Unit III

Biogenic amines-tyramine, tryptamine and histamine. Phenyl ketonuria,, Alkaptonuria, Tyrosinaemias, albinism.

Disorders of sulpher containing amino acids - Cystinuria, Hartnup disease, Maple syrup urine disease, Creatinuria, Inborn errors of metabolism.
Uric acid metabolism and disorders of purine and pyrimidine metabolismGout, Lesch-Nyhan syndrome, Xanthinuria.

biogenic amines

A biogenic amine is a biogenic substance with one or more amine groups. (A biogenic substance is a substance produced by life processes. It may be either constituents, or secretions, of plants or animals. A more specific name for these substances is biomolecules) Histamine - a substance derived from the amino acid histidine that acts as a neurotransmitter mediating arousal and attention, as well as a pro-inflammatory signal released from mast cells in response to allergic reactions or tissue damage. Histamine is also an important stimulant of HCl secretion by the stomach through histamine H2 receptors. Tyramine - a substance that is found in many common foods, and is associated with increased blood pressure and headaches. Tryptamine - a monoamine alkaloid found in trace amounts in the brains of mammals, and believed to play a role neuromodulator or neurotransmitter.

Tyramine
Tyramine

(4-hydroxyphenethylamine; paratyramine, mydrial or uteramin) is a naturally occurring monoamine compound and trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine (dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline)] releasing agent. Notably, however, it is unable to cross the bloodbrain barrier, resulting in only non psychoactive peripheral sympathomimetic effects. When tyramine-rich foods are ingested in conjunction with a monoamine oxidase inhibitor (MAOI), tyramine is responsible for the socalled "cheese effect" sometimes seen with their use.

 Tyramine In

is physiologically metabolized by MAOA.

humans, if monoamine metabolism is compromised by the use of monoamine oxidase inhibitors (MAOIs) and foods high in tyramine are ingested, a hypertensive crisis can result, as tyramine can cause the release of stored monoamines, such as dopamine, norepinephrine and epinephrine.

large dietary intake of tyramine (or a dietary intake of tyramine while taking MAO inhibitors) can cause the tyramine pressure response, which is defined as an increase in systolic blood pressure of 30 mmHg or more. The displacement of norepinephrine (noradrenaline) from neuronal storage vesicles by acute tyramine ingestion is thought to cause the vasoconstriction and increased heart rate and blood pressure of the pressure response. In severe cases, adrenergic crisis can occur.

 However,

if one has had repeated exposure to tyramine, there is a decreased pressor response; tyramine is degraded to octopamine, which is subsequently packaged in synaptic vesicles with norepinephrine (noradrenaline). Therefore, after repeated tyramine exposure, these vesicles contain an increased amount of octopamine and a relatively reduced amount of norepinephrine. When these vesicles are secreted upon tyramine ingestion, there is a decreased pressure response, as less norepinephrine is secreted into the synapse, and octopamine does not activate alpha or beta adrenergic receptors.

Tryptamine

Tryptamine is a monoamine alkaloid found in plants, fungi, and animals. It contains an indole ring structure, and is structurally similar to the amino acid tryptophan, from which it derives its name. Tryptamine is found in trace amounts in the brains of mammals and is believed to play a role as neuromodulator or neurotransmitter. The tryptamine chemical structure is the backbone for a group of compounds termed collectively tryptamines. This group includes many biologically active compounds, including neurotransmitters and psychedelic drugs. The concentration of tryptamine in rat brains is about 3.5 pmol/g.

