMT1 does not do so (Conrad et al 2000)
Summary
Hinokitiol, a natural lipophilic chelator, appears capable of replacing several iron transporters after they have been genetically ablated. We have compared DMT1 and hinokitiol in multiple fashions to learn if the smaller molecule is a suitable substitute using two HEK293 cell lines engineered to overexpress different isoforms of DMT1 Both the macromolecule and the lipophilic chelator enable import of ferrous ions into HEK293 cells. ‘‘(yet) ‘‘the corresponding active iontransport proteins typically remain functional,’’ (so) ‘‘there may be a buildup of ion gradients upstream of the membranes that normally host these missing proteins.’’ They argued that a smaller molecule like hinokitiol could serve as a channel to relieve this buildup Their paper supported this rationale by showing that hinokitiol could substitute for divalent metal-ion transporter (DMT1) and other iron transport proteins when they were deficient
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