Hereditary diseases of amino acid metabolism.
(Yu.I. Barashnev, Yu.E. Veltishchev, 1978)
1. Hereditary disorders of amino acid metabolism, accompanied by an increase in their concentration in the blood and urine: phenylketonuria, histidinemia, tryptophanuria, maple syrup disease, ornithinemia, citrullinemia, etc. Inheritance is mainly of an autosomal recessive type. The development of diseases is based on a violation of the synthesis or structure of certain enzymes.
2. Hereditary disorders of amino acid metabolism, accompanied by an increase in their excretion in the urine without changing the level in the blood: homocystinuria, hypophosphatasia, arginosuccinate aciduria, etc. With these enzymopathies, reabsorption in the kidneys is impaired, which leads to an increase in their content in the urine.
3. Hereditary disorders of amino acid transport systems: cystinuria, tryptophanuria, Hartnep's disease, etc. This group includes enzymopathies, the development of which is caused by a decrease in the reabsorption of amino acids in the kidneys and intestines.
4. Secondary hyperaminociduria: Fanconi syndrome, fructosemia, galactosemia, Wilson-Konovalov disease, etc. In these conditions, secondary generalized hyperaminoaciduria occurs as a result of secondary tubular disorders.
Phenylketonuria (PKU)
First described in 1934 by Folling under the name “phenylpyruvic imbecility.” The type of inheritance is autosomal recessive. The incidence of the disease is 1:10,000-1:20,000 newborns. Prenatal diagnosis is possible using genetic probes and chorionic villus sampling.
The development of the classic clinical picture in PKU is caused by deficiency of phenylalanine hydroxylase and deficiency of dihydropterin reductase, the 2nd enzyme that ensures the hydroxylation of phenylalanine. Their deficiency leads to the accumulation of phenylalanine (PA) in body fluids (Scheme 1). As you know, FA is an essential amino acid. When supplied with food and not used for protein synthesis, it breaks down along the tyrosine pathway. In PKU, there is a restriction in the conversion of FA to tyrosine and, accordingly, an acceleration of its conversion into phenylpyruvic acid and other ketonic acids.
Scheme 1. Variants of phenylalanine metabolism disorders.
The existence of various clinical and biochemical variants of PKU is explained by the fact that phenylalanine hydroxylase is part of a multienzyme system.
The following forms of PKU are distinguished:
1. Classic
2. Hidden.
3. Atypical.
The development of atypical and latent forms of PKU is associated with deficiency of phenylalanine transaminase, tyrosine transaminase and parahydroxyphenylpyruvic acid oxidase. Atypical PKU usually does not involve lesions nervous system as a result of late development of an enzymatic defect.
Women with phenylketonuria may give birth to children with microcephaly, mental retardation, and developmental disorders of the urinary system, so it is necessary to prescribe diet therapy during pregnancy.
Clinical symptoms in patients with PKU
At birth, a child with phenylketonuria appears healthy. The disease in these children manifests itself in the first year of life.
1. Intellectual defect. An untreated child loses about 50 IQ points by the end of the 1st year of life. In patients, there is no relationship between the level of physical activity and the degree of intellectual defect.
2. Convulsive syndrome(4 50%), eczema, hypopigmentation.
3. Impaired movement coordination.
4. Delayed development of static and motor functions.
5. Damage to the pyramidal tracts and striopallidal system. Clinical manifestations of classic PKU are rare in countries that have a neonatal screening program for the disease.
Children with phenylketonuria have increased urinary levels of FA metabolites. An increase in the content of FA and underoxidized products of its metabolism in physiological fluids leads to damage to the nervous system. A certain role in these disorders belongs to an imbalance of amino acids (deficiency of tyrosine, which is normally actively involved in the construction protein component myelin). Demyelination is a characteristic pathological sign of phenylketonuria. Violation of the ratio of amino acids in
blood leads to disruption of the level of free amino acids in the brain, which causes dementia, hyperkinesis and other neurological symptoms.
Pyramidal symptoms are caused by impaired myelination processes. The selective nature of the damage to the nervous system is explained by the peculiarities of myelination; the phylogenetically youngest parts that perform complex and differentiated functions are affected. Insufficient formation of melanin from tyrosine is associated with blue eye color and fair skin. The smell of "mold" ("mouse", "wolf") is explained by the presence of phenylacetic acid in the urine. Skin manifestations(exudative diathesis, eczema) are associated with the release of abnormal metabolites. Insufficient formation of adrenergic hormones from tyrosine leads to arterial hypotension.
It should be noted that with PKU in pathological process the liver is involved, but the nature of the morphological disorders is not specific: signs of tissue hypoxia, disturbances of oxidative and protein synthesizing functions, and lipid overload are revealed. Along with this, compensatory and adaptive changes are observed: high glycogen content, mitochondrial hyperplasia. Generalized hyperaminoacidemia in PKU can be explained by a secondary disorder of amino acid metabolism due to damage to hepatocytes, because many enzymes involved in amino acid metabolism are localized in the liver.
In untreated patients with classical PKU, there is a significant decrease in the concentration of catecholamines, serotonin and their derivatives in the urine, blood, and cerebrospinal fluid. Therefore in complex treatment PKU requires promediator correction, since a partial intellectual defect may be associated with neurotransmitter disorders.
Diagnostic criteria classic shape phenylketonuria:
1. Plasma FA level is above 240 mmol/l.
2. Secondary tyrosine deficiency.
3. Increased level in urine of FA metabolites.
4. Reduced tolerance to ingested PA.
Methods for diagnosing phenylketonuria:
1. Felling's test with FeCl 3 - with a positive test, a blue-green color of urine appears.
2. Detection of excess phenylalanine in the blood is possible using the Goldfarb bacterial express test or the Guthrie test (since during the first days of life, phenylpyruvic acid may be absent in the urine).
In case of PKU, treatment is carried out with a diet with a limited content of PA (mainly vegetable dishes, honey, and fruits are prescribed). Products such as milk, dairy products, eggs, fish should be completely excluded during the stay of patients with PKU on acute diet. Appointed special drugs(cymogran, lofenalac) and vitamins.
The optimal time for examination of newborns is 6-14 days of life, the start of therapy is no later than 21 days of life. It must be remembered that conducting the study on the first day does not exclude false-positive or false-negative results (repeated studies are carried out up to 21 days of life). The effectiveness of treatment is assessed by the patient’s intellectual level of development. It should be noted that treatment started after a year does not completely normalize intelligence (this may be due to the development irreversible changes in the brain).
Leon E. Rosenberg ( Leon E. Rosenberg)
All polypeptides and proteins are polymers of 20 different amino acids. Eight of them, called essential, are not synthesized in the human body, so they must be administered with food. The rest are formed endogenously. Despite the fact that most of the amino acids contained in the body are bound in proteins, small pools of free amino acids are still contained within the cell, which are in equilibrium with their extracellular reservoirs in the plasma. cerebrospinal fluid and lumens of the intestines and renal tubules. From a physiological point of view, amino acids are more than just “building blocks”. Some of them (glycine, γ-aminobutyric acid) function as neurotransmitters, others (phenylalanine, tyrosine, tryptophan, glycine) serve as precursors of hormones, coenzymes, pigments, purines and pyrimidines. Each amino acid is broken down in its own way, resulting in its nitrogenous and carbon components being used for the synthesis of other amino acids, carbohydrates and lipids.
Modern ideas about congenital metabolic diseases are largely based on the results of studying disorders of amino acid metabolism. Currently, more than 70 congenital aminoacidopathies are known; the number of disorders of amino acid catabolism (approximately 60) far exceeds the number of disorders of their transport (approximately 10). Each of these disorders is rare; their frequency ranges from 1:10,000 for phenylketonuria to 1:200,000 for alkaptonuria. However, their combined incidence is probably 1:500-1:1000 live births.
