Amino Acids: Chemistry, Biochemistry & Nutrition

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The summery below is for educational purposes only. It is adapted in most part from the book Prof. Nir Ben-Tal and I wrote, Introduction to Proteins: Structure, Function, & Motion:

The book discusses protein structure & function while referring to many everyday applications of protein science, such as disease & cure, drugs of abuse, toxins, industrial engineering and much more. Some of the figures are taken from other sources, such as Lehninger’s Principles of Biochemistry, 5th edition textbook.

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1. WHAT ARE AMINO ACIDS?

Amino acids are small organic molecules that play several important roles in living organisms:

  1. They are the principle building blocks of proteins, Nature’s most functionally diverse biomolecules. For more details on these remarkable molecules see this section.
  2. They serve as precursors for many biologically active molecules, such as neurotransmitters (e.g. dopamine, serotonin, GABA, epinephrine), local mediators (e.g. the allergy mediator histamine), energy-related metabolites (e.g. creatine, citrulline, carnitine), the oxygen-binding molecule ‘heme‘, and DNA bases called purines. For details, see section 5 below.
  3. They serve as an energy source during prolonged fasting, diabetes, and when the diet is rich in proteins.
  4. Some act as regulators of gene expression and cellular signalling. This effect multiple physiological processes that are related to growth, maintenance, reproduction and immunity.

The following subsections provide a short description of amino acid structure, function & metabolism. Most of the topics are described in detail in my book (see top of this page), whereas others are taken from biochemistry textbooks (e.g. Lehninger’s) and from Wu’s article ‘Amino acids: metabolism, functions, and nutrition‘ (Amino Acids (2009) 37:1–17).

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2. GENERAL STRUCTURE & PROPERTIES

As their names suggests, all amino acids contain both amino and carboxylic acid groups. There are roughly 300 types of amino acids in nature, only 20 of which serve as building blocks of proteins. Others function as metabolites, messengers and regulators of biological processes. As we will see below, there are two amino acids, selenocysteine and pyrrolysine, which are not considered as one of the 20 types of protein building blocks, although they are genetically incorporate into proteins. This is because the two amino acids appear only in certain proteins, whereas the other 20 appear in all. Some books and websites refer to selecnocysteine and pyrrolysine as the ’21st & 22nd amino acids, but this reference is not generally accepted.

All amino acids that appear in proteins (a.k.a. ‘α-amino acids) possess a structure which includes a central carbon atom called , surrounded by four substituents: a hydrogen atom, an amino group (α-amino), a carboxyl group (α-carboxyl), and a fourth group referred to as side-chain:

Figure 1a. The general structure of an amino acid

  • The α-carboxyl group has a low pKa (~2), and is therefore deprotonated and negatively charged at physiological pH (7).
  • The α-amino group has a high pKa (9–10), and is therefore protonated and positively charged at physiological pH.
  • The side-chain is chemically different in each of the amino acids (Fig. 1b). They determine the uniqueness of the 20 natural amino acids found in proteins.
  • Amino acids in proteins almost exclusively possess an L configuration. Amino acids with D configuration can be found in microorganisms (e.g. in the bacterial cell wall and in antibiotic peptides) and in certain animals (e.g. the frog skin peptide ‘dermorphin’)

20 types of amino acids

Figure 1b. The 20 types of amino acids. The side chains are in pink.

(source)

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3. AMINO ACIDS GROUPS

It is customary to group the 20 natural amino acids found in proteins into 4 types, according to the polarity of their side chains (Fig. 1b). Amino acids that have polar side chains are hydrophilic. That is, they tend to appear on the surface of water-soluble proteins where they can interact favorably with the surrounding water. Amino acids that have nonpolar side chains are hydrophobic. That is, they tend to be buried inside proteins, where they are away from water and can interact favorably with each other.

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I. Nonpolar amino acids

These include the following (Fig. 2):

  • Glycine (gly, G) – has a single hydrogen atom as a side chain.
  • Alanine (Ala, A) – has a methyl group (CH3) as a side chain.
  • Valine (val, V), leucine (leu, L) and isoleucine (ile, I) – have a branched aliphatic side chain.
  • Methionine (met, M) – has a sulfur-containing linear aliphatic side chain.
  • Proline (pro, P) – has an aliphatic side chain which is covalently attached to the α-amino group.

