16.3: Amino Acids and the Urea Cycle

Source: BiochemFFA_6_5.pdf. The entire textbook is available for free from the authors at http://biochem.science.oregonstate.edu/content/biochemistry-free-and-easy

In contrast to some of the metabolic pathways described to this point, amino acid metabolism is not a single pathway. The 20 amino acids have some parts of their metabolism that overlap with each other, but others are very different from the rest. In discussing amino acid metabolism, we will group metabolic pathways according to common metabolic features they possess (where possible). First, we shall consider the anabolic pathways.

Transamination

Before beginning discussion of the pathways, it is worthwhile to discuss a reaction common to the metabolism of most of the amino acids and other nitrogen-containing compounds and that is transamination. In cells, nitrogen is a nutrient that moves from one molecule to another in a sort of hand-off process. A general transamination reaction is shown below.

 

Glutamate and glutamine play central roles in transamination, each containing one more amine group than α-ketoglutarate and glutamate, respectively. Transamination reactions, as noted earlier, occur by a ping-pong mechanism and involve swaps of amines and oxygens.  

Synthesis varies

It is also important to recognize that organisms differ considerably in the amino acids that they can synthesize. Humans, for example, cannot make 9 of the 20 amino acids needed to make proteins, and the number of these that can be synthesized in needed amounts varies between adults and children.

Amino acids that cannot be made by an organism must be in the diet and are called essential amino acids. Non-essential amino acids are those an organism can make in sufficient quantities (Figure 6.135). Though amino acids do not have a common pathway of metabolism, they are often organized in “families” of amino acids with overlapping metabolic reactions common to members of each group. To designate amino acid families in the text we will use a blue font for headings to distinguish them.

α-ketoglutarate family

This family of amino acids arises from α-ketoglutarate of the citric acid cycle. It includes the amino acids glutamic acid, glutamine, proline, and arginine. It is also called the glutamate family, since all the amino acids in it derive from glutamate.

Glutamate

α-ketoglutarate is readily converted to glutamate in transamination reactions, as noted above. It can also be produced by the enzyme glutamate dehydrogenase, which catalyzes the reaction below (in reverse) to make glutamate.

In the forward direction, the reaction is a source of ammonium ion, which is important both for the urea cycle and for glutamine metabolism. Because it is a byproduct of a citric acid cycle intermediate, glutamate can therefore trace its roots to any of the intermediates of the cycle. Citrate and isocitrate, for example, can be thought of as precursors of glutamate. In addition, glutamate can be made by transamination from α-ketoglutarate in numerous transamination reactions involving other amino acids.

Aspartate family

Metabolism of aspartic acid is similar to that of glutamate. Aspartic acid can arise from transamination of a citric acid cycle intermediate (oxaloacetate).

Aspartate is also a precursor to four amino acids that are essential in humans. They are methionine, isoleucine, threonine, and lysine. Because oxaloacetate can be produced from aspartate, aspartate is an important intermediate for gluconeogenesis when proteins are the energy source

Aromatic amino acids

The aromatic amino acids, tryptophan, phenylalanine, and tyrosine can all be made starting with two simple molecules - PEP and erythrose-4-phosphate (Figure 6.145). All three aromatic amino acids are also important sources of hormones, neurotransmitters, and even the skin pigment melanin.

Tryptophan synthesis

Tryptophan is an essential amino acid. 

Regulation

Tryptophan is an important precursor of serotonin (neurotransmitter) and melatonin (hormone).

Melatonin

Melatonin is a compound made from tryptophan that is found in a wide spectrum of biological systems, including plants, animals, fungi, and bacteria. In animals, it acts as a hormone for circadian rhythm synchronization, signaling the onset of darkness each day. It has effects on the timing of sleep, seasonal effects, and can affect blood pressure, among other physiological phenomena. It can cross cell membranes, as well as the blood-brain barrier. Melatonin is a potent anti-oxidant and provides protective functions for nucleic acids. It is used sometimes to help in treatment of sleep disorders. Some reports have indicated that children with autism have abnormal melatonin pathways with low levels of the hormone.

Blue light

Melatonin production is affected by blue light and may be linked to sleep abnormalities for people using computer monitors after dark. To protect against this, some computer programs are available that reduce the screen’s blue light output in the evenings. Special eyeglasses that block blue light are also available. Though melatonin is linked to sleep in some animals (including humans), nocturnal animals are activated by increasing melatonin levels. Varying day/night lengths during the year alter melatonin production and provide biological signals of the seasons. These are especially important in the seasonal coloring and breeding habits of some animals. Melatonin is present in cherries, bananas, grapes, rice, cereals, olive oil, wine, and beer.

Serotonin

Serotonin, or 5-hydroxytryptamine, is a monoamine neurotransmitter derived from tryptophan. Blood platelets store serotonin and release it when they bind to a clot, causing vasoconstriction. Serotonin plays a role in cognitive functions and enhances memory and learning. Serotonin is widely thought to be a contributor to feelings of happiness and well-being. Some common anti-depressant drugs, including Prozac, Paxil and Zoloft, act to modulate action of serotonin at synapses.

Phenylalanine

Phenylalanine is an essential, hydrophobic amino acid in humans that is a precursor of tyrosine and since tyrosine is a precursor of several important catecholamines, phenylalanine is, thus, a precursor of them as well.

PKU

Phenylalanine is linked to the genetic disease phenylketonuria (PKU) which arises from an inability to metabolize the amino acid in people lacking (or deficient in) the enzyme phenylalanine hydroxylase. If left untreated, the disease can cause brain damage and even death, but if detected early, it can be easily managed by carefully monitoring dietary intake of the amino acid. Because of this, newborns are routinely tested for PKU. Phenylalanine is a component of the artificial sweetener known as aspartame (Nutrasweet - Figure 6.154) and is consequently dangerous for people suffering from this disorder.