As a rule, these disorders are named after the substance that accumulates in the highest concentrations in the blood (-emia) or urine (-uria). In many conditions, an excess of the precursor amino acid is determined; in others, its breakdown products accumulate. Naturally, the nature of the disorder depends on the location of the enzymatic block, the reversibility of reactions occurring above the damaged link, and the existence of alternative pathways for the “leakage” of metabolites. For some amino acids, such as sulfur-containing or branched-chain amino acids, disturbances in almost every step of catabolism are known, but for others there are still many gaps in our knowledge. Aminoacidopathies are characterized by biochemical and genetic heterogeneity. Thus, there are four forms of hyperphenylalaninemia, three types of homocystinuria and five types of methyl-malonic acidemia. All these options are of not only chemical, but also clinical interest.
The manifestations of aminoacidopathies vary widely. Some of these, such as sarcosine or hyperprolinemia, appear to have no clinical consequences at all. At the opposite end of the spectrum are conditions (complete deficiency of ornithine transcarbamylase or branched-chain dehydrogenase) that, if left untreated, lead to neonatal death. In more than half of the cases, the function of the central nervous system is affected, which is manifested by developmental delays, seizures, sensory disorders or behavioral changes. With many anomalies of the urea cycle, vomiting appears after eating protein foods, neurological disorders and hyperammonemia. Metabolic ketoacidosis, often accompanied by hyperammonemia, is usually detected in disorders of branched-chain amino acid metabolism. Some disorders lead to local damage to tissues and organs, such as the liver, kidneys (failure), skin or eyes.
The clinical manifestations of many conditions can be prevented or reduced with early diagnosis and timely initiation of adequate treatment (restriction of protein and amino acids in the diet or vitamin supplements). That is why large populations of newborns are screened for aminoacidopathy using a variety of chemical and microbiological methods of blood or urine analysis. A presumptive diagnosis can be confirmed directly enzyme method using extracts of leukocytes, erythrocytes, fibroblast culture or liver tissue, as well as DNA-DNA hybridization studies. The latter approach has been applied to the diagnosis and characterization of phenylketonuria, ornithine transcarbamylase deficiency, citrullinemia, and propionic acidemia. As advances are made in cloning other genes, DNA-based analysis will need to be used more frequently. Some disorders (cystinosis, branched-chain ketoaciduria, propionic acidemia, methylmalonic acidemia, phenylketonuria, ornithine transcarbamylase deficiency, citrullinemia and arginine succinic
Hyperphenylalaninemia
Definition. Hyperphenylalaninemia is caused by impaired conversion of phenylalanine to tyrosine. The most important of these is phenylketonuria, characterized by an increased concentration of phenylalanine in the blood, as well as its by-products(especially phenylpyruvate, phenylacetate, phenyllactate and phenylacetylglutamine) in the urine and severe retardation mental development.
Etiology and pathogenesis. Any of Hyperphenylalaninemia is caused by a decrease in the activity of an enzyme complex called phenylalanine hydroxylase. This complex is found in noticeable quantities only in the liver and kidneys. The enzyme's substrates are phenylalanine and molecular oxygen, and the cofactor is reduced pteridine (tetrahydrobiopterin). The products of the enzymatic reaction are tyrosine and dihydrobiopterin. The latter is converted back into tetrahydrobiopterin under the action of another enzyme, dihydropteridine reductase. In classic phenylketonuria, the activity of the apoenzyme hydroxylase is reduced to almost zero, but the hydroxylase gene is still present and has not undergone major rearrangement or deletion. Benign hyperphenylalaninemia is associated with a less severe enzyme deficiency, and transient hyperphenylalaninemia (sometimes called transient phenylketonuria) is caused by delayed maturation of the hydroxylase apoenzyme. However, in two variants of phenylketonuria, a persistent violation of hydroxylation activity is determined not by a defect in apohydroxylase, but by the absence of tetrahydrobiopterin. Tetrahydrobiopterin deficiency can be caused by two reasons: blockade of biopterin synthesis from its precursors and deficiency of dihydropteridine reductase, which reduces tetrahydrobiopterin from dihydrobiopterin.
All variants of Hyperphenylalaninemia generally occur with a frequency of approximately 1:10,000 newborns. Classic phenylketonuria, which accounts for almost half of all cases, is an autosomal recessive trait and is widespread among Caucasians and Orientals. It is rare among representatives of the Negroid population. The activity of phenylalanine hydroxylase in obligate heterozygotes is lower than normal, but higher than in homozygotes. Heterozygous carriers are clinically healthy, although their plasma phenylalanine concentrations are usually slightly elevated. Other hyperphenylalaninemias also appear to be inherited as an autosomal recessive trait.
A direct consequence of impaired hydroxylation is the accumulation of phenylalanine in the blood and urine and a decrease in the formation of tyrosine. In untreated individuals with phenylketonuria and its variants due to tetrahydrobiopterin deficiency, plasma phenylalanine concentrations reach levels high enough (more than 200 mg/L) to activate alternative metabolic pathways to form phenylpyruvate, phenylacetate, phenyllactate and other derivatives that undergo rapid renal clearance and are excreted in the urine. The level of other amino acids in plasma is moderately reduced, which is probably explained by inhibition of their absorption in the gastrointestinal tract or impaired reabsorption from the renal tubules in conditions of excess phenylalanine in body fluids. Severe brain damage may be due to a number of effects of excess phenylalanine: depriving the brain of other amino acids needed for protein synthesis, impaired formation or stabilization of polyribosomes, decreased myelin synthesis, and insufficient synthesis of norepinephrine and serotonin. Phenylalanine is a competitive inhibitor of tyrosinase, a key enzyme in the pathway of melanin synthesis. Blockage of this pathway, along with a decrease in the availability of the melanin precursor (tyrosine), causes insufficient pigmentation of hair and skin.
Clinical manifestations. In newborns, no deviations from the norm are noted. However, if left untreated, children with classic phenylketonuria are developmentally delayed and develop progressive brain dysfunction. Most of them, due to hyperactivity and seizures that accompany severe mental retardation, require hospitalization in the first few years of life. Clinical signs include electrocardiogram changes, a mouse-like odor of the skin, hair, and urine (due to phenylalanine accumulation), and a tendency toward hypopigmentation and eczema. In contrast, children who are diagnosed immediately after birth and treated promptly do not have all of these signs. Children with transient hyperphenylalaninemia or its benign variant do not face any of the clinical consequences of those observed with classical phenylketonuria in untreated patients. On the other hand, children with tetrahydrobiopterin deficiency are in the most unfavorable conditions. They have early onset of seizures and then develop progressive dysfunction of the brain and basal ganglia (muscle rigidity, chorea, spasms, hypotension). Despite the early diagnosis and standard treatment, they all die in the first few years of life from a secondary infection.
Sometimes untreated women with PKU reach adulthood and give birth. More than 90% of children in this case are retarded in mental development, many of them are diagnosed with other congenital anomalies, such as microcephaly, growth retardation and heart defects. Because these children are heterozygotes rather than homozygotes for the mutation causing phenylketonuria, their clinical manifestations should be attributed to damage associated with elevated maternal phenylalanine concentrations and exposure to excess phenylalanine during the prenatal period.
Diagnostics. In a newborn, the plasma phenylalanine concentration may be within the normal range for all types of hyperphenylalaninemia, but after the start of protein feeding it increases rapidly and usually exceeds the norm already on the 4th day. Since diagnosis and initiation of dietary interventions must be carried out before the child reaches one month old(if we mean the prevention of mental retardation), then in North America and Europe, most newborns are screened with the determination of phenylalanine concentrations in the blood using the Guthrie method (inhibition of bacterial growth). Children whose phenylalanine levels are elevated are further evaluated using more sensitive quantitative fluorometric or chromatographic methods. In classical phenylketonuria and tetrahydrobiopteria deficiency, the concentration of phenylalanine is usually higher. 200 mg/l. With transient or benign Hyperphenylalaninemia, it is usually lower, although higher than the figures in the control (less than 10 mg/l). Sequential serial determinations of plasma phenylalanine concentrations as a function of age and dietary restrictions help distinguish classic phenylketonuria from its benign variants. With transient hyperphenylalaninemia, the level of this amino acid is normalized within 3-4 months. In benign Hyperphenylalaninemia, dietary restrictions are accompanied by more noticeable decrease plasma phenylalanine levels than in classic phenylketonuria. Every child with hyperphenylalaninemia who, despite early diagnosis and dietary treatment, progresses neurological signs, tetrahydrobiopterin deficiency should be suspected. Confirmation of the diagnosis of these variants, which account for 1-5% of all cases of phenylketonuria, can be achieved using an enzymatic method using fibroblast culture. From a therapeutic point of view, however, more important is the fact that oral administration of tetrahydrobiopterin makes it possible to distinguish children with classic phenylketonuria (in whom phenylalanine levels do not decrease) from patients with tetrahydrobiopterin deficiency (in whom plasma phenylalanine concentrations sharply decrease). Currently, classical phenylketonuria can be diagnosed prenatally by restriction fragment length polymorphisms identified by DNA-DNA blot hybridization.
