Pathology of amino acid metabolism

Feature congenital metabolic disorders due to the inability to convert phenylalanine to tyrosine. Characteristics of the disease maple syrup. General analysis of multisystem frustration of connective tissue with the help of classical homocystinuria.

Рубрика Иностранные языки и языкознание
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Язык английский
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Home task

On the discipline: “Biochemistry”

Topic: “Pathology of amino acid metabolism”

Student: Litvin Irina

Group IES 304

Leader: Vasylchenko O.A

Kyiv 2013



1. Phenylketonuria

2. Maple Syrup Urine Disease

3. Homocystinuria

4. Cystinuria

5. Glycine encephalopathy




Twenty amino acids, including nine that cannot be synthesized in humans and must be obtained through food, are involved in metabolism. Amino acids are the building blocks of proteins; some also function as or are synthesized into important molecules in the body such as neurotransmitters, hormones, pigments, and oxygen-carrying molecules. Each amino acid is further broken down into ammonia, carbon dioxide, and water. Amino acids accumulate in body fluids when there are genetic defects i.e. inborn errors of metabolism (IEM), that affect their metabolism or transport. Sometimes the opposite can happen and an IEM can result in the deficiency of an amino acid, for example some disorders of the urea cycle result in arginine deficiency.

Amino acids are more likely to accumulate the closer they are to the metabolic block. Metabolic blocks may result in the accumulation of novel compounds that are not normally observed-for example succinylacetone accumulates in tyrosinaemia type 1.

Inborn errors of amino acid metabolism are associated with clinical disease in most cases. For some disorders the toxic agent is readily apparent. For example high plasma concentrations of leucine cause damage to the brain-encephalopathy. For other conditions the nature of the toxicity is less well characterised. For example in phenylketonuria there remains debate as to how the high plasma phenylalanine concentrations cause damage to the developing brain and to what extent the novel compounds, the phenylketones and the deficiency of neurotransmitters contribute to the pathophysiology.

In this home work I try to explain such amino acid disorder diseases as phenylketonuria, maple syrup disease, homocystinuria, cystinuria, glycine encephalopathy.

1. Phenylketonuria

Phenylketonuria (PKU) is an inborn error of metabolism due to the inability to convert phenylalanine to tyrosine; it produces mental retardation, seizures, and imperfect hair pigmentation.

Folling in 1934 first called attention to the condition, since then the disease has been found in all parts of the world, although it is rare in Negroes or in Jews of European descent. It is transmitted as an autosomal recessive disorder.

The metabolic defect in PKU is a failure in the hydroxylation of phenylalanine to tyrosine. It is important to note that phenylketonuria can occur even if the hydroxylase enzyme is normal. This is because the hydroxylase enzyme requires another molecule called tetrahydrobiopterin to function properly. When the enzyme (dihydrobiopterin reductase) that produces tetrahydrobiopterin is deficient, it gunks up the entire system and slows the ability of phenylalanine hydroxylase to convert phenylalanine to tyrosine (Figure 1).

Figure 1. Biochemistry of phenylketonuria.

As phenylalanine hydroxylase normally converts phenylalanine to tyrosine, the block occurs between phenylalanine and tyrosine. As phenylalanine cannot be converted to tyrosine it builds up in the blood, when it reaches high levels it is termed hyperphenylalaninemia.

This is not the only result of this disrupted pathway (Figure 2). As we can see, tyrosine is ordinarily used to produce thyroxine, dopa and subsequently melanin, in PKU the defective enzyme causes deficiency of all these products as well as tyrosine.

Figure 2. Phenylalanine methabolic pathway.

The raised phenylalanine in the blood results in increased phenylpyruvic acid which is excreted in the urine in PKU, this is useful in diagnosis.

The phenylpyruvic acid has also been shown to inhibit the enzyme pyruvate decarboxylase in brain. This would lead to a decrease in energy for the developing brain and decreased myelin formation, which is found in PKU. Together, these could explain the mental retardation found in PKU.

Many substances are harmful to the developing foetus and phenylalanine appears to be one of these, hyperphenylalaninemia resulting in congenital heart defects and microcephaly (An abnormally small head and brain).

The lack of melanin leads to decreased pigmentation of the person with PKU. Such patients therefore have blond hair and blue eyes and certain normally pigmented parts of the brain (such as the substantia nigra) may also lack pigment [1].

Thyroxine deficiency can lead to hypothyroidism, which can be treated with hormone replacement.

The generally accepted therapy for PKU restricts the dietary intake of phenylalanine, using a commercially available casein hydrolysate from which the amino acid has been removed. Generally, patients tolerate this diet well, and within

one to two weeks the serum phenylalanine concentration becomes normal. Various complications of dietary treatment, all due to insufficient intake of phenylalanine, include osteoporosis, poor weight gain, and cutaneous lesions. There is

also some evidence that prolonged nutritional deprivation during infancy interferes with intellectual development.

Frequent serum phenylalanine determinations are essential to ensure

adequate regulation of the diet. As restriction of phenylalanine intake has definite inherent risks, the criteria for initiating treatment of infants needs re-evaluation.

