Three Major Deficiency Diseases Harming Mankind (Protein, Retinoid, Iron) Operate Under Tryptophan Dependency

Abstract

This story began half a century ago with the discovery of an unusually high presence of tryptophan (Trp, W) in transthyretin (TTR), one of the three carrier proteins of thyroid hormones. With the Trp-rich retinol-binding protein (RBP), TTR forms a plasma complex implicated in the delivery of retinoid compounds to body tissues. W has the lowest concentration among all AAs involved in the sequencing of human body proteins. The present review proposes molecular maps focusing on the ratio of W/AA residues found in the sequence of proteins involved in immune events, allowing us to ascribe the guidance of inflammatory processes as fully under the influence of W. Under the control of cytokine stimulation, plasma biomarkers of protein nutritional status work in concert with major acute-phase reactants (APRs) and with carrier proteins to release, in a free and active form, their W and hormonal ligands, interacting to generate hot spots affecting the course of acute stress disorders. The prognostic inflammatory and nutritional index (PINI) scoring formula contributes to identifying the respective roles played by each of the components prevailing during the progression of the disease. Glucagon demonstrates ambivalent properties, remaining passive under steady-state conditions while displaying stronger effects after cytokine activation. In developing countries, inappropriate weaning periods lead to toddlers eating W-deficient cereals as a staple, causing a dramatic reduction in the levels of W-rich biomarkers in plasma, constituting a novel nutritional deficiency at the global scale. Appropriate counseling should be set up using W implementations to cover the weaning period and extended until school age. In adult and elderly subjects, the helpful immune protections provided by W may be hindered by the surge in harmful catabolites with the occurrence of chronic complications, which can have a significant public health impact but lack the uncontrolled surges in PINI observed in young infants and teenagers. Biomarkers of neurodegenerative and neoplastic disorders measured in elderly patients indicate the slow-moving elevation of APRs due to rampant degradation processes.

Keywords: immune reactions; inflammatory disorders; iron deficiency; lean body mass; protein malnutrition; retinol-binding protein; transthyretin; tryptophan deficiency.

Figure 1

Schematic representation of the main metabolic pathways of W. L-W is a natural EAA found in human and animal tissues. Dietary L-W is absorbed by the intestinal mucosa and circulates in the bloodstream mainly bound and transported by ALB with minor values remaining in free form. Three main W pathways are identified: ❶ Quantitatively, the Kyn pathway is endowed with the largest representation under the control of several rate-limiting enzymes (indoleamine-2,3-dioxygenase, W-2,3-dioxygenase, kyn-3-monooxygenase and W-hydroxylase). Most Kyn derivatives may cross the BBB and control brain function, degeneration and apoptosis. The conversion of 3-HAA to the neurotoxic QA is implicated in deterioration of cognitive functioning and Alzheimer’s disease. ❷ W may be converted into 5-HTP and further into 5-OH-tryptamine (serotonine) that take place in both the gut and the brain and is stored in the platelets, being involved in vasoconstrictive processes and stimulation of smooth muscular cells. Functioning of serotonine is depending on a large set of cellular receptors operating in many organs, including in cerebral tissues where it may be converted to melatonin in the pineal gland, assuming the regulation of circadian rhythms (sleep-wakefulness and light-dark cycles). ❸ The intestinal flora metabolizes W to indole and derivatives, including skatole and tryptamine. The roles played by these derivatives is the maintenance of intestinal immune homeostasis and preservation of microbiota.