Treatment. It was in classical phenylketonuria that it was first discovered that reducing the accumulation of the “culprit” metabolite prevents the development of clinical symptoms. This reduction is achieved through a special diet in which the bulk of the protein is replaced by an artificial mixture of amino acids containing only a small amount of phenylalanine. By enriching this diet with a certain amount of natural products, you can select the amount of phenylalanine in it that will be sufficient for normal height, but not sufficient to significantly increase the level of phenylalanine in the blood. Typically, the phenylalanine concentration is maintained at a level between 30-120 mg/L.
Until there is confidence in the safety of discontinuing dietary treatment at any age, dietary restrictions should be continued. With transient and benign forms of hyperphenylalaninemia, long-term dietary restrictions are not required. On the other hand, as already noted, the condition of children with tetrahydrobiopterin deficiency worsens, despite restrictions on phenylalanine in the diet. The effectiveness of pteridine cofactor replacement is under study.
Homocystinuria
Homocystinuria refers to three biochemically and clinically different disorders, but each of them is characterized by an increase in the concentration of the sulfur-containing amino acid homocystine in the blood and urine. Most common form the disease is caused by a decrease in the activity of cystathion-R-synthase, an enzyme involved in the transsulfuration of methionine into cysteine. The other two forms are caused by a violation of the conversion of homocysteine to methionine. This reaction is catalyzed by homocysteine methyltetrahydrofolate methyltransferase and requires two cofactors, methyltetrahydrofolate and methylcobalamin (methylvitamin B12). The cause of homocystinuria in some patients determines the biochemical and, in some cases, clinical condition after enriching the diet with a certain vitamin (pyridoxine, folate or cobalamin).
Cystathionine deficiency-P-synthases
Definition. Deficiency of this enzyme results in increased levels of methionine and homocystine in body fluids and decreased levels of cysteine and cystine. The main clinical sign is dislocation eye lenses. Mental retardation, osteoporosis and vascular thrombosis are often associated.
Etiology and pathogenesis. The sulfur atom of the essential amino acid methionine is eventually transferred to a cysteine molecule. This occurs through a transsulfuration reaction, in one step of which homocysteine condenses with serine to form a cystathione. This reaction is catalyzed by the pyridoxal phosphate-dependent enzyme cystathione-R-synthase. More than 600 patients with deficiency of this enzyme have been reported. The disease is common in Ireland (1:40,000 births), but is rare in other regions (less than 1:200,000 births).
Homocysteine and methionine accumulate in cells and body fluids; Cysteine synthesis is disrupted, which leads to a decrease in its level and the disulfide form of cysteine. In approximately half of patients, synthase activity cannot be determined in the liver, brain, leukocytes, and cultured fibroblasts. In other patients, enzyme activity in tissues does not exceed 1-5% of normal, and this residual activity can often be increased by adding pyridoxine. Heterozygous carriers of this autosomal recessive trait do not exhibit permanent chemical changes in body fluids, although their synthase activity is reduced.
Homocysteine disrupts normal collagen cross-linking, which appears to play an important role in the development of ocular, bone and vascular complications. Abnormal collagen in the suspensory ligament of the eye's lens and bone matrix may determine lens dislocation and osteoporosis. In the same way, disturbances in the metabolism of basal substances in the vascular wall can predispose to arterial and venous thrombotic diathesis. Mental retardation may be based on repeated strokes caused by thrombosis, although direct chemical effects on the metabolism of brain cells cannot be ruled out.
Clinical manifestations. More than 80% of homozygotes with absolute synthase deficiency suffer from displacement of the eye lenses. This pathology usually manifests itself in the 3-4th year of life and often leads to acute glaucoma and decreased visual acuity. Approximately half of the patients have mental retardation with vague changes in behavioral reactions. X-rays usually reveal osteoporosis (in 64% of patients by the age of 15 years), but it rarely manifests itself clinically. Life-threatening vascular complications, likely due to damage to the vascular endothelium, are a leading cause of morbidity and mortality. Thrombosis of coronary, renal and cerebral arteries with accompanying tissue infarction can occur already in the first 10 years of life. Almost 25% of patients die before the age of 30 years as a result of vascular pathology, which is probably provoked by angiographic procedures. It is important to emphasize that in patients who can be treated with pyridoxine, all clinical manifestations of the disease are less pronounced. Heterozygous carriers of synthase deficiency (approximately 1:70 in the population) may be at risk for the premature development of peripheral and cerebral vascular obstruction.
Diagnostics.A simple method for detecting increased excretion of sulfhydryl compounds in urine is the cyanide nitroprusside test. Since its positive results can also be determined by the presence of cystine and S -sulfocysteine, it is necessary to exclude other disorders of sulfur metabolism, which can usually be done based on clinical signs. Distinguish deficiency R-synthase from other causes of homocystinuria is usually possible by determining the level of methionine in plasma, which tends to increase in patients with synthase deficiency and remains within normal limits or is reduced when methionine formation is impaired. To confirm the diagnosis, determination of synthase activity in tissue extracts is required. Heterozygotes can be identified by peak homocystine levels after oral methionine loading and by determining tissue synthase activity.
Treatment. As with classical phenylketonuria, the effectiveness of treatment is determined by early diagnosis. In several children diagnosed in the neonatal period, the effect was accompanied by a cystine-enriched diet accompanied by methionine restriction. Until now, their disease has been benign compared to untreated sick siblings. In approximately half of the patients, taking pyridoxine (25-500 mg/day) is accompanied by a decrease in the level of methionine and homocystine in plasma and urine and an increase in the level of cystine in body fluids. This effect is probably associated with a moderate increase in synthase activity in the cells of patients in whom the enzymatic disorder is characterized by either a decrease in affinity for the cofactor or an acceleration of the breakdown of the mutant enzyme. Because this vitamin supplement is simple and apparently safe, it should be prescribed to all patients. There are no data yet on the effectiveness of treatment with pyridoxine supplements started soon after birth. Similarly, there is no information on the effectiveness of pyridoxine supplementation in heterozygous carriers of the disease.
5, 10-methylenetetrahydrofolate reductase deficiency
Definition. In this form of homocystinuria, the concentration of methionine in body fluids is within normal limits or reduced, since deficiency of 5,10-methylenetetrahydrofolate reductase causes a disruption in the synthesis of 5-methyltetrahydrofolate, a cofactor for the formation of methionine from homocysteine. Most patients experience dysfunction of the central nervous system.
Etiology and pathogenesis. The enzyme 5-methyltetrahydrofolate homocysteine methyltransferase catalyzes the conversion of homocysteine to methionine. The donor of the methyl group transferred in this reaction is 5-methyltetrahydrofolate, which in turn is synthesized from 5, 10-methylenetetrahydrofolate under the action of the enzyme 5, 10-methylenetetrahydrofolate reductase. Thus, reductase activity controls both the synthesis of methionine and the formation of tetrahydrofolate. This sequence of reactions plays a key role in normal DNA and RNA synthesis. A primary decrease in reductase activity leads secondarily to a decrease in methyltransferase activity and a disruption in the conversion of homocysteine to methionine. Methionine deficiency and impaired nucleic acid synthesis can determine dysfunction of the central nervous system. This pathology is apparently inherited as an autosomal recessive trait.