Figure 2. Nonpolar amino acids

In water-soluble proteins, nonpolar amino acids reside mainly in the hydrophobic core. There, their interactions with each other (the ‘hydrophobic effect‘) is what holds together the 3-dimensional fold of the protein. In membrane-bound proteins, nonpolar amino acids reside on the surface, where they can interact favorably with membrane lipids. Finally, nonpolar interactions involving these amino acids serve as a driving force for the binding of ligands and substrates to the protein.

Here are some interesting facts on some of the nonpolar amino acids:

  • Methionine, despite being overall nonpolar, is still able to interact weakly with polar species, such as metals. This is thanks to the non-bonding electrons of methionine’s sulfur atom, which are only weakly held by the nucleus.
  • Glycine, having only hydrogen as side chain, confers flexibility to the protein areas in which it is present. Proline does the opposite (confers rigidity) due to its side chain being fused to the rest of the amino acid.
  • The branched amino acids (valine, leucine, isoleucine) are an important source of energy in muscles and signal cells to synthesize proteins.

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II. Polar-uncharged amino acids

These include the following (Fig. 3):

  • Serine (ser, S) and threonine (thr, T) – have a hydroxyl group in their side chain.
  • Cysteine (cys, C) – has a thiol (sulfhydril) group in its side chain.
  • Glutamine (gln, Q) and asparagine (asn, N) – have an amide group in their side chains.

Figure 3. Polar-uncharged amino acids

In proteins, polar-uncharged amino acids form hydrogen bonds with each other and with the protein’s ligand/substrate. This confers specificity to protein-ligand interactions, in contrast to the hydrophobic effect which confers stability and serves as a driving force for the interactions. Some of the polar-uncharged amino acids also function as nucleophiles in enzymatic catalysis.

Here are interesting facts on some polar-uncharged amino acids:

  • Serine and threonine are often phosphorylated in proteins that participate in cell-cell communication. This modification is reversible and serves as a chemcial, signal transduction tag. The two amino acids may also function as nucleophiles in enzymatic catalysis, thanks to the hydroxyl group in their side chain.
  • Serine and threonine on the surface of membrane/secreted proteins may also be glycosylated (attached with sugar groups). This protects the protein and increases its water solubility. In some cases, the attached sugar groups serve also as a recognition code for other extra-cellular elements.
  • Cysteine, despite being polar, tends to appear in core of water-soluble proteins. Under oxidizing conditions, its thiol side chain deprotonates and tends to form a (covalent) disulfide bond with a thiol group of a neighboring cysteine. These bonds are important for stabilizing proteins that are secreted from cells (hormones, antibodies, some enzymes). Cysteine also serves as a nucleophile and an electron-transfer agent in enzymatic catalysis. Both are the result of the non-bonding electrons of cysteine’s sulfur atom, conferring it high chemical reactivity and the ability to exist in different oxidation states.
  • The carboxamide group of glutamine and asparagine can serve as both hydrogen bond donor and acceptor. As a result, these amino acids are commonly involved in hydrogen bond networks within proteins. This group in asparagine is also glycosylated in membrane/secreted proteins (see above for the benfits of glycosylation).

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III. Polar-charged amino acids

These include the following (Fig. 4):

  • Aspartate (asp, D) and glutamate (glu, E) – have a carboxyl group in their side chains. As explained above, this group has a low pKa and therefore tends to become deprotonated and negatively charged at physiological pH. For this reason, aspartate and glutamate are referred to as ‘acidic‘. In proteins, they tend to interact electrostatically with positively charged groups in other amino acids or in the protein’s ligand/substrate.
  • Lysine (lys, K) and arginine (arg, R) – have nitrogen-containing groups in their side chains (amino group in lysine and guanidine group in arginine). These groups have high pKa and therefore tend to become protonated and positively charged at physiological pH. For this reason, lysine and arginine are referred to as ‘basic‘. In proteins, they tend to interact electrostatically with negatively charged groups in other amino acids or in the protein’s ligand/substrate.
  • Histidine (his, H) – has an imidazole group in its side chain. This group has a pKa of ~6, and therefore has a 50% chance of being protonated (positively charged) or deprotonated (neutral) at physiological pH. This allows histidine to function in hydrogen-transfer enzymatic catalysis, where it may functions as the hydrogen donor, acceptor, or both.

Figure 4. Polar-charged amino acids.

