Metabolic map about ketogenic and glucogenic amino acids

Amino acids as neurotransmitters

In addition to being used as building blocks for protein synthesis, amino acids play many other important physiological functions. One is undoubtedly the fact that there are several amino acids that play neurotransmitter functions:

- Glutamate is the main excitatory neurotransmitter in the central nervous system. It plays central roles in terms of rapid nerve transmission (i.e. rapid response to a stimulus), cognition, memory, movement and sensation. It is recognized by two classes of receptors: ionotropic receptors, which are receptors that when activated allow ion flow across the membrane; and metabotropic receptors, which when activated stimulate the production of secondary messengers.

 - Aspartate, it is also an excitatory neurotransmitter of the central nervous system. Due to biochemical similarities between glutamate and aspartate (more on this subject here), the actuation mechanism and effects are identical between them (although glutamate is, from a quantitative point of view, more important than aspartate).

 

- Glycine is the simplest amino acid, and has inhibitory functions in the central nervous system, with particular emphasis on the spinal cord, brain stem and in the retina. In addition to its role as a neurotransmitter, it also plays immunomodulatory functions, anti-inflammatory and cytoprotection (cell protection). The activation of its receptors allows influx of chloride ion.

Isoelectric point (aminoacids and proteins)

Amino acids are, as mentioned in other posts, molecules that have an amino group and a carboxylic group. These two groups are ionizable, ie, they may undergo protonation/deprotonation. Moreover, the side chains of various amino acids may present additional ionizable groups. This means that amino acids are molecules that can display positive, negative, or neutral charge. What influences the overall charge of each amino acid in a given context is:
1. Chemical composition of the amino acid and the molecule where it is inserted (if that is the case ...). The presence of certain atoms/functional groups in a molecule alters the distribution of its electron cloud, making some covalent bonds stronger and other weaker. The weakening of the bonds involving hydrogen atoms turn easier the occurrence of deprotonation.
2. The pH of the solution in which the amino acid is inserted. As is logical, functional groups will present a state of protonation that is influenced by the pH, that means, if the pH is lower than its pKa, the functional group tends to be protonated, and if it is greater than the pKa, it tends to be deprotonated.
Therefore, based on the characteristics of each amino acid, and the environment where it is, it is possible to obtain different total charges.
The isoelectric point is defined as the pH value for which the total charge of the amino acid is zero. Note that this does not mean that there are no charges on the amino acid, because in reality there are charges, indeed. This means is that when subjected to this pH, total positive charges equal the total negative charges. At this point, the amino acid solubility decreases. When an amino acid is placed in a solution with a pH below its isoelectric point, it acquires positive charge as the functional groups tend to be protonated (gain H+). If the pH is above the isoelectric point, total charge is negative, because the functional groups tend to be predominantly deprotonated (lose H+).

In the case of proteins, it applies exactly the same concept. However, in this case one must consider the total of ionizable groups present in the molecule, and the isoelectric point is defined as the pH value for which the total charge of the protein is zero. 

Again, at this value the solubility of the protein is zero, and it tends to precipitate. This is explored in the laboratory by means of a technique called isoelectric focusing.

.

Standard and non-standard amino acids

Amino acids are molecules that, from a chemical standpoint, are characterized by the presence of an amine group and a carboxylic group (acid), and hence its name: amino acid. Its main function is to serve as monomers for the synthesis of peptides and proteins. Of all the amino acids in nature, there is a set of 20 amino acids which are designated by standard amino acids, and that are used as building blocks for most of the proteins produced by any living being. These amino acids are widely studied and have been the central elements in my last posts. Just to remember, the standard amino acids are:

- glycine
- alanine
- proline
- valine
- leucine
- isoleucine
- methionine
- phenylalanine
- tyrosine
- tryptophan
- serine
- threonine
- cysteine
- asparagine
- glutamine
- lysine
- arginine
- histidine
- aspartate
- glutamate

