Human transferrin: An inorganic biochemistry perspective Original paper

What was reviewed?

This review examined the inorganic biochemistry of human transferrin (Tf)—with emphasis on structure, Fe(III) coordination chemistry, iron loading/release mechanisms, transferrin receptor (TfR)–mediated cycling, and functionally important microheterogeneity (genetic variants and post-translational modifications). Importantly for clinicians working with microbiome-related phenotypes, transferrin and microbiome interactions sit at the center of “nutritional immunity,” because Tf reduces free iron availability (limiting microbial growth) while still enabling tightly controlled delivery of iron to host tissues via TfR1-mediated endocytosis and endosomal iron release. The authors synthesize crystallographic, kinetic, and spectroscopic evidence to clarify how Tf binds Fe(III) using conserved ligands plus a synergistic carbonate, how pH and anions tune release, and how disease-linked modifications (e.g., glycation, oxidation) may impair iron handling—potentially reshaping the iron landscape that gut and mucosal microbes compete for.

Who was reviewed?

Because this is a mechanistic biochemistry review (not a clinical cohort study), the “who” is best understood as the biological systems and experimental models represented across decades of transferrin research. The review integrates evidence from humans and human-derived materials (serum transferrin, receptor complexes, and clinical contexts such as inflammation and diabetes), alongside comparative insights from other transferrin-family proteins (e.g., lactoferrin) and microbial/pathogen biology where iron acquisition pressure is strong. It also draws on structural biology datasets (apo-/holo-Tf, Tf/TfR complexes), kinetic studies of iron release under endosomal-like conditions, and mechanistic studies involving iron donors/chelators (e.g., citrate), all of which are directly relevant to host–microbe competition for iron and to interpreting iron biomarkers in dysbiosis-associated disease states.

Most important findings

Transferrin binds Fe(III) with extremely high affinity using Asp/Tyr/Tyr/His ligands in each lobe plus a synergistic carbonate, forming distorted octahedral high-spin Fe(III) centers; affinity differs by lobe and is strongly pH- and bicarbonate-dependent, explaining why iron release is favored in acidic endosomes. Iron trafficking is dominated by TfR1-mediated endocytosis, where endosomal acidification (≈pH 5.6) and accessory chemistry (anion effects, chelators, ferrireductases such as STEAP3, and Fe(II) export via DMT1) accelerate iron release to match rapid cellular recycling. A clinically intriguing paradox is that in vivo monoferric occupancy often favors the N-lobe despite higher C-lobe affinity, implying that iron donors (notably citrate) and tissue-specific utilization influence physiological Tf iron speciation. From a microbiome signatures perspective, the most microbiome-relevant thread is that transferrin (and lactoferrin) restricts bioavailable iron to suppress bacterial expansion, yet many pathogens evolve dedicated receptors to pirate Tf/Lf-bound iron—meaning host iron status, Tf saturation, and Tf modifications can indirectly select for iron-scavenging taxa and virulence programs. Post-translational modifications (glycation, phosphorylation, oxidation) occur at structurally strategic residues and can hinder iron loading/release kinetics or receptor interactions, offering a plausible biochemical bridge between metabolic disease, altered iron pools (including NTBI), and microbiome shifts driven by iron availability.

Key implications

For clinicians, this review reframes transferrin not just as a laboratory marker (e.g., transferrin saturation) but as an active regulator of iron ecology—inside the host and at host–microbe interfaces. The mechanistic dependence of iron release on pH, anions, chelators, and TfR binding helps explain why inflammation (lower circulating Tf), iron overload/deficiency (altered Tf expression and saturation), and diabetes (Tf glycation with impaired iron loading and higher NTBI signals) can plausibly shift microbial behavior toward more aggressive iron acquisition and oxidative stress pathways. In practice, interpreting microbiome-associated phenotypes alongside iron biomarkers should consider that “iron availability” is not synonymous with total iron, and that transferrin microheterogeneity may modulate both systemic iron delivery and microbial selection pressures—useful context when evaluating iron supplementation, chronic inflammatory states, or infections where iron piracy is part of pathogenesis.

Citation

Silva AMN, Moniz T, de Castro B, Rangel M. Human transferrin: An inorganic biochemistry perspective. Coordination Chemistry Reviews. 2021;449:214186. doi:10.1016/j.ccr.2021.214186