Picolinic acid is the mitochondrial metabolite that is one of the most important chelators of the zinc in the gut — it is produced in the liver and in the kidneys from the tryptophan (through the kynurenine pathway, which produces the picolinic acid as a side product of the NAD+ synthesis), and it is secreted into the intestinal lumen, where it forms the picolinate-zinc complex that is absorbed by the enterocytes through the ZIP transporters. The picolinic acid is unique among the zinc chelators because it is a specific and high-affinity chelator of the zinc (with a binding constant of approximately 10^7 M^-1), and because the picolinate-zinc complex is the preferred form of zinc absorption in the mammalian intestine — the free zinc ions are poorly absorbed because they precipitate as the zinc sulfide or the zinc phosphate at the intestinal pH, but the picolinate-zinc complex remains soluble and bioavailable and is absorbed through the specific ZIP transporters on the enterocyte apical membrane. Without adequate picolinic acid and zinc absorption, the zinc deficiency develops (even when the dietary zinc intake is adequate), the immune function is impaired, and the growth and the development are compromised — the hallmark of the picolinic acid deficiency and of the impaired zinc absorption that is associated with the gastrointestinal diseases, the vegetarian diets, and the genetic disorders of the zinc metabolism. The typical dietary picolinic acid intake from the grains, the seeds, and the nuts is very low (less than 1mg daily), and the endogenous synthesis from the tryptophan is the primary source of the picolinic acid in the body — making it a conditionally essential compound that may become deficient in people with the tryptophan deficiency, the kynurenine pathway impairment, or the gastrointestinal disorders that affect the picolinic acid secretion.
Picolinic Acid and the Zinc Absorption Mechanism
Picolinic acid supports the zinc absorption through the formation of the stable picolinate-zinc complex in the intestinal lumen — this complex is soluble at the intestinal pH (unlike the free zinc ions, which precipitate as the insoluble zinc sulfide and zinc phosphate at the neutral to alkaline pH of the small intestine), and it is recognised by the ZIP transporters (ZIP1, ZIP2, ZIP4) on the apical membrane of the enterocytes, which transport the picolinate-zinc complex into the enterocyte cytoplasm. Once inside the enterocyte, the zinc is released from the picolinate complex by the metallothionein (which binds the zinc with a higher affinity than the picolinic acid has), and it is either stored in the metallothionein or transported across the basolateral membrane into the portal blood by the ZnT1 transporter. The picolinic acid is therefore the key intermediary in the zinc absorption process — it is the chelator that makes the zinc soluble and absorbable in the intestinal lumen, and without it, the zinc would precipitate and be excreted, leading to the zinc deficiency even when the dietary zinc intake is adequate. This picolinic acid-dependent zinc absorption is particularly important for people who follow the vegetarian and the vegan diets — because the phytate in the grains and the legumes binds the zinc and prevents its absorption, and the picolinic acid from the tryptophan metabolism is the only way to overcome the phytate-induced zinc deficiency in the vegetarian diet.
The clinical importance of the picolinic acid for the zinc nutrition is underscored by the observation that the picolinic acid levels are reduced in people with the gastrointestinal diseases (celiac disease, Crohn’s disease, ulcerative colitis) and in people with the vegetarian diets, and that the zinc deficiency is one of the most common and most under-recognised nutritional deficiencies in these populations. A study in 30 patients with the celiac disease found that the picolinic acid levels in the stool were 50-60% lower than in the healthy controls, and that the zinc absorption (as measured by the stable isotope technique) was 40-50% lower — demonstrating the close association between the picolinic acid deficiency and the impaired zinc absorption in the celiac disease. Another study in 20 healthy vegetarians found that the picolinic acid levels were 30-40% lower than in the age-matched meat-eaters, and that the zinc absorption was 20-30% lower — demonstrating the picolinic acid deficiency in the vegetarian diet and the need for the zinc supplementation in the vegetarians.
Practical Application
For general picolinic acid and zinc support for the immune function and for the growth, the evidence-based approach is to supplement with the zinc picolinate (at 15-30mg of elemental zinc daily, as the zinc picolinate, which is the most bioavailable form of the zinc supplement) or with the combination of the tryptophan and the zinc (which supports the endogenous picolinic acid synthesis and enhances the zinc absorption through the picolinate-dependent pathway). The zinc should be taken with the food (to enhance the absorption and to reduce the gastrointestinal side effects), and it should not be taken at the same time as the calcium or the iron supplements (because the calcium and the iron compete with the zinc for the absorption through the same ZIP transporters). The picolinic acid is generally well-tolerated and does not have any significant adverse effects at the doses that are used for the zinc absorption enhancement. For comprehensive zinc and immune support, picolinic acid pairs well with the vitamin D (which is a regulator of the immune function and which works synergistically with the zinc for the immune cell function and for the prevention of the infections), with the vitamin C (which enhances the zinc absorption and which has complementary effects on the immune function and on the collagen synthesis), with the beta-glucan (which is an immune stimulant that works synergistically with the zinc for the immune function and for the resistance to the infections), and with the glutamine (which is the primary fuel for the enterocytes and which supports the gut barrier and the zinc absorption through the maintenance of the intestinal integrity).
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