On a low phenylalanine diet seizures disappear and the electroencephalogram often reverts to normal. Abnormally blond hair regains its natural color. The effects on mental ability are less clear-cut.

2. Maple Syrup Urine Disease

Maple syrup urine disease (MSUD) also called branched-chain ketoaciduria is a rare (1:185,000), autosomal recessive disorder in which there is a partial or complete deficiency in branched-chain б-keto acid dehydrogenase, an enzyme complex that decarboxylates leucine, valine, and isoleucine. These amino acids and their corresponding by-products б-keto acids (alphaketoisocaproic acid (KIcA), alpha-ketoisovaleric acid (KivA), and alpha-keto-beta-methylvaleric acid (KMA)) accumulate in the blood, causing a toxic effect that interferes with brain functions (Figure 3). MSUD can result from mutations in any of the genes that code for the enzyme subunits.

The disease is characterized by feeding problems, vomiting, dehydration, severe metabolic acidosis, and a characteristic maple syrup odor to the urine. The smell is also present and sometimes stronger in the ear wax of an affected individual. The compound responsible for the odor is sotolon (sometimes spelled sotolone) [2]. Infants with this disease seem healthy at birth but if untreated, the disease leads to mental retardation, physical disabilities, and even death.

Diagnosis is made by finding elevated concentrations of all branched chain amino acids in plasma and less reliably in urine together with the presence of the unusual amino acid alloisoleucine. Finding characteristic keto acids in urine by organic acid GCMS analysis can also be helpful.

As in PKU a diet containing restricted amounts of the inadequately handled amino acids-in this instance leucine, isoleucine and valine-has been used in treatment. For optimal results the diet should be initiated during the first few days of life, and frequent quantitation of the serum amino acids is necessary.

Figure 3. Branched chain amino acids catabolism.

3. Homocystinuria

Classical Homocystinuria, also known as cystathionine beta synthase deficiency or CBS deficiency,[3] is an inherited disorder of the metabolism of the amino acid methionine, often involving cystathionine beta synthase (Figure 4). It is an inherited autosomal recessive trait, which means a child needs to inherit a copy of the defective gene from both parents to be affected.

This defect leads to a multisystemic disorder of the connective tissue, muscles, CNS, and cardiovascular system. Homocystinuria represents a group of hereditary metabolic disorders characterized by an accumulation of homocysteine in the serum and an increased excretion of homocysteine in theurine. Infants appear to be normal and early symptoms, if any are present, are vague.

Homocysteine is an intermediate in the metabolic pathway between methionine and cysteine. In addition to the enzyme, cystathionine synthase, in the main pathway, there are two additional enzymes which can remethylate homocysteine back to methionine. All three enzymes have vitamin cofactors. Homocysteine is present in body fluids in several forms. It is a sulphydryl compound that dimerises (oxidises) readily to form homocystine. Traditionally it was the `free' homocystine (dimer) in plasma and urine that was measured by amino acid analysis to detect and monitor homocystinuria.

But homocysteine can exist in plasma covalently bound to protein and to other sulphhydryl compounds. Therefore the most consistent and sensitive way to measure plasma homocysteine is to start by reducing all forms back to the monomer homocysteine initially. In this way total homocysteine is assayed.

No specific cure has been discovered for homocystinuria; however, many people are treated using high doses of vitamin B6 (also known as pyridoxine) [4]. Slightly less than 50% respond to this treatment and need to intake supplemental vitamin B6 for the rest of their lives. Those who do not respond require a low methionine diet, and most will need treatment with trimethylglycine. A normal dose of folic acid supplement and occasionally adding cysteine to the diet can be helpful, as glutathione is synthetized from cysteine (so adding cysteine can be important to reduceoxidative stress).

Figure 4. Homocystine metabolism.

Neither a low-methionine diet nor medication will improve existing intellectual disability. Medication and diet should be closely supervised by a physician who has experience treating homocystinuria.

4. Cystinuria

Cystinuria is an inherited autosomal recessive[5] disease that is characterized by the formation of cystine stones in the kidneys, ureter, and bladder.

Cystinuria is caused by the defective transport of cystine and several other amino acids (arginine, ornithine and lysine),through the cells of the kidney and the intestinal tract. Although cystine is not the only overly excreted amino acid in cystinuria, it is the least soluble of all naturally occurring amino acids. Cystine precipitates, or crystallizes out of urine and forms stones (calculi) (Figure 5) in the kidney, ureter, bladder, or anywhere in the urinary tract.

Small stones are passed in the urine. However, big stones remain in the kidney (nephrolithiasis) impairing the outflow of urine while medium size stones make their way from the kidney into the ureter and lodge there further blocking the flow of urine (urinary obstruction).

Figure 5. The cystine stones compared in size to a quarter (a U.S. $0.25 coin).

The foremost aim of treatment is to prevent the formation of cystine stones. This goal is attained mainly by increasing the volume of urine. The reason for the increased urine volume is simple. By increasing the volume of urine, the concentration of cystine in the urine is reduced which prevents cystine from precipitating from the urine and forming stones. Cystine stones in many patients can be dissolved and new ones prevented by a high fluid intake (5-7 liters per day).