Clinical manifestations. To date, information about homocystinuria caused by reductase deficiency has been obtained from examinations of less than 10 children. In the most severe cases, a sharp developmental delay and brain atrophy were noticeable in the child at an early age. The remaining patients after the age of 10 years had mental disorders (catatonia) or some developmental delay. Clinical manifestations probably depend on the degree of reductase deficiency.
Diagnosis and treatment. The basis for the diagnosis should be the combination of an increased concentration of homocystine in body fluids with a normal or reduced level of methionine. Some patients have decreased serum folate levels. To confirm the diagnosis, direct determination of reductase activity in tissue extracts (brain, liver, fibroblast culture) is necessary. Despite the fact that the experience of treatment with this condition is small, one teenage girl with catatonic psychosis showed a noticeable improvement in her condition and normalization of biochemical parameters after the administration of folate (5-10 mg/day). When it was discontinued, mental disorders became more severe. This observation provides hope that early diagnosis followed by folate therapy may prevent neurological and psychiatric manifestations.
Insufficiency of synthesis of cobalamin (vitamin B 12) coenzymes
Definition. This form of homocystinuria is also caused by a violation of the conversion of homocysteine to methionine. The primary defect is localized at the stage of synthesis of methylcobalamin, a cobalamin (vitamin B 12) coenzyme necessary for the functioning of methyltetrahydrofolate homocysteine methyltransferase. At the same time, methylmalonic acid accumulates in body fluids, since the synthesis of the second coenzyme, adenosylcobalamin, necessary for the isomerization of methylmalonyl enzyme A (CoA) into succinyl-CoA, is disrupted.
Etiology and pathogenesis. Like 5,10-methylenetetrahydrofolate reductase deficiency, this defect results in impaired homocysteine remethylation. It is based on insufficient synthesis of cobalamin coenzymes. Since methylcobalamin is required to transfer the methyl group from methyltetrahydrofolate to homocysteine, impaired metabolism of vitamin B12 causes a decrease in methyltransferase activity. The synthesis of methylcobalamin is disrupted at some point early stage activation of a vitamin precursor in lysosomes or cytosol. Genetic studies on somatic cells indicate the possibility of the existence of three mechanisms for disrupting the formation of coenzymes, each of which is inherited in an autosomal recessive manner.
Clinical manifestations. The first patient died of infection at the age of 6 weeks. He was noted to have severe developmental delay. In other children, clinical manifestations varied: two had megaloblastic anemia and pancytopenia, three had severe dysfunction of the spinal cord and brain, and one clinical symptoms was very scarce.
Diagnosis and treatment. Biochemical signs of the disease are homocystinuria, hypomethioninemia and methylmalonic aciduria. These changes can also be detected in pernicious anemia of the juvenile or adult type, in which the absorption of cobalamin in the intestine is impaired. Differential diagnosis helps determine the serum concentration of cobalamin: low when pernicious anemia and normal in patients with impaired conversion of cobalamin into coenzymes. The final diagnosis requires evidence of impaired coenzyme synthesis in cell culture. Treatment of sick children with cobalamin supplements (1-2 mg/day) is quite promising: the excretion of homocystine and methyl malonate almost reaches normal; hematological and neurological signs are also leveled out to varying degrees.
T.P. Harrison. Principles of internal medicine.Translation by Doctor of Medical Sciences A. V. Suchkova, Ph.D. N. N. Zavadenko, Ph.D. D. G. Katkovsky
The central place in the interstitial metabolism of proteins is occupied by the reaction transamination, as the main source of the formation of new amino acids. A violation of transamination can occur as a result of a deficiency of vitamin B 6 in the body. This is explained by the fact that the phosphorylated form of vitamin B 6 - phosphopyrodoxal - is an active group of transaminases - specific transamination enzymes between amino and keto acids. Pregnancy, long-term use sulfonamides inhibit the synthesis of vitamin B 6 and can serve as the basis for disorders of amino acid metabolism. Finally, the reason for the decrease in transamination activity may be inhibition of transaminase activity due to disruption of the synthesis of these enzymes (during protein starvation), or disruption of the regulation of their activity by a number of hormones.
The processes of transamination of amino acids are closely related to the processes oxidative deamination, during which the enzymatic removal of ammonia from amino acids is carried out. Deamination determines both the formation of the final products of protein metabolism and the entry of amino acids into energy metabolism. Weakening of deamination may occur due to a violation oxidative processes in tissues (hypoxia, hypovitaminosis C, PP, B 2). However, the most sharp violation deamination occurs when the activity of amino oxidases decreases, or due to a weakening of their synthesis ( diffuse lesion liver, protein deficiency), or as a result of a relative insufficiency of their activity (an increase in the content of free amino acids in the blood). The consequence of a violation of the oxidative deamination of amino acids will be a weakening of urea formation, an increase in the concentration of amino acids and an increase in their excretion in the urine - aminoaciduria.
The intermediate exchange of a number of amino acids occurs not only in the form of transamination and oxidative deamination, but also through their decarboxylation(loss of CO 2 from the carboxyl group) with the formation of the corresponding amines, called “biogenic amines”. Thus, when histidine is decarboxylated, histamine is formed, tyrosine - tyramine, 5-hydroxytryptophan - serotin, etc. All these amines are biologically active and have a pronounced pharmachologic effect on the vessels.
GOUT -standard form pathologies of purine metabolism, characterized by a chronic increase in blood levels uric acid, deposition of excess salts in organs, tissues, joints, urate nephropathy, nephro- and urolithiasis.
Manifestations of gout: Constantly increased concentration of uric acid in blood plasma and urine; Inflammation various joints(most often monoarthritis); Fever; Strong pain in the zone of urate accumulation (may have the character of long-term episodes: up to 2-3 days); Reappearance of tophi; Signs of kidney failure; Nephro- and urolithiasis, recurrent pyelonephritis; Changes in the kidneys culminate in nephrosclerosis, renal failure, and uremia.
Pathogenesis.
Violations carbohydrate metabolism, hypo- and hyperglycemia, their causes and types. Experimental models of insulin deficiency.
1. Hypoglycemia - decrease in blood glucose level less than 3.5 mmol/l:
1. Nutritional (3-5 hours after consuming a large amount of carbohydrates, insulin).
2. Hard physical work.
3. In nursing women.
4. Neurogenic (with excitement - hyperinsulinemia).
5. For diseases:
a) accompanied by increased pancreatic function (insuloma, adenoma, cancer);
b) insulin overdose in the treatment of diabetes mellitus;
c) liver damage;
d) decrease in the incretion of counter-insular hormones - glucagon, cortisone, adrenaline, somatotropin (hypofunction of the adrenal cortex; anterior pituitary gland, thyroid gland);
e) damage to the gastrointestinal tract;
e) fasting.
6. For tumors of the hypothalamus, hypofunction of the pituitary gland, Addison's disease.
Hypoglycemic syndrome(blood glucose less than 3.3 mmol/l):
Hunger
Drowsiness, weakness
Short-term restlessness, aggressiveness
Tachycardia
Sweating, trembling, cramps
Amnesia, aphasia
Loss of consciousness (hypoglycemic coma, blood glucose less than 2.5 mmol/l)
Increased breathing and heart rate
Dilated pupils
Tense eyeballs
Involuntary urination and defecation.
1st help:
IV 60-80 ml 40% glucose
Sweet tea upon return of consciousness
When blood glucose levels drop below 2.5 mmol/l, hypoglycemic coma may develop.
Hyperglycemia - increase in blood glucose by more than 5.7 mmol/l:
1. Nutritional - 1-1.5 hours after taking a large amount of carbohydrates.
2. Neurogenic - emotional arousal (rapidly passing).
3. Hormonal:
a) with absolute or relative insufficiency of the islet apparatus of the pancreas:
Absolute - due to decreased insulin production
Relative - due to a decrease in the number of insulin receptors on cells
b) for diseases of the pituitary gland (increased growth hormone and ACTH)
c) tumor of the adrenal medulla (pheochromocytoma) - release of adrenaline
d) excess levels of glucagon, thyroidin, glucocorticoids, somotropin and corticotropin in the blood.
