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HEPH

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All listed services and products are For Research Use Only. Do Not use in any diagnostic or therapeutic applications.

Background

Hephaestin (HEPH), encoded by the HEPH gene located on chromosome Xq12, is a member of the mammalian multicopper ferroxidase (MCF) family that includes ceruloplasmin (CP) and zyklopen (ZP). The HEPH gene spans approximately 96 kb and encodes a protein of 1,135 amino acids. HEPH shares approximately 50% sequence identity with serum ceruloplasmin and contains six cupredoxin domains with six copper centers—three mononuclear sites in domains 2, 4, and 6, and three in the form of trinuclear clusters at the interface of domains 1 and 6. Unlike CP, which occurs in both secreted and GPI-linked forms, HEPH is a single-pass type I transmembrane protein containing a C-terminal transmembrane domain and a short cytoplasmic tail. The large extracellular/ectodomain, comprising approximately 120 kDa, contains the copper-binding domains and the ferroxidase active site. HEPH is expressed predominantly in the small intestine, with lower levels reported in the central nervous system, lungs, heart, and exocrine pancreas; unlike CP, no HEPH expression has been detected in the liver or serum. Within intestinal enterocytes, HEPH is localized to the basolateral membrane, where it functions as a key component of the iron export machinery.

HEPH functions as a plasma membrane ferroxidase that mediates the extracellular conversion of ferrous iron (Fe²⁺) into its ferric form (Fe³⁺). This enzymatic reaction—catalyzing 4 Fe²⁺ + 4 H⁺ + O₂ = 4 Fe³⁺ + 2 H₂O—is coupled to the iron export activity of ferroportin (FPN1/SLC40A1), the only known intestinal iron exporter. Ferroportin specifically exports ferrous iron from enterocytes across the basolateral membrane; HEPH then oxidizes Fe²⁺ to Fe³⁺, enabling the iron to bind to its carrier protein transferrin, which under physiological conditions only binds ferric iron. HEPH thus forms a functional complex with ferroportin and transferrin to transfer iron from cells to the circulation. The importance of HEPH in dietary iron absorption has been demonstrated through the sex-linked anemia (sla) mouse model, in which a mutation in the Heph gene results in iron deficiency and microcytic anemia. HEPH is the major multicopper ferroxidase in the small intestine and is critical for dietary iron absorption; however, knockout studies have shown that HEPH is not absolutely essential, as other mechanisms can partially compensate for its deficiency. These properties make HEPH an important research target for studies of iron metabolism, multicopper oxidase biology, basolateral iron transport, and the molecular mechanisms underlying systemic iron homeostasis.

Fig. 1 The ferroxidase-permease iron transport machinery in yeast and human cells. (OA Literature) Fig. 1 The yeast and human ferroxidase–permease system.1

HEPH Protein Function: Roles in Ferroxidase Activity, Basolateral Iron Export, and Systemic Iron Homeostasis

HEPH, encoded by the HEPH gene, functions as a membrane-bound multicopper ferroxidase that facilitates cellular iron export through oxidation-coupled transferrin loading:

  • Ferroxidase Activity: HEPH catalyzes the oxidation of ferrous iron (Fe²⁺) to ferric iron (Fe³⁺) in the extracellular space, a reaction requiring six copper atoms as electron acceptors.
  • Ferroportin-Coupled Iron Export: HEPH functions in a complex with ferroportin (FPN1/SLC40A1) on the basolateral membrane of enterocytes, oxidizing Fe²⁺ exported by ferroportin to Fe³⁺ for binding to transferrin.
  • Basolateral Membrane Localization: HEPH is localized to the basolateral membrane of duodenal enterocytes, positioning it to mediate the transfer of dietary iron from intestinal cells to the circulation.
  • Dietary Iron Absorption: As the major multicopper ferroxidase in the small intestine, HEPH plays a critical role in dietary iron absorption and whole-body iron acquisition.
  • Systemic Iron Homeostasis: Beyond the intestine, HEPH has been reported to function in multiple tissues including the central nervous system, lungs, heart, and exocrine pancreas, contributing to extra-intestinal roles in maintaining whole-body iron homeostasis.