Another strategy that has been attempted to treat cystinuria is alkalization of the urine. The rationale is that in an alkaline (nonacidic) liquid, cystine tends to stay in solution and there it does no harm. To make the urine alkaline, sodium bicarbonate (and similar substances) have been used. This treatment is not without hazard because it can, while preventing cystine stones, lead to the formation of other types of kidney stones. metabolic phenylalanine disease homocystinuria

5. Glycine encephalopathy

Glycine encephalopathy (also known as non-ketotic hyperglycinemia or NKH) is a rare autosomal recessive disorder of glycine metabolism. After phenylketonuria, glycine encephalopathy is the second most common disorder of amino acid metabolism. The disease is caused by defects in the glycine cleavage system, an enzyme responsible for glycine catabolism. There are several forms of the disease, with varying severity of symptoms and time of onset. The symptoms are exclusively neurological in nature, and clinically this disorder is characterized by abnormally high levels of the amino acid glycine in bodily fluids and tissues, especially the cerebral spinal fluid.

Glycine is the simplest amino acid, having no stereoisomers. It can act as a neurotransmitter in the brain, acting as an inhibitor in the spinal cord and brain stem, while having excitatory effects in the cortex of the brain. Glycine is metabolized to eventual end products of ammonia and carbon dioxide through the glycine cleavage system (GCS), an enzyme complex made up of four protein subunits (Figure 6). Defects in these subunits can cause glycine encephalopathy, although some causes of the disease are still unknown. The GCS has its highest activity levels in liver, brain and placental tissue. One of its main functions is to keep glycine levels low in the brain. Defects in GCS cause an increase of glycine concentration in blood plasma and cerebrospinal fluid [6]. The exact pathophysiology of the disorder is not known, but it is considered likely that buildup of glycine in the brain is responsible for the symptoms [7].

Glycine encephalopathy (nonketotic hyperglycinemia) should not be confused with other metabolic disorders that can produce elevated glycine. For example, certain inherited 'organic acidurias' (aka 'organic acidemias') can produce elevated glycine in plasma and urine, although the disorders are not caused by defects in the glycine cleavage system [8]. Glycine encephalopathy is unique in the fact that levels of glycine are disproportionately elevated in CSF (in addition to blood and urine), whereas CSF glycine levels are normal or near-normal in patients with inherited organic acidurias.

Glycine is metabolized in the body to end products of carbon dioxide and ammonia. The glycine cleavage system, which is responsible for glycine metabolism in the mitochondrion is made up of four protein subunits, the P-protein, H-protein, T-protein and L-protein.

Figure 6. Nonketonic hyperglycinemia.


Inborn errors of metabolism are commonly caused by mutant genes that generally result in abnormal proteins, most often enzymes. The inherited defects may be expressed as a total loss of enzyme activity or, more frequently, as a partial deficiency in catalytic activity. Without treatment, the inherited defects of amino acid metabolism almost invariably result in intellectual disability or other developmental abnormalities as a consequence of harmful accumulation of metabolites. Although more than 50 of these disorders have been described, many are rare, occurring in less than 1 per 250,000 in most populations (Figure 7). Collectively, however, they constitute a very significant portion of pediatric genetic diseases (Figure 8).

Figure 7. Incidence of inherited diseases of amino acid metabolism.

Figure 8. Summary of the metabolism of amino acids in humans.


1. Disorders of amino acids metabolism/ John Menkes/ Los Angeles,1971. - p.14-16.

2. Strauss, Kevin A; Puffenberger, Erik G; Morton, D Holmes. "Maple Syrup Urine Disease", in Pagon, Roberta A; Bird, Thomas D; Dolan, Cynthia R; Stephens, Karen; Adam, Margaret P, GeneReviews, University of Washington, Seattle,2006 - p. 24-25.

3. Online 'Mendelian Inheritance in Man' (OMIM)236200

4. Bakker, R. C.; Brandjes, D. P. (Jun 1997). "Hyperhomocysteinaemia and associated disease".Pharmacy world & science : PWS 19 (3): 126-132.

5. Fjellstedt, Erik; Harnevik, Lotta; Jeppsson, Jan-Olof; Tiselius, Hans-Gцran; Sцderkvist, Peter; Denneberg, Torsten (2003). "Urinary excretion of total cystine and the dibasic amino acids arginine, lysine and ornithine in relation to genetic findings in patients with cystinuria treated with sulfhydryl compounds". Urological Research 31 (6): 417-25

6. Sarafoglou, Kyriakie; Hoffmann, Georg F.; Roth, Karl S. (eds.). Pediatric Endocrinology and Inborn Errors of Metabolism. New York: McGraw Hill Medical. p. 811.

7. "Nonketotic hyperglycinemia". McGraw Hill. Retrieved 2011-09-22.

8. "The Organic Acidemias: An Overview - GeneReviews - NCBI Bookshelf".

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