Glycotricoids are involved in the mechanism of hyperglycemia in diabetes mellitus and Itsenko-Cushing's disease.
4. Excretory - if glucose is more than 8 mmol/l, it appears in the urine:
With insufficient pancreatic function
With a lack of phosphorylation and dephosphorylation enzymes in the kidneys
For infectious and nervous diseases.
5. Irritation of the gray tubercle of the hypothalamus, lenticular nucleus and striatum of the basal nuclei of the brain.
6. When pain; during attacks of epilepsy.
Slowing down the rate of hexokinase reaction, increasing glyconeogenesis and increasing glucose-6-phosphatase activity are the main reasons diabetic hyperglycemia.
Manifestations:
Dry skin and mucous membranes
Itchy skin
Polyuria.
Meaning:
Short-term hyperglycemia has an adaptive significance.
Constant - loss of carbohydrates and harmful consequences.
2. Basic information about the etiology and pathogenesis of diabetes mellitus became known through animal experiments. First experimental its model was obtained by Mehring and Minkowski (1889) by removing all or most (9/10) of the pancreas from dogs.
This form of experimental diabetes was characterized by all the signs observed in humans, but was more severe; always complicated by high ketonemia, fatty infiltration of the liver, and the development of diabetic coma. As a result of the removal of the entire pancreas, the body suffered not only from insulin deficiency, but also from a deficiency digestive enzymes The model of alloxan diabetes, which occurs when alloxan is administered to animals, has become widespread. This substance selectively damages the I3 cells of the pancreatic islets, resulting in insulin deficiency of varying severity. To others chemical, which causes diabetes mellitus, is dithizone, which binds zinc, which is involved in the deposition and secretion of insulin. The antibiotic streptozotocin damages the pancreatic islets. Diabetes mellitus in animals can be produced using antibodies to insulin. Such diabetes occurs with both active and passive immunization.
Experimental diabetes also develops with the introduction of contrainsular hormones. Thus, after prolonged administration of hormones of the anterior lobe of the pituitary gland (somatotropin, corticotropin), as noted above, pituitary diabetes can develop. The introduction of glycocorticoids can cause the development of steroid diabetes.
Diabetes mellitus, its types. Disorders of carbohydrate and other types of metabolism and physiological functions with diabetes mellitus. Diabetic comas (ketoacidotic, hyperosmolar), their pathogenetic features.
DIABETES- a disease that is characterized by a violation of all types of metabolism and a disorder of the body’s vital functions; develops as a result of hypoinsulinism (i.e. absolute or relative insulin deficiency).
Primary forms of diabetes mellitus. Primary forms of diabetes are characterized by the absence in the patient of any specific diseases that secondarily lead to the development of diabetes. There are two types of primary diabetes:
Insulin-dependent diabetes mellitus (IDDM);
Non-insulin dependent diabetes mellitus (NIDDM).
Secondary forms of diabetes mellitus. Secondary forms of diabetes are characterized by the presence in the patient of any underlying disease or pathological condition that damages the pancreas, as well as the effect of physical or chemical factors. This leads to the occurrence of diabetes. Such diseases, pathological conditions and factors include:
Diseases that affect pancreatic tissue (for example, pancreatitis).
Other diseases of the endocrine system (for example, familial polyendocrine adenomatosis).
Exposure of the pancreas to chemical or physical agents.
Diabetes mellitus types I and II. In more early classifications DM types I and II were distinguished. These designations were initially used as synonyms for IDDM and NIDDM, respectively.
Insulin deficiency is accompanied by a violation of all types of metabolism in the body, primarily carbohydrate, the manifestation of which is hyperglycemia and glycosuria.
Main reasons hyperglycemia are: slowing down the hexokinase reaction (→ slowing down the formation of glucose-6-phosphate → slowing down the synthesis of glycogen, the pentose phosphate pathway and glycolysis), increasing glyconeogenesis (the lack of G-6-P is compensated by the reaction of glyconeogenesis) and increasing the activity of G-6-P (→ increasing glucose formation in the liver and decreased glycogen formation).
Hyperglycemia and disruption of the processes of phosphorylation and dephosphorylation of glucose in the nephron tubules lead to glycosuria. Promotion osmotic pressure urine leads to polyuria which leads to dehydration and increased thirst (polydipsia).
Violations fat metabolism: fatty liver (due to increased lipolysis and intake fatty acids to the liver, increased formation ketone bodies)
Violation protein metabolism: inhibition of anabolic processes, increased protein catabolism using deaminated amino acids for glyconeogenesis → negative nitrogen balance.
Complications: Diabetic coma = hyperketonemic = hyperglycemic. (occurs due to intoxication of the body with ketone bodies.) Characterized by loss of consciousness, Kussmaul-type breathing, and decreased blood pressure. Coma can develop in the absence of ketone bodies, but with hyperglycemia of 50 mmol/l and above.
Diabetic ketoacidosis. Diabetic ketoacidosis is characteristic of IDDM. Ketoacidosis and ketoacidotic coma are among the leading causes of death in patients with diabetes.
Causes: Insufficient levels of insulin and/or its effects in the blood and Increased concentration and/or severity of the effects of counter-insular hormones (glucagon, catecholamines, growth hormone, cortisol, thyroid hormones).
Development mechanism includes several links: significant activation of gluconeogenesis, occurring against the background of stimulation of glycogenolysis, proteolysis and lipolysis; disruption of glucose transport into cells, leading to an increase in hyperglycemia; stimulation of ketogenesis with the development of acidosis.
Hyperosmolar coma. Hyperosmolar non-ketoacidotic (hyperglycemic) coma is most common in elderly patients with NIDDM. Hyperosmolar coma develops much more slowly than ketoacidotic coma. However, the mortality rate is higher.
Impaired transamination and oxidative deamination. The processes of transamination and deamination are of universal importance for all living organisms: transamination promotes the synthesis of amino acids, deamination promotes their destruction.
The essence of the transamination reaction is the reverse transfer of the amino group from an amino acid to an α-keto acid without the intermediate formation of a free ammonium ion. The reaction is catalyzed by specific aminotransferase enzymes (transaminases), the cofactors of which are phosphorylated forms of pyridoxine (pyridoxal phosphate and pyridoxamine phosphate).
Disturbances in transamination reactions can occur for several reasons, primarily as a result of pyridoxine deficiency (pregnancy, inhibition by sulfonamide drugs intestinal microflora, inhibition of pyridoxal phosphate synthesis during treatment with ftivazide). A decrease in aminotransferase activity also occurs in the case of inhibition of protein synthesis (fasting, severe liver pathology). If necrosis occurs in some organs (myocardial or pulmonary infarction, pancreatitis, hepatitis, etc.), then due to cell destruction, tissue aminotransferases enter the blood, and an increase in their activity in the blood with such a pathology is one of the diagnostic criteria. In changing the rate of transamination, an important role is played by the imbalance in the ratio of reaction substrates, as well as the influence of hormones, especially glucocorticoids and thyroid hormones, which stimulate this process.
Inhibition of the process of oxidative deamination, as a result of which unused amino acids break down, causes their increased concentration in the blood - hyperaminoacidemia. The consequences of this are increased excretion of amino acids by the kidneys ( aminoaciduria) and a change in the ratio of individual amino acids in the blood, which creates unfavorable conditions for the synthesis of protein molecules. Deamination is disrupted by a deficiency of components that directly or indirectly take part in this reaction (pyridoxine, riboflavin, nicotinic acid), as well as by hypoxia and starvation (protein deficiency).
Impaired decarboxylation. This process is an important, although not universal, direction of protein metabolism, and occurs with the formation carbon dioxide and biogenic amines. Only some amino acids undergo decarboxylation: histidine is converted into histamine, tyrosine into tyramine, γ-glugamic acid into γ-aminobutyric acid (GABA), 5-hydroxytryptophan into serotonin, tyrosine derivatives (3,4-dioxyphenylalanine) and cystine (L -cysteine acid - into 3,4-dioxyphenylethylamine (dopamine) and taurine, respectively.