Transamination of phenylpyruvate yields phenylalanine.

Hydroxylation of phenylalanine by aromatic amino acid hydroxylase (phenylalanine hydroxylase) yields tyrosine.

Tyrosine

Because tyrosine is made from phenylalanine and the latter is an essential amino acid in humans, it is not clear whether to classify tyrosine as essential or non-essential. Some define it as a conditionally essential amino acid. Others simply categorize it as non-essential.

As noted above, tyrosine can arise as a result of hydroxylation of phenylalanine. 

The hydroxyl group on tyrosine is a target for phosphorylation by protein kinase enzymes involved in signal transduction pathways.  When located in membranes, these enzymes are referred to as receptor tyrosine kinases and they play important roles in controlling cellular behavior/response.

Tyrosine metabolites

Tyrosine is a precursor of catecholamines, such as L-dopa, dopamine, norepinephrine, and epinephrine. 

Dopamine

Dopamine plays several important roles in the brain and body. A member of the catecholamine and phenethylamine families, its name comes from the fact that it is an amine made by removing a carboxyl group from L-DOPA. Dopamine is synthesized in the brain and kidneys. Dopamine is a neurotransmitter, being released by one nerve cell and then traveling across a synapse to signal an adjacent nerve cell. Dopamine plays a major role in the brain’s reward-mediated behavior. Rewards, such as food or social interaction, increase dopamine levels in the brain, as do addictive drugs. Other brain dopamine pathways are involved in motor control and in managing the release of various hormones.

Chemical messenger

Outside the nervous system, dopamine is a local chemical messenger. In blood vessels, it inhibits norepinephrine release and causes vasodilation. In the kidneys, it increases sodium excretion and urine output. It reduces gastrointestinal motility and protects intestinal mucosa in the digestive system and in the immune system, it reduces lymphocyte activity. The effect dopamine has on the pancreas is to reduce insulin production. With the exception of the blood vessels, dopamine is synthesized locally and exerts its effects near the cells that release it.

Epinephrine

Epinephrine (also called adrenalin) is a catecholamine chemically related to norepinephrine that is a hormone with medical applications. It is used to treat anaphylaxis, cardiac arrest, croup, and, in some cases, asthma, when other treatments are not working, due to its ability to favor bronchodilation.

Epinephrine is the drug of choice for treating anaphylaxis. The compound may be given through inhalation, by intravenous injection, or subcutaneous injection and exerts effects through the α- and β-adrenergic receptors. In the body, it is produced and released by adrenal glands and some neurons.

Effects

Physiological effects of epinephrine may include rapid heart beat, increased blood pressure, heart output, pupil dilation, blood sugar concentration and increased sweating. Other physical effects may include shakiness, increased anxiety, and an abnormal heart rhythm.

Norepinephrine

Norepinephrine (also called noradrenalin) is a catecholamine molecule that acts as a hormone and neurotransmitter. It is chemically similar to epinephrine, differing only in the absence of a methyl group on its amine. Norepinephrine is made and released by the central nervous system (locus coeruleus of the brain) and the sympathetic nervous system. The compound is released into the blood stream from adrenal glands and affects α- and β-adrenergic receptors.

Norepinephrine is at its lowest levels during sleep and at its highest levels during stress (fight or flight response). The primary function of norepinephrine is to prepare the body for action. It increases alertness, enhances memory functions, and helps to focus attention. Norepinephrine increases heart rate and blood pressure, increases blood glucose and blood flow to skeletal muscle and decreases flow of blood to the gastrointestinal system.

Medical considerations

Norepinephrine may be injected to overcome critically low blood pressure and drugs countering its effects are used to treat heart conditions. α-blockers, for example, are used to battle cardiovascular and psychiatric disorders. β-blockers counter a different set of norepinephrine’s effects than α-blockers and are used to treat glaucoma, migraine headaches and other cardiovascular problems.

Pyruvate family

Alanine

Alanine is the amino acid that is most easily produced from pyruvate. The simple transamination catalyzed by alanine transaminase produces alanine from pyruvate.

Leucine

Like valine and isoleucine, leucine is an essential amino acid in humans.

Urea cycle

The urea cycle holds the distinction of being the first metabolic cycle discovered - in 1932, five years before the citric acid cycle. It is an important metabolic pathway for balancing nitrogen in the bodies of animals and it takes place primarily in the liver and kidney.

Ammonia, of course, is generated by metabolism of amines and is toxic, so managing levels of it is critical for any organism. Excretion of ammonia by fish is one reason that an aquarium periodically requires cleaning and replacement of water.

Liver failure can lead to accumulation of nitrogenous waste and exacerbates the problem.

Urea is less toxic than ammonia and is released in the urine. 

Complete deficiency of any urea cycle enzyme is fatal at birth.

Energy generation

Amino acid catabolism

Amino acids are divided according to the pathways involved in their degradation. There are three general categories. Ones that yield intermediates in the glycolysis pathway are called glucogenic and those that yield intermediates of acetyl-CoA or acetoacetate are called ketogenic. Those that involve both are called glucogenic and ketogenic. 

As seen in the two figures, amino acids largely produce breakdown products related to intermediates of the citric acid cycle or glycolysis, but this isn’t the complete picture. Some amino acids, like tryptophan, phenylalanine, and tyrosine yield hormones or neurotransmitters on further metabolism (as noted earlier). Others like cysteine and methionine must dispose of their sulfur and all of the amino acids must rid themselves of nitrogen, which can happen via the urea cycle, transamination, or both.