Histamine
Histamine

is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues

Roles in the body

Although

histamine is small compared to other biological molecules (containing only 17 atoms), it plays an important role in the body. It is known to be involved in 23 different physiological functions. Histamine is known to be involved in so many physiological functions because of its chemical properties that allow it to be so versatile in binding. It is Coulombic (able to carry a charge), conformational, and flexible. This allows it to interact and bind more easily

Sleep regulation Histamine is released as a neurotransmitter. The cell bodies of histaminergics, the neurons which release histamine, are found in the posterior hypothalamus, in various tuberomammillary nuclei. From here, these neurons project throughout the brain, to the cortex through the medial forebrain bundle. Histaminergic action is known to modulate sleep. Classically, antihistamines (H1 histamine receptor antagonists) produce sleep. Likewise, destruction of histamine releasing neurons, or inhibition of histamine synthesis leads to an inability to maintain vigilance. Finally, H3 receptor antagonists increase wakefulness. It has been shown that histaminergic cells have the most wakefulness-related firing pattern of any neuronal type thus far recorded. They fire rapidly during waking, fire more slowly during periods of relaxation/tiredness and completely stop firing during REM and NREM (non-REM) sleep. Histaminergic cells can be recorded firing just before an animal shows signs of waking.

Suppressive effects While histamine has stimulatory effects upon neurons, it also has suppressive ones that protect against the susceptibility to convulsion, drug sensitization, denervation supersensitivity, ischemic lesions and stress. It has also been suggested that histamine controls the mechanisms by which memories and learning are forgotten. Erection and sexual function Libido loss and erectile failure can occur following histamine (H2) antagonists such as cimetidine and ranitidine. The injection of histamine into the corpus cavernosum in men with psychogenic impotence produces full or partial erections in 74% of them. It has been suggested that H2 antagonists may cause sexual difficulties by reducing the uptake of testosterone. Disorders As an integral part of the immune system, histamine may be involved in immune system disorders and allergies. Mastocytosis is a rare disease in which there is a proliferation of mast cells that produce excess histamine. Histamine intolerance is a condition in which the body reacts to histamine in foods.

Schizophrenia Metabolites of histamine are increased in the cerebrospinal fluid of people with schizophrenia, while the efficiency of H(1) receptor binding sites is decreased. Many atypical antipsychotic medications have the effect of increasing histamine turnover. Multiple Sclerosis Histamine therapy for treatment of multiple sclerosis is currently being studied. The different H receptors have been known to have different effects on the treatment of this disease. The H1 and H4 receptors, in one study, have been shown to be counterproductive in the treatment of MS. The H1 and H4 receptors are thought to decrease permeability in the Blood Brain Barrier, thus increasing infiltration of unwanted cells in the Central Nervous System. This can cause inflammation, and MS symptom worsening. The H2 and H3 receptors are thought to be helpful when treating MS patients. Histamine has been shown to help with T-cell differentiation. This is important because in MS, the immune system attacks its own myelin sheaths on nerve cells (which causes loss of signaling function and eventual nerve degeneration). By helping T cells to differentiate, the T cells will be less likely to attack the body's own cells, and instead attack invaders.

PHENYLKETONURIA (PKU)

 Phenylketonuria

(commonly known as PKU) is an inherited disorder that increases the levels of a substance called phenylalanine in the blood. is a building block of proteins (an amino acid) that is obtained through the diet. is found in all proteins and in some artificial sweeteners. PKU is not treated, phenylalanine can build up to harmful levels in the body, causing intellectual disability and other serious health problems.

Phenylalanine

It

If

 Phenylketonuria

(PKU) is the most common autosomal recessive disorder of amino acid metabolism. disease is caused mainly by mutations in the phenylalanine hydroxylase (PAH) gene, encoding phenylalanine hydroxylase (PAH) enzyme. PAH enzyme deficiency results in the elevation of phenylalanine in the blood, which may cause severe irreversible mental retardation in the affected individuals.
than 500 different disease causing mutations have been identified in the PAH gene.