Biogenic amines are known to have specific biological activity, and an increase in their number can cause certain pathological changes in the body. A large amount of biogenic amines can be the result of not only increased decarboxylation of the corresponding amino acids, but also inhibition of amine oxidation and impaired binding by proteins. For example, during hypoxia, ischemia and tissue destruction (trauma, radiation, etc.), oxidative processes slow down, thereby promoting increased decarboxylation. Excess of biogenic amines (especially histamine and serotonin) in tissues can cause significant damage local circulation, increased permeability vascular wall and damage to the nervous system.
Hereditary disorders of the metabolism of certain amino acids
The metabolism of amino acids is determined by a certain amount and activity of the corresponding enzymes. Hereditary disorders of enzyme synthesis lead to the fact that the necessary amino acid is not included in metabolism, but accumulates in the biological media of the body: blood, urine, feces, sweat, cerebrospinal fluid. The clinical picture in such cases is due, firstly, to the presence of a sufficiently large amount of a substance that should have been metabolized using a blocked enzyme; secondly, a deficiency of the substance that should have been formed.
Quite a lot of genetically determined disorders of amino acid metabolism are known, all of them are inherited in an autosomal recessive manner. Some of them are given in table. 2.
Phenylalanine metabolism disorder. Normally, phenylalanine is converted to tyrosine. If the synthesis of the enzyme phenylalanine hydroxylase necessary for this is disrupted in the liver (Scheme 4), then the oxidation of phenylalanine occurs through the formation of phenylpyruvic and phenyllactic acids - phenylketonuria develops. However, this pathway has a low “throughput” capacity, so a large amount of phenylalanine accumulates in the blood, tissues and cerebrospinal fluid, which in the first months of a newborn’s life manifests itself in severe damage to the central nervous system and incurable dementia. Due to insufficient synthesis of tyrosine, the formation of melanin is inhibited, which causes lightening of the skin and hair. Moreover, as a result advanced education Phenylpyruvic acid inhibits the activity of the enzyme dopamine hydroxylase, which is necessary for the synthesis of catecholamines (adrenaline, norepinephrine). The severity of hereditary pathology is determined by the complex of all these disorders. Patients die in childhood if not carried out special treatment, consisting of constant but careful (control amino acid composition blood) limiting the intake of phenylalanine from food. Early diagnosis diseases should be carried out immediately after the birth of the child. For this purpose, various biochemical test systems are used.
Tyrosine metabolism disorder. Tyrosine exchange occurs in several ways. In case of insufficient conversion of tyrosine to homogentisic acid (see diagram 4), which may be due to a defect in various enzymes, tyrosine accumulates in the blood and is excreted in the urine. This disorder is called tyrosinosis and is accompanied by hepatic and renal failure And early death child or only delayed psychomotor development. If a disturbance in tyrosine metabolism occurs at the time of oxidation of homogentisic acid (see Diagram 4), alkaptonuria develops. The enzyme that oxidizes homogentisic acid (homogentisin oxidase) is produced in the liver. Normally, it breaks its hydroquinone ring so quickly that the acid “does not have time” to enter the blood, and if it does, it is quickly excreted by the kidneys. In the case of a hereditary defect of this enzyme, homogentisic acid in large quantities accumulates in blood and urine. The urine of patients with alkaptonuria turns black in air or after adding alkali. This is explained by the oxidation of homogentisic acid with atmospheric oxygen and the formation of alkapton in it (from the Latin alcapton - capturing alkali). Homogentisic acid enters the tissues through the bloodstream - cartilage, tendons, ligaments, the inner layer of the aortic wall, as a result of which dark spots form in the ears, nose, cheeks, and on the sclera. Alcaptone makes cartilage and tendons brittle, sometimes leading to severe joint changes.
Tyrosine is also the starting product for the formation of the melanin pigment found in skin and hair. If the conversion of tyrosine to melanin is slow due to hereditary tyrosinase deficiency (see diagram 4), albinism, which is accompanied by increased skin sensitivity to sunlight and visual impairment.
Finally, tyrosine is a precursor to thyroxine. In case of insufficient synthesis of the enzyme that catalyzes the interaction of tyrosine with free iodine, the formation of thyroid hormones is disrupted.
Violation of tryptophan metabolism. The main metabolic pathway of tryptophan, like nicotinic acid, ensures the synthesis of nicotinamide adenine dinucleotide (NAD) and NADP, which play an important role in the life of the body, being coenzymes of many metabolic reactions, and a significant deficiency of these substances causes the development pellagra. A disturbance in tryptophan metabolism may also be accompanied by a change in the amount of serotonin produced from it.
Providing the body with proteins from several sources determines diverse etiology protein metabolism disorders. The latter can be primary or secondary in nature.
One of the most common reasons general disorders of protein metabolism is quantitative or qualitative protein deficiencyprimary (exogenous) origin. Defects associated with this are caused by limited intake of exogenous proteins during complete or partial starvation, low biological value of food proteins, and deficiency of essential amino acids (valine, isoleucine, leucine, lysine, methionine, threonine, tryptophan, phenylalanine, histidine, arginine).
In some diseases, disturbances in protein metabolism can develop as a result of disorders of the digestion and absorption of protein products (with gastroenteritis, ulcerative colitis), increased protein breakdown in tissues (with stress, infectious diseases), increased loss of endogenous proteins (with blood loss, nephrosis, injuries), disorders of protein synthesis (with hepatitis). The consequence of these violations is oftensecondary (endogenous) protein deficiency with a characteristic negative nitrogen balance.
With prolonged protein deficiency, the biosynthesis of proteins in various organs is sharply disrupted, which leads to pathological changes metabolism in general.
Protein deficiency can develop even if there is sufficient protein intake from food, but if protein metabolism is disrupted.
It may be due to:
- violation of the breakdown and absorption of proteins in the gastrointestinal tract;
- slowing down the flow of amino acids into organs and tissues;
- disruption of protein biosynthesis; violation of intermediate amino acid metabolism;
- changing the rate of protein breakdown;
- pathology of the formation of end products of protein metabolism.
Disturbances in the breakdown and absorption of proteins.
IN digestive tract proteins are broken down under the influence of proteolytic enzymes. At the same time, on the one hand, protein substances and other nitrogenous compounds that make up food lose their specific features, on the other hand, amino acids are formed from proteins, nucleotides from nucleic acids, etc. Nitrogen-containing substances with a small molecular weight formed during the digestion of food or contained in it are absorbed.
There are primary ones (with various forms pathologies of the stomach and intestines - chronic gastritis, peptic ulcer, cancer) and secondary (functional) disorders of the secretory and absorption functions of the epithelium as a result of swelling of the mucous membrane of the stomach and intestines, impaired digestion of proteins and absorption of amino acids in the gastrointestinal tract.
The main causes of insufficient protein breakdown consist in a quantitative decrease in secretion of hydrochloric acid and enzymes, a decrease in the activity of proteolytic enzymes (pepsin, trypsin, chymotrypsin) and the associated insufficient formation of amino acids, a decrease in the time of their action (acceleration of peristalsis). Thus, when the secretion of hydrochloric acid is weakened, the acidity of gastric juice decreases, which leads to a decrease in the swelling of food proteins in the stomach and a weakening of the conversion of pepsinogen into its active form- pepsin. Under these conditions, part of the protein structures passes from the stomach to duodenum in an unchanged state, which impedes the action of trypsin, chymotrypsin and other intestinal proteolytic enzymes. Deficiency of enzymes that break down proteins plant origin, leads to intolerance to cereal proteins (rice, wheat, etc.) and the development of celiac disease.
Insufficient formation of free amino acids from food proteins can occur if the flow of pancreatic juice into the intestine is limited (with pancreatitis, compression, blockage of the duct). Insufficiency of pancreatic function leads to a deficiency of trypsin, chymotrypsin, carbonic anhydrase A, B and other proteases that act on long polypeptide chains or cleave short oligopeptides, which reduces the intensity of cavity or parietal digestion.