Here are interesting facts on some polar-uncharged amino acids:

  • Carboxylation of glutamate on its γ carbon (see Fig. 6 below) allows it to bind efficiently cations, such as divalent calcium. This is very useful in clotting proteins, such as prothrombin, the activity of which is regulated by blood calcium levels.
  • The amino group of lysine’s side chain is able to form Schiff base with aldehydes. This helps some proteins bind aldehyde-containing prosthetic groups (e.g. the pyridoxal phosphate coenzyme of aminotranferase enzyme).
  • Oxidation of lysine’s side chain in structureal proteins like collagen allows it to participate in cross-linking reactions that stabilize these proteins.
  • As explained above, the imidazole side chain of histidine can serve as both acid and base thanks to its pKa, which is close to the physiological pH. This is important, for example, for the catalytic mechanism of the enzyme acetylcholine esterase, which inactivates the neurotransmitter acetylcholine. The inactivation is important for preventing our nervous system from going into paralysis and death, which is what happens when the enzyme is attacked and inactivated by toxic nerve agents. Acetylcholine is an ester, and it is hydrolyzed to choline and acetate by the enzyme, via nucleophilic attack of a catalytic serine residue on the ester bond. To do that, the serine must deprotonate, and this is made possible by a nearby histidine which acts as a base, abstracting serine’s proton:

 Figure 4a. Acetylcholine hydrolysis by its respective esterase (source)

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IV. Aromatic amino acids

These includes the following (Fig. 5):

  • Phenylalanine (phe, F) – has a phenyl group in its side chain.
  • Tyrosine (tyr, Y) – has a phenol group in its side chain.
  • Tryptophan (trp, W) – has an indole group in its side chain.

Figure 5. Aromatic amino acids.

In contrast to the other amino acids groups, this one is considered not according the polarity of the side chain but rather on its aromatic nature (in the chemical sense, not the olfactory one…). Aromatic groups contain delocalized π electrons which can interact with similar electrons in other aromatic groups, as well as with positively-charged groups. Indeed, all of these interactions are observed in proteins between aromatic side chains. The aromatic amino acids are important in forming closed scaffolds within proteins, especially binding sites for ligands and substrates.

Here are interesting facts on some aromatic amino acids:

  • Like serine and threonine, tyrosine may also become phosphorylated on proteins involved in cellular communications. A well-known example is the membrane-bound receptors which respond to growth factors. Binding of the latter to these receptors results in their phosphorylation, which in turn conveys the signal into the cell and results in cellular division. Genetic defects that allows for hormone-independent phosphoryaltion of these proteins often lead to cancer.
  • The phenol group of tyrosine also participates in differnt mechanisms of enzymatic catalysis (e.g. nucleophilic attack, acid-base catalysis and stabilization of reaction intermediates).
  • The indole group in tryptophan’s side chain is capable of participating in different polar and nonpolar non-covalent interactions with other chemical fspecies. Therefore, it is common in protein binding sites. It also participates in enzymatic catalysis and electron transfer.
  • Tryptophan’s side chain fluoresce when absorbing UV light. This allows biochemists to identify proteins or study changes in their structure by  UV-irradiating them and then recording the fluorescence of their tryptophan amino acids.

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The 20 naturally-occurring amino acids can be clustered according to their physical-chemical properties, as shown in the following Venn diagram:

Venn diagram

The 20 types of amino acids clustered by their physical-chemical properties (taken from Esquivel et al. (2013))

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As mentioned above, the 20 types of α-amino acids normally found in proteins are only a small part of the ~300 types of amino acids found in Nature, altogether. The rest include derivatives which, although similar to α-amino acids, may have slightly different chemical structure. For example, taurine and β-alanine have their amino group attached to rather than to Cα.

Such ‘special’ amino acids may be separated into two types:

  1. Amino acid derivatives that are formed by post-translational modification.
  2. Biogenic amines that act independently (as non-protein entities) in various cellular & physiological processes.

The two types are described in the following sections.

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4. AMINO ACIDS DERIVATIVES FOUND IN PROTEINS

I. Selenocysteine and pyrrolysine

Selenocysteine and pyrrolysine are two amino acids derivatives that evolution found a way to genetically incorporate into certain proteins. For this reason they are often referred to as the ’21st & 22nd amino acids’. Protein incorporation is achieved by loading these amino acids on a specialized tRNA molecule, which binds inside the ribosome to a mRNA ‘stop’ codon (UGA in the case of selenocysteine and UAG in the case of pyrrolysine). A stop codon normally signals the translation machinery to stop translation, but in the case of selenocysteine and pyrrolysine the codon also contains an addition sequence motif which prevents termination.