The

The

More

The normal metabolism of phenylalanine (pathways a and b)

BREAKDOWN

Dietry sources, particularly plant proteins

PHENYLALANINE

PHENYLALANINE HYDROXYLASE

(a) (b)

TYROSINE

BODY PROTEINS

The abnormal metabolism in phenylketonuric subjects (pathway c)

HYDROXYPHENYLACETIC ACID

Dietry sources, particularly plant proteins

(c)
PHENYLALANINE HYDROXYLASE

PHENYLALANINE* (a)

(c)
(b) PHENYLACETIC ACID*
*Agents, thought to be responsible for mental retardation

BODY PROTEINS

ENZYMATIC ACTIVITY
In cases of PKU, the enzyme that breaks down

phenylalanine, phenylalanine hydroxylase, is completely or nearly completely deficient.

amino acid, tyrosine, which is utilized by the body.

This enzyme normally converts phenylalanine to another

When this enzyme, phenylalanine hydroxylase, is absent

or deficient, phenylalanine and its breakdown chemicals from other enzyme routes, accumulate in the blood and body tissues.

LEVELS OF BLOOD PHENYLALANINE

A

normal blood phenylalanine level is about 1mg/dl. cases of PKU, levels may range from 6-80mg/dl, but are usually greater than 30mg/dl.

In

WHAT HAPPENS WHEN THERE IS TOO MUCH BLOOD PHENYLALANINE?

Chronically,

high levels of phenylalanine and some of its breakdown products can cause significant brain problems.

There

are other disorders of hyperphenylalaninemia, but classic PKU is the most common cause of high levels of phenylalanine in the blood.

WHAT HAPPENS WHEN THERE IS TOO LITTLE BLOOD PHENYLALANINE?

It

is important to remember that some phenylalanine is needed to maintain normal body function. phenylalanine intake may cause mental and physical sluggishness, loss of appetite, anemia, rashes, and diarrhea.

Insufficient

Test
Ferric

chloride + urine of new born baby Green colour in the presence of ketone bodies

Symptoms of PKU

The signs and symptoms of PKU vary from mild to severe. The most severe form of this disorder is known as classic PKU. Infants with classic PKU appear normal until they are a few months old. Without treatment with a special low-phenylalanine diet, these children develop permanent intellectual disability. Seizures, delayed development, behavioral problems, and psychiatric disorders are also common. Untreated individuals may have a musty or mouse-like odor as a side effect of excess phenylalanine in the body. Children with classic PKU tend to have lighter skin and hair than unaffected family members and are also likely to have skin disorders such as eczema.

Frequency
1

in 10 000 in Caucasians of NW Europe

Catabolic pathways for phenylalanine and tyrosine.

Alkaptonuria
Alkaptonuria

is a rare condition in which a person's urine turns a dark brownish-black color when exposed to air. defect in the HGD gene causes alkaptonuria. gene defect makes the body unable to properly break down certain amino acids (tyrosine and phenylalanine). a result, a substance called homogentisic acid builds up in the skin and other body tissues. acid leaves the body through the urine. The urine turns brownish-black when it mixes with air.

The

As

The

 Another

inheritable disease of phenylalanine catabolism is alkaptonuria, in which the defective enzyme is homogentisate dioxygenase. serious than PKU, this condition produces few ill effects, although large amounts of homogentisate are excreted and its oxidation turns the urine black. with alkaptonuria are also prone to develop a form of arthritis. is of considerable historical interest.

Less

Individuals

Alkaptonuria

Symptoms Urine in an infant's diaper may darken and can turn almost black after several hours. However, many persons with this condition may not know they have it until mid-adulthood (around age 40), when joint and other problems occur.
Symptoms may include: Arthritis (especially of the spine) that gets worse over time Darkening of the ear Dark spots on the white of the eye (sclera) and cornea.

Signs and tests A urine test (urinalysis) is done to test for alkaptonuria. If ferric chloride is added to the urine, it will turn the urine a black color in patients with this condition.

Complications People with this condition also can get arthritis in adulthood. The build-up of homogentisic acid in the cartilage causes arthritis in about 50% of older adults with alkaptonuria. Homogentisic acid also can build up on the heart valves, especially the mitral valve. This can sometimes lead to the need for valve replacement. Coronary artery disease may develop earlier in people with alkaptonuria. Kidney stones and prostate stones may be more common in people with alkaptonuria.