Endocytic Analytics is a company created in February, 2022 by Noah Chriss (B.S. in Molecular, Cellular, and Developmental Biology from U.C. Santa Cruz) for the purpose of facilitating research on a unique cell line.
What is endocytosis?
Let’s start at the beginning…
Not too long after the earth cooled (4.4 to 4.3 billion years ago) cellular life developed. These first cells needed some way to allow nutrients to pass through their outer membrane (referred to as the plasma membrane) as well as allow waste products to leave the cell. Certain proteins, called transporters, evolved to fulfill this function.
Proteins are chains of amino acids and when placed in water all proteins will wiggle constantly. Imagine a protein that is located on a membrane and that has a binding location (a small pocket that is sticky for a specific element or molecule) for a nutrient such as iron. If, while wiggling, that binding location can be exposed to either the exterior of the cell or the interior of the cell then the protein will act as a transporter.
The atom or molecule will bind to the protein in one form and then after the protein wiggles the atom or molecule can be knocked free on the other side of the membrane. This process can occur both ways.
If something is taken from the environment that is present in a low concentration and brought into the cell where there is a high concentration the nutrient must, in a sense, be ‘pushed’ into the cell. All cells maintain a voltage across their cell membrane (like a battery) which can be used to power this process. A membrane protein that requires both a nutrient and also a positively charged ion (such as an H3O+ ion or a sodium ion) in order to change shape can very effectively push nutrients into the cell against a high concentration. Likewise a protein that requires both a waste product and also a negatively charged ion (such as chloride ion) can very effectively push waste products out of the cell. These proteins are referred to as ‘active transporters’.
The earliest primitive cells, bacteria and archaea, are referred to collectively as prokaryotes (see this video by PBS eons for a discussion on the differences between the two branches of life). For a long time these transporters were all that they had available to absorb nutrients (other than gasses and other molecules that could easily pass through the plasma membrane on their own).
Sometime between 2.4-1.9 billion years ago a species of archaea and a species of bacteria began to collaborate. Each life form provided a solution to problems that the other life form was facing. This collaboration eventually became the eukaryotes, which includes plants, animals, fungi, algea, protists, and various other single-celled and colonial organisms. The word eukaryote means ‘true nucleus’ however the true signature of a eukaryote is a vast, organized network of interior compartments such as the endoplasmic reticulum, the Golgi apparatus, lysosomes, mitochondria, etc…
The eukaryotes took this simple method of nutrient absorption that the prokaryotes had been using for 2 billion years and added an extra layer of complexity, called endocytosis. Let’s look at the process:
- For eukaryotes nutrients from the environment will bind to specialized proteins called receptors that are embedded within each cell’s outer membrane (the plasma membrane).
2. On the inner side of the membrane some proteins come together, gradually distending it.
3. Eventually a bubble (called an endosome) that contains the receptor-bound nutrients is pinched off.
4. The endosome is trafficked towards the interior of the cell where it combines with other endosomes to form a large endosome called the endocytic compartment. Computer animator John Liebler has created a sequence that depicts the trafficking of endosomes.
5. Proton pumps push positively charged hydronium ions (which is a water with an extra proton) into the interior of the endocytic compartment, greatly increasing the acidity.
6. Those protons bind to various locations on the proteins inside the endocytic compartment, such as histidine residues for example. This changes the affinity of the proteins to the nutrients, which causes the nutrients to loosen from the receptor proteins and go into solution.
7. The increasing acidity also enables the activity of membrane transporters, which then push the nutrient through the membrane of the endocytic compartment into the cytoplasm.
8. If the concentration of the nutrient is too high in the cytoplasm the nutrient is forced back into the endosome.
Why such a complex process?
- Endocytosis allows our cells, and other eukaryotic cells such as in plants and fungi, to absorb nutrients from the environment in extremely low concentrations. Our cells ‘pay twice’ in order to do this. They pay once by concentrating the membrane-bound receptors in an interior chamber, and then they pay again to ‘push’ the nutrients into the cell using prokaryotic transporters.
- The process also allows our cells to carry a reservoir of nutrients such that we can go a long time without needing nutrients. This reservoir is the assemblage of nutrient-bound proteins that are continually circulating between the plasma membrane and the endocytic compartment. For animals the reservoir also includes proteins that travel through the bloodstream but never actually enter the cell. Once the reservoir is filled up (from a large meal for example) the cells can draw from that reservoir over the next several days.
- In the paper “A metabolic anomaly permits an expanded model of endocytic nutrient absorption” another benefit is described. The process allows us to synthesize new nutrients at the surface of the cell. The membrane-bound receptors not only are able to strongly bind various chemical species but they can also form those species from their corresponding reactants. This happens because proteins in the endocytic context provide a local environment that facilitates an exergonic chemical reaction that would ordinarily (in a test tube for example) be endergonic. After the reaction occurs the holoenzyme (the enzyme plus the new nutrient) resides in a lower energy state and cannot synthesize another molecule until passing through the endocytic compartment and having the nutrient ‘pried’ from the enzyme via the acidification process. Let’s take a look at a few examples:
Pyridoxine 5′-phosphate, a form of Vitamin B6, can be absorbed via the endocytic process, or it can be synthesized from B6 and inorganic phosphate and then absorbed.
Nicotinamide, a form of Vitamin B3, can be absorbed via the endocytic process, or it can be synthesized from Niacin and glutamine and then absorbed. Nicotinamide can also be synthesized from Niacin and ammonia.