However, besides the standard amino acids, there are many others that are found in some proteins and are called non-standard amino acids. The idea of ​​using these non-standard amino acids is simple to understand. By having a composition different from the standard amino acids, they present different physicochemical properties. Therefore, when it is necessary to introduce in a protein a local with certain properties, if they cannot be provided by the standard amino acid, it is incorporated in the sequence a non-standard amino acid. With regard to translation, in these cases, at these sites are introduced standard amino acids, which suffer post-translation covalent modifications to give amino acids with other features. I would like to highlight something that I think it is important. How you will notice below, several of the non-standard amino acids are found in the extracellular matrix proteins. As the extracellular matrix is a very complex structure, establishing numerous interactions with many different molecules (extracellular and cellular molecules), it is necessary that the proteins that make up the matrix may present a high versatility in the interactions that they establish, hence the need to specifically include some amino acids that have different characteristics. Some non-standard amino acid examples include:
- Cystine, desmosine and isodesmosine, which are amino acids found in extracellular matrix proteins such as elastin;

 

- Hydroxyproline and hydroxylysine, found in the most abundant protein of  the extracellular matrix – collagen;

 

- Gamma-carboxyglutamate, found in osteocalcin which is an extracellular matrix protein of bone, but also in the pro-thrombin, which is important for the coagulation cascade;

- Phosphoserine, phosphothreonine and phosphotyrosine, which are found in many different proteins, as protein phosphorylation is the most common post-translational modification, and always involves amino acids with hydroxyl groups in their side chains;

- N-acetillysine, which is fundamental to the structure of histones:

- Methyllyisine, which is found in myosin, a motor protein of our cytoskeleton, more specifically of actin filaments.

Amino acids with acidic side chains

This is the latest group of standard amino group that I will describe. It consists of 2 amino acids, glutamate (also called glutamic acid) and aspartate (also called aspartic acid). Both have a carboxylic group in its side chain, which, being a weak acid group, confers acidic properties to the side chain. In other words, these side chains tend to have a negative charge as a result of deprotonation of the carboxylic group. They are, therefore, very important amino acids to establish ionic interactions with amino acids with alkaline side chains (more information on these amino acids here), and these forces may also be called salt bridges. In order to avoid confusion in the nomenclature of the carboxylic group of the side chain and the carboxylic group attached to the alpha carbon, the side chain group is typically referred to as gamma-carboxylic. The difference between glutamate and aspartate is just a methylene group -CH2 -. Indeed, glutamate has one more carbon (in the form of methylene group) than aspartate. Both can be obtained from intermediates of the Krebs cycle (glutamate from alpha-ketoglutarate and aspartate from oxaloacetate), and besides being building blocks for protein synthesis, they are also used as neurotransmitters. Glutamate also plays a very important role in terms of the sense of taste, and is also important as a donor of amino groups in several reactions of biosynthesis of nitrogenous molecules.

Amino acid with alkaline side chains

This class of amino acids includes those amino acids who have in their side chain an alkaline functional group. This means that these amino acids tend to have positive charge on their side chain as the alkali groups tend to pick up H+. As a result, they usually establish ionic bonds (or salt bridges) with amino acids with negatively charged side chains There are 3 amino acids belonging to this class:

Lysine - This amino acid has in its side chain a primary amine, that means, an amine group which is bonded to only one carbon, while the remaining nitrogen substituents are hydrogen atoms. The amine group is the main alkaline group in biochemistry (more information on this post). Lysine is the primary site of glycosylation of proteins, and in this case, the established connections are N-glycosidic bonds.

 

Arginine - This amino acid has in its side chain a more complex alkali functional group, called guanidine. This is a functional group comprising 3 nitrogen atoms, which displays electronic resonance, and they can be protonated.

Histidine - This amino acid has a cyclic structure in its side chain, more specifically an imidazole ring. It is a heterocycle composed of nitrogen and carbon atoms, in which one of the nitrogens can be protonated. Histidine has a particularly important feature in biochemistry: it is the only amino acid that has substantial buffering capacity at physiological pH (between 6.5 and 7.5), since its pKa is about 6. In this regard, it should be noted, firstly, that the pKa of histidine changes, as this amino acid is inserted into different polypeptide chains, but usually it is not much different from the original value (isolated histidine). Also, the fact that it is important to have a pKa close to physiological pH, relates to the ability of histidine to exist in medium in its acid and alkaline forms at the physiological pH, functioning as an acid-base pair conjugate.