HEPH Protein Product

Creative Biolabs offers high-quality HEPH proteins produced using optimized expression systems, including full-length type I transmembrane protein and isolated extracellular domain variants containing the cupredoxin domains and copper-binding sites. The extracellular domain mediates ferroxidase activity and ferroportin coupling, making these proteins suitable for studies of iron oxidation kinetics, multicopper oxidase mechanism, and basolateral iron transport characterization. All HEPH proteins undergo strict quality control to support consistent performance across applicable research platforms.

Custom HEPH Protein Product

Not finding the protein product you need? Contact us to start your one-stop custom service!

HEPH Stable Cell Line Product

Creative Biolabs provides custom-engineered HEPH stable cell lines, including overexpression and knockdown models. These cell lines are optimized for studies of ferroxidase activity, basolateral iron export, ferroportin-HEPH coupling, and systemic iron homeostasis. Each cell line undergoes stringent validation to ensure stable expression profiles and consistent functional performance in diverse experimental contexts.

HEPH Stable Cell Line Product

Not finding the stable cell line product you need? Contact us to start your one-stop custom service!

HEPH Recombinant Antibody Product

High-specificity recombinant antibodies targeting HEPH are developed using antibody engineering technologies for research applications involving HEPH expression and localization. These antibodies can be used in studies of HEPH distribution in intestinal enterocytes and other tissues, and may also support characterization of HEPH-ferroportin complexes and basolateral membrane localization in combination with appropriate detection reagents.

HEPH Recombinant Antibody Product

Not finding the recombinant antibody product you need? Contact us to start your one-stop custom service!

Product Features

  • Native Multicopper Oxidase Structure Preservation: Maintains the characteristic six cupredoxin domain architecture and copper-binding sites essential for ferroxidase activity and iron metabolism studies.
  • Iron Metabolism Research Compatibility: Optimized reagent series for studies of ferroxidase activity, basolateral iron export, ferroportin coupling, and systemic iron homeostasis.
  • High Specificity for HEPH: Minimizes non-specific cross-reactivity with other multicopper ferroxidases including ceruloplasmin (CP) and zyklopen (ZP).
  • Comprehensive Customization Support: Facilitates end-to-end development of customized proteins, antibodies and stable cell lines to address iron metabolism and multicopper oxidase research demands.

Custom HEPH Research Services

Beyond catalog products, Creative Biolabs offers specialized custom services for HEPH research:

  • Custom HEPH Protein Production: Tailored expression of mutant and tagged HEPH constructs for ferroxidase activity and iron transport studies.
  • Custom Antibody Development: Generation of HEPH-specific antibodies for immunostaining, flow cytometry, and protein detection applications.
  • Stable Cell Line Engineering: Construction of HEPH-modified cell models for iron metabolism, ferroxidase function, and basolateral transport research.
  • Functional Assay Development: Custom design of ferroxidase activity, iron export, and ferroportin coupling detection workflows.

Frequently Asked Questions (FAQs)

  1. What is the primary function of HEPH?

    HEPH is a membrane-bound multicopper ferroxidase that oxidizes Fe²⁺ to Fe³⁺ on the basolateral membrane of intestinal enterocytes, facilitating iron binding to transferrin and systemic iron distribution.

  2. Why is HEPH a significant research target?

    HEPH is the major multicopper ferroxidase in the small intestine and plays a critical role in dietary iron absorption. Its function is coupled to ferroportin-mediated iron export, making it a key target for studies of iron metabolism, multicopper oxidase biology, and the molecular mechanisms of systemic iron homeostasis.

  3. Are Creative Biolabs' HEPH products suitable for clinical use?

    No, all HEPH products and services are strictly for research use only, not intended for clinical diagnosis or treatment.

  4. What types of HEPH products does Creative Biolabs offer?

    Offerings include full-length HEPH transmembrane proteins, extracellular domain variants, specific detection antibodies, and custom stable cell lines for iron metabolism and ferroxidase research.

  5. How are HEPH proteins validated for activity?

    HEPH proteins are validated via ferroxidase activity assays, iron oxidation kinetics measurements, and relevant functional characterization in applicable research platforms.

Reference
  1. Amadei, Matteo, et al. "The Ferroxidase-Permease System for Transport of Iron Across Membranes: From Yeast to Humans." International Journal of Molecular Sciences 26.3 (2025): 875. Under Open Access license CC BY 4.0, without modification. https://doi.org/10.3390/ijms26030875
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