Selenocysteine is very similar to cysteine, with the sulfur atom replaced by selenium. However, it is created enzymatically from serine rather than from cysteine. The replacement of sulfur with selenium turns (seleno)cysteine into a better nucleophile, which is an advantage in enzymatic catalysis. Indeed, selenocysteine appears in certain oxidation-reduction enzymes. Some selenocysteine-containing enzymes, like glutathione peroxidase and some forms of thioredoxin reductase, act as antioxidants. That is, they are part of the body’s built-in system that fights and reverses oxidative damage, caused by free radicals. In addition, selenocysteine appears in enzymes that form T3, the most potent thyroid hormone. This is why selenium in the diet is important for the function of the thyroid gland.

Pyrrolysine appears in an enzyme (methyltransferase) of methane-producing Archaea and 0ne Eubacterium. It is enzymatically created from the natural amino acid lysine.

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II. Amino acids that are formed post-translationally

In some cases, a natural amino acid already present in a protein can be enzymatically modified to form a chemical derivative. For example, collagen, a protein that is widespread in animal connective tissues, contains hydroxyproline and hydroxylysine. These are produced by attachment of a hydroxyl group to the natural amino acids proline and lysine, respectively. Another non-natural amino acid, γ-carboxyglutamate, is formed by attachment of a carboxyl group to the amino acid glutamate in blood-clotting proteins.

Figure 6a. Some examples of non-natural amino acids.

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III.D-amino acids

Amino acids with the opposite configuration (D-amino acids), can be found in some proteins and peptides. Most of the latter are bacterial proteins/peptides. For example, the bacterial cell wall (peptidoglycan) contains D-alanine, while the bacterial antibiotic valinomycin contains D-valine. However, D-amino acids can also be found in multicellular organisms. For example, a peptide called dermorphin, which is produced by a South American frog to repel predators, contains D-alanine.

D-amino acids peptides

Figure 6b. Two peptides containing D-amino acids.

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5. AMINO ACIDS AS A SOURCE OF OTHER COMPOUNDS

Some amino acids, such as tyrosine, tryptophan, histidine and glutamate serve as precursors of ‘biogenic amines‘, compounds that are non-proteogenic (do not appear in proteins), yet have different cellular & physiological roles. Many biogenic amines act as neurotransmitters, hormones, or local mediators. Here are some examples:

  • Tyrosine is the source of a group of excitatory neurotransmitters and hormones called ‘catecholamines‘, which include epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine. They are called that because each of them contains the catechol (aromatic) ring that is part of the tyrosine side chain. Tyrosine is also the source for the pigment melanin and the thyroid hormones thyroxine (T4) and thriiodothyronine (T3).

Figure 7. Catecholamines biosynthesis from tyrosine (source)

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  • Tryptophan is the source of ‘indolamines‘ (a.k.a. ‘tryptamines‘). That is, biogenic amines containing the indole ring of tryptophan’s side chain. The most well-known indolamine is the neurotransmitter serotonin, involved in the regulation of moodappetite, and sleep. Indeed, the serotonergic mechanism in the brain is the target of the popular antidepressant/anxiolytic drugs called ‘selective serotonin reuptake inhibitors (SSRIs)‘. These increase serotonin levels in the brain, which has anti-depression and anti-anxiety effects. Serotonergic neuro-transmission is also targeted by other types of drugs, such as  antipsychoticsantiemetics, and antimigraine drugs, as well as the psychedelic drugs and empathogens.

Figure 8. Serotonin biosynthesis from tryptophan (source)

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  • Another well-known indolamine is melatonin, which regulates the sleep-wake cycle (circadian rhythm) in humans.

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  • Histidine is the source of histamine, local mediator of inflammation and the immune response to certain pathogens. As such, histamine also mediates allergy, and its receptors are targeted by anti-histamines (allergy-fighting drugs).

Figure 9. Histamine biosynthesis from histidine (source)

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  • Glutamate is the source of gamma-amino-butyric-acid (GABA), a major inhibitory brain neurotransmitter.