Insufficient action of digestive enzymes on proteins can occur due to fast track food masses through the intestines with increased peristalsis (with enterocolitis) or with a decrease in the absorption area (with prompt removal significant areas small intestine). This leads to a sharp reduction in the time of contact of the chyme contents with the apical surface of enterocytes, incompleteness of the processes of enzymatic breakdown, as well as active and passive absorption.
Causes of amino acid malabsorption are damage to the wall of the small intestine (swelling of the mucous membrane, inflammation) or uneven absorption of individual amino acids over time. This leads to a disruption (imbalance) of the ratio of amino acids in the blood and protein synthesis in general, since essential amino acids must enter the body in certain quantities and ratios. Most often there is a lack of methionine, tryptophan, lysine and other amino acids.
Besides common manifestations disorders of amino acid metabolism may bespecific disorders associated with the lack of a specific amino acid. Thus, a lack of lysine (especially in developing organism) stunts growth and general development, lowers the content of hemoglobin and red blood cells in the blood. With a lack of tryptophan in the body, hypochromic anemia occurs. Arginine deficiency leads to impaired spermatogenesis, and histidine deficiency leads to the development of eczema, growth retardation, and inhibition of hemoglobin synthesis.
In addition, insufficient protein digestion in upper sections the gastrointestinal tract is accompanied by an increase in the transfer of products of its incomplete breakdown into the large intestine and an acceleration of the process of bacterial breakdown of amino acids. As a result, the formation of toxic aromatic compounds (indole, skatole, phenol, cresol) increases and general intoxication of the body with these decay products develops.
Slowing down the flow of amino acids into organs and tissues.
Amino acids absorbed from the intestines enter directly into the blood and partially into lymphatic system, representing a reserve of various nitrogenous substances, which then participate in all types of metabolism. Normally, amino acids absorbed into the blood from the intestines circulate in the blood for 5–10 minutes and are very quickly absorbed by the liver and partly by other organs (kidneys, heart, muscles). An increase in the time of this circulation indicates a violation of the ability of tissues and organs (primarily the liver) to absorb amino acids.
Since a number of amino acids are the starting material for the formation of biogenic amines, their retention in the blood creates conditions for the accumulation of corresponding proteinogenic amines in the tissues and blood and their manifestation pathogenic action on various organs and systems. Increased content In the blood, tyrosine promotes the accumulation of tyramine, which is involved in the pathogenesis of malignant hypertension. A prolonged increase in histidine content leads to an increase in the concentration of histamine, which contributes to impaired blood circulation and capillary permeability. In addition, an increase in the content of amino acids in the blood is manifested by an increase in their excretion in the urine and the formation of a special form of metabolic disorders - aminoaciduria. The latter can be general, associated with an increase in the concentration of several amino acids in the blood, or selective - with an increase in the content of any one amino acid in the blood.
Violation of protein synthesis.
The synthesis of protein structures in the body is the central link in protein metabolism. Even small disturbances in the specificity of protein biosynthesis can lead to profound pathological changes in the body.
Among the reasons causing disturbances in protein synthesis, an important place is occupied by various types of nutritional deficiency (complete, incomplete fasting, lack of essential amino acids in food, violation quantitative relationships between essential amino acids entering the body). If, for example, tryptophan, lysine, and valine are contained in tissue protein in equal ratios (1:1:1), and these amino acids are supplied with food protein in the ratio (1:1:0.5), then tissue protein synthesis will be ensured at this is only half of it. If at least one of the 20 essential amino acids is absent in cells, protein synthesis as a whole stops.
An impairment in the rate of protein synthesis may be due to a disorder in the function of the corresponding genetic structures on which this synthesis occurs (DNA transcription, translation, replication). Damage to the genetic apparatus can be either hereditary or acquired, arising under the influence of various mutagenic factors (ionizing radiation, ultraviolet irradiation and etc.). Some antibiotics can disrupt protein synthesis. Thus, errors in reading the genetic code can occur under the influence of streptomycin, neomycin and some other antibiotics. Tetracyclines inhibit the addition of new amino acids to the growing polypeptide chain. Mitomycin inhibits protein synthesis due to DNA alkylation (the formation of strong covalent bonds between its chains), preventing the splitting of DNA strands.
One of important reasons, causing disruption protein synthesis, dysregulation of this process may occur. The intensity and direction of protein metabolism are regulated by the nervous and endocrine systems, the action of which is probably their influence on various enzyme systems. Clinical and experimental experience show that disconnection of organs and tissues from the central nervous system leads to local disruption of metabolic processes in denervated tissues, and damage to the central nervous system causes disorders of protein metabolism. Removal of the cerebral cortex in animals leads to a decrease in protein synthesis.
The growth hormone of the pituitary gland, sex hormones and insulin have a stimulating effect on protein synthesis. Finally, the cause of protein synthesis pathology can be a change in the activity of cell enzyme systems involved in protein biosynthesis. In extreme cases we're talking about about a metabolic block, which is a type of molecular disorder that forms the basis of some hereditary diseases.
The result of the action of all of these factors is a break or decrease in the rate of synthesis of both individual proteins and the protein as a whole.
There are qualitative and quantitative disorders of protein biosynthesis. About. what significance can qualitative changes in protein biosynthesis have in pathogenesis? various diseases, can be judged by the example of some types of anemia with the appearance of pathological hemoglobins. Replacing only one amino acid residue (glutamine) in the hemoglobin molecule with valine leads to a serious disease - sickle cell anemia.
Of particular interest are quantitative changes in the biosynthesis of proteins in organs and blood, leading to a shift in the ratios of individual protein fractions in the blood serum - dysproteinemia. There are two forms of disproteinemia: hyperproteinemia (increased content of all or individual types of proteins) and hypoproteinemia (decreased content of all or individual proteins). Thus, a number of liver diseases (cirrhosis, hepatitis), kidney diseases (nephritis, nephrosis) are accompanied by a pronounced decrease in albumin content. A number of infectious diseases accompanied by extensive inflammatory processes lead to an increase in the content of γ-globulins.
The development of dysproteinemia is usually accompanied by serious changes in the body's homeostasis (impaired oncotic pressure, water metabolism). A significant decrease in the synthesis of proteins, especially albumins and γ-globulins, leads to a sharp decrease in the body's resistance to infection and a decrease in immunological resistance. The significance of hypoproteinemia in the form of hypoalbuminemia is also determined by the fact that albumin forms more or less strong complexes with various substances, providing their transport between various organs and transport through cell membranes with the participation of specific receptors. It is known that iron and copper salts (extremely toxic to the body) are poorly soluble at blood serum pH and their transport is possible only in the form of complexes with specific serum proteins (transferrin and ceruloplasmin), which prevents intoxication with these salts. About half of the calcium is retained in the blood in a form bound to serum albumin. In this case, a certain dynamic balance is established in the blood between the bound form of calcium and its ionized compounds.
In all diseases accompanied by a decrease in albumin content (kidney disease), the ability to regulate concentration is also weakened. ionized calcium in blood. In addition, albumins are carriers of some components of carbohydrate metabolism (glycoproteins) and the main carriers of free (non-esterified) fatty acids and a number of hormones.
For liver and kidney damage, some acute and chronic inflammatory processes(rheumatism, infectious myocarditis, pneumonia) the body begins to synthesize special proteins with altered properties or unusual ones. A classic example of diseases caused by the presence of pathological proteins are diseases associated with the presence of pathological hemoglobin(hemoglobinosis), blood coagulation disorders with the appearance of pathological fibrinogens. Unusual blood proteins include cryoglobulins, which can precipitate at temperatures below 37 °C, leading to thrombus formation. Their appearance is accompanied by nephrosis, cirrhosis of the liver and other diseases.
Pathology of intermediate protein metabolism (disorder of amino acid metabolism).
The main pathways of intermediate protein metabolism are the reactions of transamination, deamination, amidation, decarboxylation, remethylation, and transsulfurization.
