Download Metabolism of Amino Acids with Branched Radicals

Kwashiorkor – caused by the deficiency of proteins in diet
The symptoms of kwashiorkor:
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change in skin and hair color (reddish-orange color)
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fatigue
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diarrhea
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loss of muscle mass
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failure to grow or gain weight
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edema (swelling)
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damaged immune system, which can lead to more frequent and severe infections
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irritability
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flaky rash
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large belly that sticks out
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shock
DISORDERS OF AMINO ACID METABOLISM
Phenylalanine Metabolism
Block 1. Phenylketonuria (PKU) – hereditary disease (phenyl-pyruvic oligofhrenia), caused by
the lack of phenylalanine 4-monooxigenase synthesis in the liver. The disease is connected with
phenylalanine and phenyl pyruvate accumulation. If untreated it can cause problems with brain
development, leading to progressive mental retardation, brain damage and convulsions.
There is no cure for PKU, but patients who are diagnosed early and maintain a strict diet can
have a normal life span with normal mental development.
Block 2. Type 1 Tyrosinemia, also known as hepatorenal tyrosinemia, is the most severe form
of tyrosinemia. It is caused by a deficiency of the enzyme fumaryl acetoacetate hydrolase, which
catalyzes the final step in the degradation of tyrosine – fumaryl acetoacetate to fumarate,
acetoacetate and succinate. Fumaryl acetoacetate accumulates in hepatocytes and proximal renal
tubal cells and causes oxidative damage and DNA damage leading to cell death and
dysfunctional gene expression which alters metabolic processes like protein synthesis and
gluconeogenesis. The increase in fumaryl acetoacetate inhibits previous steps in tyrosine
degradation leading to an accumulation of tyrosine in the body. Tyrosine is not directly toxic to
the liver or kidneys but causes dermatologic and neurodevelopmental problems.
Type 1 tyrosinemia typically presents in infancy as failure to thrive and hepatomegaly. The
primary effects are progressive liver and kidney dysfunction. The liver disease causes cirrhosis,
conjugated hyperbilirubinemia, hypoglycemia and coagulation abnormalities. This can lead to
jaundice, ascites and hemorrhage. There is also an increased risk of hepatocellular carcinoma.
The kidney dysfunction presents as Fanconi syndrome: renal tubular acidosis, hypophosphatemia
and aminoaciduria. Cardiomyopathy, neurologic and dermatologic manifestations are also
possible.
Block 3. Albinism (from Latin albus, "white"; also called achromia, achromasia, or
achromatosis) is a congenital disorder characterized by the complete or partial absence of
pigment in the skin, hair and eyes due to absence or defect of an enzyme tirosinase involved in
the production of melanin. Because individuals with albinism have skin that partially or entirely
lacks the dark pigment melanin, which helps protect the skin from the sun's ultraviolet radiation,
their skin can burn more easily from overexposure.
The human eye normally produces enough pigment to color the iris blue and lend opacity to the
eye. However, there are cases in which the eyes of an albinistic person appear red or purple,
depending on the amount of pigment present, due to the red of retina being visible through the
iris. Lack of pigment in the eyes also results in problems with vision, both related and unrelated
to photosensitivity.
The albinistic are generally as healthy as the rest of the population (but see related disorders
below), with growth and development occurring as normal, and albinism by itself does not cause
mortality, although the lack of pigment blocking ultraviolet radiation increases the risk of skin
cancer and other problems.
Block 4. Alkaptonuria hereditary disease, caused by the lack of enzyme homogentisate 1,2dioxygenase (EC 1.13.11.5) and accumulation of homogentisate which is not catabolysed, but
excreted with urine or oxidised by polyphelnoloxidase into dark-coloured, polyphenols which
partly are excreted with urine and giving it dark colour. Another part of polyphenols is deposited
either in eye sclera, ears, causing their dark colour – the symptoms obvious in the first turn, or in
different tissues - cartilage (ochronosis, leading to osteoarthritis) and heart valves as well as
precipitating as kidney stones.
Alkaptonuria is often asymptomatic, but the sclera of the eyes may be pigmented (often only at a
later age), and the skin may be darkened in sun-exposed areas and around sweat glands; sweat
may be coloured brown. Urine may turn brown if collected and left exposed to open air,
especially when left standing for a period of time. Kidney stones and stone formation in the
prostate (in men) are common and may occur in more than a quarter of cases.
The main symptoms of alkaptonuria are due to the accumulation of homogentisic acid in tissues.
In the joints this leads to cartilage damage, specifically in the spine, leading to low back pain at a
young age in most cases. Cartilage damage may also occur in the hip and shoulder. Joint
replacement surgery (hip and shoulder) and Valvular heart disease, mainly calcification and
regurgitation of the aortic and mitral valves, may occur, and in severe and progressive cases
valve replacement may be necessary. Coronary artery disease may be accelerated in
alkaptonuria.
A distinctive characteristic of alkaptonuria is that ear wax exposed to air turns red or black
(depending on diet) after several hours because of the accumulation of homogentisic acid.
Disturbance of the catecholamines’ synthesis
Parkinson's disease
The disease develops when dopamine deficiency in the substantia nigra of the brain. This is one
of the most common neurological diseases (incidence 1: 200 among people older than 60 years).
In this pathology there is observed reduced activity of tyrosine hydroxylase, DOPA
decarboxylase. The disease is accompanied by three main symptoms: akinesia (stiffness), rigidity
(muscle tension), tremor (involuntary shaking). Dopamine does not penetrate the blood-brain
barrier and is not used as a drug. Treatments are effective at managing the early motor symptoms
of the disease, mainly through the use of L-DOPA and dopamine agonists.
Main principles of therapy - application of
DOPA precursors
Inhibitors of monoaminooxidases, which cleave dophamine
Depression is often associated with a low level in the nerve cells of dopamine and
norepinephrine.
Schizophrenia is accompanied by hypersecretion of dopamine in the temporal lobe of the brain.
Tryptophan Metabolism
Hartnup’s disease (the name of a patient, whose parents were cousins)
Defect of tryptophane uptake in intestine (malabsorbtion) and decrease of its reabsorbtion in
kidney tubules.
Hyperaminoacidemia with tryptophan absence in blood. Symptoms of vitamin PP deficiency. In
urine there are many Try derivatives like indolylacetate, giving it blue (green colour).
Metabolism of Amino Acids with Branched Radicals
Maple syrup urine disease (leucinosis)
Defect of oxidative decarboxylation of branched amino acids - leucine, isoleucine and valine,
which leads to these amino acids accumulation in the organism. In children retardation of
physical and mental development, deprivation of CNS. Leucine accumulation is the most
harmful. Symptoms: hypoglykemia, hypotension, ketoacidosis.