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Human serum transferrin plays a critical physiological role in cellular iron delivery via the transferrin receptor-mediated endocytosis pathway in nearly all eukaryotic organisms. It is widely used in mammalian cell cultures for the production of biotherapeutic proteins and vaccines and is also being explored for use as a therapy and targeted drug delivery system to treat a number of diseases. With the increasing concerns over the risk of transmission of infectious pathogenic agents of human plasmaderived transferrin, recombinant production of human serum transferrin has been pursued in various heterologous expression systems. However, high costs and limited yields of recombinant human serum transferrin remain the major challenges to many expression systems. Recently, rice seed-based expression system has been shown to produce large amounts of inexpensive and animal-free recombinant human serum transferrin. Here, we review the rice-derived recombinant human serum transferrin: its cost-effective production, molecular and functional characterisation, as well as its many potential therapeutic and clinical applications. Conclusion Rice seed-based expression system is shown to be able to produce large scale of recombinant human serum transferrin with high yield and at low cost. The rice-derived rhTF is shown to be biochemically, structurally and functionally similar to native hTF, and it is a low-cost alternative to other plasma-derived and recombinant forms of hTF suitable for bioprocessing and biopharmaceutical applications. Introduction Transferrin (TF) plays an important role in tightly controlling the cellular iron uptake, storage and transport to maintain cellular iron homeostasis in all eukaryotic organisms. TF is a single-chain glycoprotein of 679 amino acid residues and can be divided into two homologous halves, each comprising about 340 amino acid residues. The two halves fold into two distinct globular lobes, designated the N-lobe and C-lobe1. Each lobe comprises two dissimilar domains, which interact to form a deep hydrophilic iron-binding site. When TF is free of iron (apo-TF), both its Nand C-lobes maintain an open conformation for easy access of the ferric iron. At pH 7.4 under physiological conditions, the apo-TF binds one (monoferric TF) or two Fe3+ ions (diferric TF or holo-TF). The resultant iron bearing TF binds to TF receptor (TFR) on cell surface, and holo-TF has 30-fold and 500-fold higher affinity for TFR than the monoferric TF and apo-TF, respectively2. Then, the TF–TFR complex is endocytosed into the early endosome, where the acidic environment (pH 5.5) result in the release of iron from TF by protonation but apoTF still remains bound to the TFR with high affinity. Finally, the apo-TF– TFR complex is recycled to the cell surface, and at pH 7.4 of the blood, the apo-TF is released from the TFTFR complex for re-use3,4. The TF/TFR-mediated cellular iron uptake and transport is critical to avoid severe cell damages associated with both the iron deficiency and overload in the body. Iron deficiency can arrest cell proliferation and even cause cell death because iron is an essential element used by all eukaryotic organisms and most micro-organisms as a cofactor of numerous proteins or enzymes for respiration, DNA synthesis and many other critical metabolic processes1. On the other hand, excessive iron can be toxic to cells by reacting with oxygen via the Fenton reaction to produce highly reactive hydroxyl radicals that cause oxidative damage to cells5. The dual challenges of iron deficiency and overload can be addressed by transferrin-binding iron ions in the ferric form (Fe3+) tightly yet reversibly. Apart from the importance of maintaining iron homeostasis in cells, TF is also shown to have a wide range of therapeutic applications, which will be described later. Because the native TF derived from plasma is associated with high risk of transmission of infectious pathogenic agents, recombinant expression of human serum transferrin (hTF) has long been pursued in a variety of heterologous expression systems6,7. In this review, we focus on rice-derived recombinant hTF’s costeffective production, its biochemical, structural and functional properties as well as its potential clinical applications. Discussion The author has referenced some of his own studies in this review. The protocols of these studies have been approved by the relevant ethics committees related to the institution in which they were performed. * Corresponding author Email: dzhang@ventria.com Ventria Bioscience, Fort Collins, CO 80524, USA

Plant seed-derived human transferrin: expression, characterisation and applications