The central place in the intermediate metabolism of proteins is occupied by the transamination reaction, as the main source of the formation of new amino acids.
Transamination disorder may result from a deficiency of vitamin B6 in the body. This is explained by the fact that the phosphorylated form of vitamin B 6 - phosphopyridoxal - is an active group of transaminases - specific transamination enzymes between amino and keto acids. Pregnancy and long-term use of sulfonamides inhibit the synthesis of vitamin B6 and can cause disturbances in amino acid metabolism.
Pathological enhancement transamination reactions are possible in conditions of liver damage and insulin deficiency, when the content of free amino acids increases significantly. Finally, a decrease in transamination activity can occur as a result of inhibition of transaminase activity due to impaired synthesis of these enzymes (during protein starvation) or impaired regulation of their activity by certain hormones. Thus, tyrosine (an essential amino acid), supplied with food proteins and formed from phenylalanine, is partially oxidized in the liver to fumaric and acetoacetic acids. However, this oxidation of tyrosine occurs only after its reamplification with α-ketoglutaric acid. With protein depletion, the transamination of tyrosine is noticeably weakened, as a result of which its oxidation is impaired, which leads to an increase in the tyrosine content in the blood. The accumulation of tyrosine in the blood and its excretion in the urine may also be associated with a hereditary defect in tyrosine aminotransferase. Clinical condition The disease that develops as a result of these disorders is known as tyrosinosis. The disease is characterized by cirrhosis of the liver, rickets-like bone changes, hemorrhages, and damage to the kidney tubules.
The processes of transamination of amino acids are closely related to the processesoxidative deamination . during which the enzymatic cleavage of ammonia from amino acids occurs. Deamination determines the formation of final products of protein metabolism and the entry of amino acids into energy metabolism. Weakening of deamination may occur due to disruption of oxidative processes in tissues (hypoxia, hypovitaminosis C, PP, B 2). However, the most severe disruption of deamination occurs when the activity of amino oxidases decreases, either due to a weakening of their synthesis (diffuse liver damage, protein deficiency), or as a result of a relative insufficiency of their activity (increased content of free amino acids in the blood). Due to a violation of the oxidative deamination of amino acids, urea formation is weakened, the concentration of amino acids increases and their excretion in the urine increases (aminoaciduria).
The intermediate exchange of a number of amino acids occurs not only in the form of transamination and oxidative deamination, but also through theirdecarboxylation (loss of CO 2 from the carboxyl group) with the formation of the corresponding amines, called “biogenic amines”. Thus, when histidine is decarboxylated, histamine is formed, tyrosine - tyramine, 5-hydroxytryptophan - serotonin, etc. All these amines are biologically active and have a pronounced pharmacological effect on blood vessels. If normally they are formed in small quantities and are destroyed quite quickly, then if decarboxylation is disrupted, conditions arise for the accumulation of the corresponding amines in the tissues and blood and the manifestation of their toxic effect. The reasons for the disruption of the decarboxylation process may be increased activity of decarboxylases, inhibition of the activity of amine oxidases and impaired binding of amines to proteins.
Changing the rate of protein breakdown.
The body's proteins are constantly in a dynamic state: in the process of continuous breakdown and biosynthesis. Violation of the conditions necessary for the implementation of this dynamic balance can also lead to the development of general protein deficiency.
Typically, the half-life of different proteins varies from several hours to many days. So, biological time The reduction in human serum albumin by half is about 15 days. The magnitude of this period largely depends on the amount of protein in food: with a decrease in retention of proteins, it increases, and with increase, it decreases.
A significant increase in the rate of breakdown of tissue and blood proteins is observed with an increase in body temperature, extensive inflammatory processes, severe injuries, hypoxia, malignant tumors, which is associated either with the action of bacterial toxins (in case of infection), or with a significant increase in the activity of proteolytic enzymes in the blood (in case of hypoxia ), or toxic effect tissue breakdown products (in case of injuries). In most cases, the acceleration of protein breakdown is accompanied by the development of a negative nitrogen balance in the body due to the predominance of protein breakdown processes over their biosynthesis.
Pathology of the final stage of protein metabolism.
The main end products of protein metabolism are ammonia and urea. Pathology of the final stage of protein metabolism can manifest itself as a violation of the formation of final products or a violation of their excretion.
Rice. 9.3. Diagram of urea synthesis disorder
The binding of ammonia in the tissues of the body is of great physiological importance, since ammonia has toxic effect primarily in relation to the central nervous system, causing its sharp excitation. In the blood of a healthy person, its concentration does not exceed 517 µmol/l. The binding and neutralization of ammonia is carried out using two mechanisms: in the liver byurea formation, and in other tissues - by adding ammonia to glutamic acid (via amination) withglutamine formation .
The main mechanism for ammonia binding is the process of urea formation in the citrulline-argininornithine cycle (Fig. 9.3).
Disturbances in the formation of urea can occur as a result of a decrease in the activity of enzyme systems involved in this process (with hepatitis, cirrhosis of the liver), and general protein deficiency. When urea formation is impaired, ammonia accumulates in the blood and tissues and the concentration of free amino acids increases, which is accompanied by the developmenthyperazotemia . In severe forms of hepatitis and cirrhosis of the liver, when its urea-forming function is sharply impaired, a pronouncedammonia intoxication (dysfunction of the central nervous system with the development of coma).
Impaired urea formation may be caused by hereditary defects in enzyme activity. Thus, an increase in the concentration of ammonia (ammonemia) in the blood may be associated with blocking carbamyl-phosphate synthetase and ornithine carbamoyltransferase. catalyzing the binding of ammonia and the formation of ornithine. With a hereditary defect of arginine succinate synthetase, the concentration of citrulline in the blood sharply increases, as a result of which citrulline is excreted in the urine (up to 15 g per day), i.e. developscitrullinuria .
In other organs and tissues (muscles, nerve tissue) ammonia is bound in the reactionamidation with the addition of free dicarboxylic amino acids to the carboxyl group. The main substrate is glutamic acid. Disruption of the amidation process can occur when the activity of enzyme systems providing the reaction (glutaminase) decreases, or as a result intensive education ammonia in quantities exceeding its binding capacity.
Another end product of protein metabolism formed during the oxidation of creatine (the nitrogenous substance of muscles) iscreatinine . Normal daily allowance creatinine in urine is about 1-2 g.
Creatinuria - increased creatinine levels in urine - observed in pregnant women and children during periods of intensive growth.
In case of fasting, vitamin E deficiency, febrile infectious diseases, thyrotoxicosis and other diseases in which metabolic disorders are observed in the muscles, creatinuria indicates a violation of creatine metabolism.
Another common form of disruption of the final stage of protein metabolism occursin case of impaired excretionend products of protein metabolism in kidney pathology. With nephritis, urea and other nitrogenous products are retained in the blood, residual nitrogen increases and developshyperazotemia. Extreme degree disturbances in the excretion of nitrogenous metabolites isuremia.
With simultaneous damage to the liver and kidneys, a violation of the formation and release of the final products of protein metabolism occurs.
Along with general disorders of protein metabolism, protein deficiency may also causespecific disorders in the metabolism of individual amino acids. For example, with protein deficiency, the function of enzymes involved in the oxidation of histidine is sharply weakened, and the function of histidine decarboxylase, as a result of which histamine is formed from histidine, not only does not suffer, but, on the contrary, increases. This entails a significant increase in the formation and accumulation of histamine in the body. The condition is characterized by skin lesions, cardiac dysfunction and gastrointestinal tract function.
Of particular importance for medical practice arehereditary aminoacidopathies , the number of which today is about 60 different nosological forms. According to the type of inheritance, almost all of them are autosomal recessive. Pathogenesis is caused by a deficiency of one or another enzyme that carries out the catabolism and anabolism of amino acids. A common biochemical sign of aminoaidopathies is tissue acidosis and aminoaciduria. The most common hereditary metabolic defects are four types of enzymopathy, which are interconnected by a common pathway of amino acid metabolism: phenylketonuria, tyrosinemia, albinism, alkaptonuria.