Figure 10a. GABA biosynthesis from glutamate (source)

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Glutamate, along with glycine and cysteine, also creates the tri-peptide glutathione – a compound that fights oxidative stress caused in our body by free radicals.

glutathione

Figure 10b. The structure of glutathione

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When glutathione is depleted by external agents, our body is exposed to oxidative damage. This happens, for example, in cases of acetaminophen (paracetamol) overdose. This common painkiller is normally metabolized in the liver to different metabolites. When consumed in large quantities, one of these metabolites depletes liver cells’ glutathione, leading to acute liver failure. The treatment in such cases involves restoration of glutathione levels in the liver, by administering its precursor, N-acetylcysteine. The latter, which is a chemical derivative of the amino acid cysteine, is also used for treating other cases of glutathione depletion, such as naphthalene toxicity.

  • Serine is used to build phosphatidylserine and phosphatidylethanolamine, two  phospholipids building the membranes of our cells. serine is also the precursor of ceramide, a waxy molecule from a group of other membrane lipids, sphingolipids, are built.

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  • Arginine is the precursor of creatine (an energy reservoir in our muscles, see more below), nitrogen oxide (a mediator of blood vessel constriction), citrulline (an antioxidant, see more below), and a group of polyamines that have various physiological and cellular roles.

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Other amines created from amino acids have other functions. Here are some examples:

Ornithine is involved in (i) ammonia detoxification (urea cycle) (ii) syntheses of proline, glutamate, and polyamines (iii) mitochondrial integrity and (iv) wound healing. It is built from the amino acid glutamate, and also as an intermediate in the urea cycle.

Citrulline is an antioxidant. It also functions in (i) arginine synthesis (ii) osmo-regulation (iii) ammonia detoxification. Finally, it constitute a reservoir of nitrogen. It is built from the amino acid arginine, and also as an intermediate during the urea cycle.

Theanine is a glutamine analog found in tea leaves. Besides acting as an antioxidant, it is involved in increasing GABA, dopamine and serotonin levels in the in brain, and thought to have a neuro-protective effect.

Carnitine facilitates the transport of long-chain fatty acids into mitochondria. It is build from the amino acid lysine.

Taurine is a sulfonic acid and a major constituent of bile. It is important for conjugation of bile acid, antioxidation, osmoregulation, membrane stabilization and calcium signalling. It is built from the amino acid cysteine.

Coenzyme A is important for central metabolism in all life forms. It is crucial to their ability to derive energy for foodstuff, as well as to build fatty acid, cholesterol and the neurotransmitter acetylcholine. It is made from the amino acid cysteine and from pantothenic acid (vitamin B5).

Creatine is a molecule in our skeletal muscles that binds a high-energy phosphate groups. During the first seconds of strenuous muscle action, ATP is consumed and there is no time to recreate it from glucose. The phosphorylated creatine is then used to replenish ATP from ADP, which is particularly important for ‘fight-or-flight’ cases.  Creatine is degraded in muscle to creatinine, which is secreted by the kidneys, and therefore considered a measure for renal function. Creatine is constructed from arginine, glycine and methionine.

S-adenosylmethionine is a molecule built from the amino acid methionine and the adenosyl group of ATP. It is a common and important enzymatic cofactor, needed for numerous biochemical reactions that involve methylation.

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6. AMINO ACIDS METABOLISM & NUTRITIONAL VALUE

Amino acids are synthesized by all living organisms. They are built from other amino acids or from different metabolites (e.g. α-keto acids):

  • Pyruvate alanine
  • Pyruvate valine, leucine, isoleucine (only in bacteria & plants)
  • Branched keto acids valine, leucine, isoleucine
  • α-ketoglutarate → glutamate
  • Histidine glutamate
  • Glutamate glutamine, proline, arginine
  • Oxoaloacetate aspartate
  • Aspartate asparagine
  • Aspartate methionine, threonine, lysine (only in bacteria & plants)
  • Ribose 5-phosphate + glutamine histidine
  • 3-phosphoglycerate → serine
  • hydroxypuruvate → serine
  • Glycine serine (in humans)
  • Glutathione serine (in humans)
  • Serine glycine, cysteine
  • Glyoxylate glycine
  • Isocitrate glycine
  • Ascorbic acid → glycine
  • phosphoenolpyruvate + erythrose 4-phosphate → chorismate → tryptophan, phenylalanine, tyrosine (only in bacteria & plants)
  • Phenylalanine tyrosine
  • Methionine cysteine

(amino acids are in red, other metabolites are in blue)

While the carbon skeleton of amino acids may come from different metabolites via different biochemical reactions, the amino group ultimately comes from atmospheric nitrogen. The latter is assimilated to its usable forms (ammonia/ammonium) by certain bacteria termed collectively diazotrophs. These include free cyanobacteria, as well as rhizobia, which are bacteria existing inside the root nodules of legumes. The fixation of nitrogen is possible thanks to an enzyme called nitrogenase, which these bacteria possess.

