“A metabolic anomaly permits an expanded model of endocytic nutrient absorption“

Abstract: This paper extends the endocytic absorption model developed for folic acid (FRα, FRβ, FRγ), iron (transferrin), and B12 absorption (haptocorrin, IF, transcobalamin) to many more nutrients, including nearly all of the naturally occurring elements on the periodic table; all 13 of the essential vitamins; various purine derivatives; choline; α-linolenic acid and linoleic acid; organic anions such as acetate and citrate; and various other organic species. This expanded model is made possible via a large catalog of observations stemming from the destabilizing effects derived from an inborn defect in which endocytic proteins are prematurely proteolyzed instead of recycling back to the plasma membrane. This paper also describes a new biochemical model that exists only in the context of continually recycling endocytic proteins in which synthesis of new molecules can occur on the outside surface of the cell. This model resolves several current questions in nutritional research and also provides much explanatory power for various human dietary habits. Several hundred extremely specific endocytic synthesis reactions (ESRs) are provided which can serve as predictions for verifying the expanded endocytic model.

by Noah Chriss, B.S. in Molecular, Cellular, and Developmental Biology from U.C.Santa Cruz (2018)

The paper can be found here.

Updates and commentary can be found here

The most recent version of the Grand Chart can be found here

For those interested in the fine details of how my nutritional regime is organized you can read the 2nd appendix in the paper in conjunction with the nutrient spreadsheet.

1000 word summary of ‘A metabolic anomaly permits an expanded model of endocytic nutrient absorption’

Summary: This paper provides an expansion of the current model of endocytic nutrient absorption, of which the most studied examples are the proteins that facilitate iron (transferrin), folic acid (FRα, FRβ, FRγ), and B12 absorption (haptocorrin, IF, transcobalamin). This expanded model is based on a large catalog of observations stemming from a self-identified metabolic anomaly wherein endocytic proteins prematurely become denatured and proteolyzed instead of performing their normal function of recycling back to the plasma membrane. This anomaly, which produces unique time-delayed waves of destabilizing effects for each nutrient, is possibly derived from a dysfunctional regulation of reducing agents within the early endocytic compartment.

The current model of endocytic absorption describes how environmentally available nutrients bind to either circulating proteins or membrane proteins, both of which are then drawn into endocytic compartments within the cell. The compartments subsequently become protonated, a process that modifies the affinity of the protein for the ligand and allows the ligands to transit through membrane transporters into the cytoplasm. In the expanded model these endocytic binding proteins perform several additional functions.

Due to their unique life cycle they are able to act as enzymes, which is to say they facilitate the synthesis of new, useful molecules at the surface of the cell. In doing so they utilize reactant species from the environment in concentrations that might appear to make the process energetically unfavorable. This process occurs because, unlike cytoplasmic enzymes which favor the transition state between the product and the reactants, the high-affinity binding sites on endocytic proteins have a binding potential for the product that matches or exceeds that of the combined, simultaneous binding of the reactants, which is to say that a holoprotein binding the product resides in a similar or lower energy state than the holoprotein simultaneously binding the reactants, thus creating a local environment that either permits or favors synthesis of the desired product. Due to the high activation energy of the reverse reaction the forward reaction is essentially irreversible, thus appearing to be highly exergonic in nature. A single binding site can also accommodate multiple reactants, creating complex, multi-step reactions. Later, within the endocytic compartment, the energy that is used to lower the pH facilitates the release of the product, priming the endocytic protein for another cycle of synthesis and release.
In the expanded model the endocytic absorption process performs an unrecognized role in allowing eukaryotes to carry a reservoir of many different nutrients for a long period of time. There is also an enhanced recognition that the endocytic process is able to induct nutrients into the cell at extremely low environmental concentrations. Both features provide a significant competitive advantage for eukaryotes over prokaryotes.
In the expanded model the endocytic absorption process has the intrinsic property of stabilizing the optimal concentration of nutrients within the cytoplasm without needing any feedback or regulatory mechanisms such as are required by prokaryotes.
The expanded model greatly increases the number of proteins currently known to be involved in this process from 10-15 proteins to over 1200 proteins, many of which are likely to be isoforms of individual gene products.
The expanded model describes a large array of newly synthesized amphiphilic molecules that are likely trafficked to the inner leaflet of the plasma membrane and other organelles via flippases and normal endocytic shuttling mechanisms.

This model explains several currently unexplained aspects of human nutrition and dietary behavior, such as:

1. the still-unexplained observation that Vitamin E and selenium deficiencies cause similar pathologies. This effect is due to Vitamin E molecules potentializing a synthesis pathway that involves selenium and serine as components, with the pathologies being due to a deficiency of the synthesis product Se-methylselenocysteine. An analogous pathway is also described that involves tellurium. Furthermore a mechanism for the phosphorylation of α-tocopherol is also provided by the expanded model.
2. the still-unexplained immunomodulatory effects, and by extension cardiovascular effects, seen from Vitamin D deficiency, which is due to over a hundred synthesis pathways involving both Previtamin D and Vitamin D3 proper. The various interactions between Previtamin D and the alkaline earth metals are proposed to be the primary vector for the immunomodulatory effects.
3. B12’s association with cognitive functioning, which is proposed to be due to an uncharacterized phosphorylated species that is formed external to the cell and which would be a good candidate for B12’s apparent role in regulating agents such as myelinolytic tumor necrosis factor-α, epidermal growth factor, and interleukin-6. A case is also presented in which B12’s endocytic process conforms to the model described by folate and iron endocytic absorption and is not a direct liberation in the lysosome as has been described in the literature.
4. the requirement of choline in the human diet, which is partially explained by several endocytic synthesis reactions (ESRs) that utilize it.
5. the requirement for α-linolenic acid and linoleic acid in the human diet, which is partially explained by several ESRs that utilize them.
6. the intrinsic nutritional impetus for seeking out free, non-polypeptide-bound glutamate (such as in monosodium glutamate), which is due both to its use as a component in several ESRs as well as the unusually restrictive manner in which mammals absorb glutamate (as well as aspartate).
7. the intrinsic nutritional impetus for seeking out 5′ nucleotides, which is due to the small number of ESRs that involve hypoxanthine derivatives (such as inosinate) and guanine derivatives (such as guanylate) as well as a large number of ESRs that involve adenine derivatives; the latter of which are utilized for the synthesis of five familiar nucleotide-bound utility molecules (AThTP, FAD, Coenzyme A, NADH, Adenosylcobalamin) as well as six other molecules that are currently uncharacterized, one of which is an adenylated form of retinaldehyde (vitamin A).
8. the intrinsic nutritional impetus for seeking out fried or browned foods, which is due to the formation during the cooking process of α-linolenamide, linoleamide, and amidated versions of other single chain fatty acids, all of which have dedicated endocytic absorption pathways.
9. the intrinsic nutritional impetus for seeking out tart and sour foodstuffs, which is due to several ESRs involving organic anions such as bicarbonate, acetate, malate, pyruvate, fumarate, citrate, and others—with an especially prominent role for acetate and citrate.