Whereas bacteria and plants can synthesize all 20 types of amino acids, humans can synthesize only 5 of them in sufficient quantities, and at any condition. These are referred to as ‘non-essential amino acids‘ (Figure 11a). All tissues in our body are capable of synthesizing amino acids, but the major sources for newly synthesized amino acids are the liver and (to a lesser extent) the intestines. Nine amino acids cannot be synthesized by our body at all, and must therefore be obtained from the diet. These amino acids are referred to as ‘essential‘. The remaining 6 amino acids, termed ‘conditionally essential’, can be synthesized, but need to be supplemented from the diet under certain conditions or situations (e.g. when the body is growing or ill). Notice that this distinction does not refer to the importance of the two types of amino acids; all 20 are important to cellular and physiological function.

Figure 11a. Essential vs. non-essential amino acids.

(Taken from Lehninger’s Principles of Biochemistry, 5th edition)

The common mnemonic for remembering the identity of essential amino acids is:”PVT. TIM HaLL” (pronounced “private TIM Hall). Note that (1) only the capital letters should be considered, (2) the two Ts stand from Threonine and Tryptophan, and (3) the two Ls stand for Lysine and Leucine.

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Essential amino acids can be obtained from different food sources:

Essential amino acids - sources

Figure 11b. Main food sources of essential amino acids. 

(adapted from Wikipedia)

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The nutritional value of a protein reflects its essential amino acid composition. Casein (the principle milk protein) is the only protein containing all essential amino acids, and therefore has a very high nutritional value.

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Proteins inside the body and those that originate from our food are constantly broken down, as part of normal homeostasis. Food-derived proteins are degraded in our digestive system by enzymes like pepsin, trypsin, chemotrypsin and elastase, while tissue proteins are degraded inside our cells either by lysosomes or by the ubiquitin-proteasome system (see this section). However, net degradation of proteins for energy production occurs only during high-protein dieting, prolonged starvation, or in untreated diabetics. In fact, the efficiency of ATP production from amino acids is lower compared to carbohydrates or fat, on a molar basis (see more below).

Amino acids that result from the degradation of ingested proteins in the stomach and intestines are absorbed into the blood and reach the liver via the portal vein. In mammals, several non-essential amino acids (e.g. Gln, Glu, and Asp) constitute an exception to this rule; they are so extensively oxidized inside the intestinal cells, that nearly all of them in a conventional diet do not enter the portal vein (Amino Acids (2009) 37 :1–17). The intestinal cells also degrade Pro to produce ornithine, citrulline, and Arg (citrulline is converted to Arg primarily by the kidneys). Finally, intestinal cells also degrade 30-50% of the essential amino acids in the diet (Amino Acids (2009) 37 :1–17).

Inside the body, amino acids may undergo various catabolic (degradative) processes (click figure to enlarge):

Amino acids catabolic processes

Figure 12.

However, in central metabolism amino acid degradation always involves the enzymatic removal of the amino group from the rest of the molecule, as ammonia. This may be done by transamination, a process in which the amino group is transferred from the amino acid to a keto acid (Fig. 13). This process is responsible for the removal of the amino group from most amino acids. The amino group is usually transferred to α-ketoglutarate, yielding Glu:

Figure 13. Transamination.

(Taken from Lehninger’s Principles of Biochemistry, 5th edition)

Another way to remove the amino group from amino acids is oxidative deamination. In this process, the amino group is released directly to the cytoplasm as ammonia (Fig. 14). This process is employed to deaminate glutamate, subsequent to its formation by transamination (Fig 13 above):

Figure 14. Oxidative deamination of glutamate

(Taken from Lehninger’s Principles of Biochemistry, 5th edition)

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The ammonia released by glutamate deamination is toxic (see more details below). It must therefore be immediately integrated into a new molecule or excreted from the body via urine. Ammonia can be integrated into a nucleotide, a new amino acid, or a biological amine.

Although some of the ammonia is excreted ‘as is’ by the kidneys, most of it is converted first by the liver (and to a lesser extent by intestinal cells) to a less toxic chemical, urea, which is then transferred to the kidneys for excretion via urine. The process, termed ‘urea cycle‘ (Fig. 15), occurs in the mitochondria and cytosol of liver/intestinal cells, and requires Asp as the source of the second amino group of urea. Besides urea, the process also produces fumarate, an intermediate of the citric acid (‘Krebs’) cycle. This couples the two metabolically important cycles.

Figure 15. The urea cycle.

(Taken from Lehninger’s Principles of Biochemistry, 5th edition)

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In some cases, ammonia may build up in the body (hyperammonemia). This happens due to:

  • Liver damage – e.g. in cirrhosis.
  • Low blood supply to the kidneys – e.g. as a result of dehydration or congestive heart failure.
  • Acute renal insufficiency.
  • Lower urinary track disease (tumor, stones).

The buildup of ammonia is dangerous; it disrupts the Krebs cycle by aminating α-ketoglutarate to glutamate, thus ‘steeling’ the important intermediate from the cycle. As a result, energy production in the brain is severely damaged, causing harsh neurological symptoms which may lead to coma (‘coma hepatica‘) or even death.

Urea may also build up in the blood (uremia), as a result of kidney damage. Indeed, a lab test of urea buildup, called ‘blood nitrogen urea’ (B.U.N), is used as a diagnostic tool for kidney failure.

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The carbon skeleton left after removal of ammonia from the amino acid is a keto acid. These carbon skeletons may be further degraded for energy production via glycolysis and/or the citric acid cycle.  As mentioned above, protein degradation yields less ATP compared to carbohydrates or fat, on a molar basis. The efficiency of energy transfer from amino acids to ATP ranges from 29% for methionine to 59% for isoleucine (Amino Acids (2009) 37 :1–17). Still, for rapidly dividing cells (e.g. enterocytes, lymphocytes, macrophages, and tumors), glutamine is a preferred fuel.

Alternatively, they may be used as a building block for different metabolites (see Figure 16 below) or biogenic amines (see section 5 above). All amino acids except leucine and lysine can be degraded to form metabolic intermediates that can be converted to glucose via gluconeogenesis. These amino acids are therefore called ‘glucogenic’. Amino acids whose degradation forms intermediates that can be converted to ketone bodies (acetoacetate, β-hydroxybutyrate or acetone) are called ‘ketogenic‘. Lysine and leucine are purely ketogenic (mnemonic: “LL“), whereas phenylalanine, isoleucine, threonine, tyrosine and tryptophan are both glucogenic and ketogenic (mnemonic: “PITTT“, where P stands for phenyalanine, not proline).

Amino acids conversion to metabilites

Figure 16. The conversion of amino acids to building blocks of central metabolism.

(Taken from Lehninger’s Principles of Biochemistry, 5th edition)

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Genetic defects in enzymes participating in amino acid degradation pathways lead to various diseases, such as Maple Syrup Disease and Phenylketonuria (PKU). In the latter, a defect in the enzyme phenylalanine hydroxylase prevents the conversion of phenylalanine to tyrosine. The accumulation of the former inhibits the transfer of other amino acids into the brain, which impairs the synthesis of proteins and myelin. This results in severe mental and developmental retardation in infants, as well as to shorter life expectancy. Thus, to avoid these severe outcomes, individuals with PKU must keep a low-protein diet and avoid drinking soda beverages which contain aspartam (has phenylalanine in its structure).

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7. AMINO ACIDS AS SUPPLEMENTS

The involvement of amino acids and their derivatives in various cellular & physiological processes suggests they can be used to boost desired processes or inhibit unwanted ones. Amino acids can be provided as dietary supplements in crystalline form (Wu 2009). This prevents their degradation during digestion, and allows them to become directly absorbed by the small intestine. The following table from Wu (2009) provides some examples of cellular and physiological processes that are likely to be affected by amino acids sumpplements (click figure to enlarge).

Amino acids effects as supplements

As the administration of large quantities of specific amino acids can seriously imbalance normal metabolism, this issue is far from being simple, and it is discussed extensively in the literature (e.g. Wu (2009)). For example, access of amino acids may result in reduced food intake, abnormal behavior, impaired growth, and other adverse effects. These may result not only from amino acid imbalance but also from antagonism, i.e. adverse-opposing actions of different amino acids.

 

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