Biological Chemistry - Berezov T. T., Korovkin B. F. 1998

Metabolism of Simple Proteins
Pathology of Nitrogen Metabolism

Nitrogen METABOLISM is closely intertwined with Protein metabolism, whose fundamental structural units are Amino Acids. Consequently, the following Structure/133.html">Discussion focuses on currently established data regarding the disruption of individual Amino acid metabolism in various pathologies. The heightened interest of biochemists, physiologists, and clinicians in the pathology of amino acid metabolism is driven by several factors. First, there is robust experimental and clinical evidence that certain pathological syndromes originate from disruptions in the normal Metabolic pathways of specific amino acids within the body. Second, Amino Acids and their derivatives have increasingly been adopted in clinical practice as therapeutic agents; for instance, Methionine is used to treat various Liver conditions, glutamic acid for certain Brain disorders, and glutamine for ketonuria, among others. Finally, A number of amino acids and their decarboxylation products (biogenic amines) exert regulatory control over many physiological Functions. Therefore, understanding the regularities of individual amino acid metabolism—both in health and, particularly, in disease—is of profound theoretical and practical significance.

Disruptions in amino acid metabolism across the whole Organism are evaluated not only by the quantitative and qualitative composition of their metabolic products in Blood and urine, but also by the levels of free amino acids themselves in biological fluids. Most Tissues are characterized by a distinct amino acid "profile." In Blood Plasma, this profile roughly mirrors the composition of free amino acids in Organs and tissues, save for lower concentrations of glutamate and aspartate and a higher level of glutamine, which accounts for up to 25% of the total amino acid pool. CEREBROSPINAL FLUID exhibits lower concentrations of nearly all amino acids, with the exception of glutamine. The amino acid profile of urine differs sharply from that of blood plasma. Notably, in individuals on A balanced diet, the urinary Amino Acid Composition remains relatively constant from day to day; however, among different people with nearly identical plasma profiles, urinary amino acid compositions can vary quite drastically.

The exact nature of Metabolic Disorders caused by a deficiency of a specific amino acid is difficult to determine experimentally, because such a deficiency alters the entire process of Protein Biosynthesis, which operates on an "all-or-none" principle. Specific clinical manifestations of amino acid deficiency typically emerge only under pathological conditions characterized by accelerated utilization of the amino acid in question. For example, in patients with carcinoid tumors, over 60% of Tryptophan is oxidized via the serotonin pathway (compared to a normal rate of 1%), which naturally results in a relative deficiency of this amino acid. In patients with malignant melanoma, Tyrosine and, likely, phenylalanine are heavily consumed in melanin biosynthesis. By utilizing artificial diets (omitting a specific amino acid from the diet of humans or animals), researchers can describe syndromes characteristic of that particular deficiency. For instance, tryptophan deficiency in humans leads to weight loss, while in newborns, even a 10-day deficit results in anorexia and hypoproteinemia. In rats, it causes tooth loss, alopecia, corneal opacification, and cataracts, whereas in chicks, it increases the requirement for Vitamin PP. Lysine deficiency in humans manifests as dizziness, nausea, and heightened sensitivity to noise, whereas Histidine deficiency is accompanied by a drop in Hemoglobin concentration. Arginine deficiency leads to testicular atrophy in rats and hypospermia in humans. The exclusion of methionine from the diet causes fatty degeneration of The Liver and Kidneys, driven by a shortage of the labile methyl groups required for phosphatidylcholine synthesis.

Certain non-Essential Amino Acids become essential if they are absent from the diet, as cellular machinery cannot synthesize them rapidly enough. According to R. Fischer, Cysteine deficiency leads to the near-total inhibition of Cell growth in vitro, even when all Other Amino Acids are present in the medium. Furthermore, it has been proven that an adequate supply of cysteine in the diet significantly lowers the requirement for methionine (see Table 12.2). Conversely, the complete exclusion of cysteine from the diet can so sharply escalate methionine demands that an otherwise adequate diet becomes insufficient. Thus, non-essential Amino acids can act as limiting factors for anabolic processes in the body.

One of the hallmark disorders of nitrogen metabolism is Protein deficiency, which stems not only from inadequate protein intake but also from various severe illnesses, even when dietary protein is sufficient. Protein deficiency in humans develops during both total and partial starvation, as well as on monotonous protein diets dominated by plant-based Proteins, whose biological value is significantly lower than that of animal proteins. These conditions result in a negative nitrogen balance, hypoproteinemia (a drop in serum protein concentration to 30–50 g/L; normal is 65–85 g/L), and disturbances in colloid-osmotic and Water-salt balance (leading to edema). In severe forms of nutritional marasmus—such as kwashiorkor, a condition fairly common among children in developing countries—patients suffer from severe liver damage, growth stunting, a sharp decline in resistance to infections, edema, and muscular atonia. The disease frequently proves fatal.

In cases of protein deficiency, the metabolic disturbances most amenable to quantitative assessment are those involving amino acids. Among the earliest signs of impaired nitrogen metabolism in protein deficiency is a drastic reduction in the rates of deamination, Transamination, and Amino acid biosynthesis, as well as urea synthesis in the liver. These impairments have been shown to stem from inadequate synthesis and accelerated degradation of the protein moieties of the Enzymes catalyzing these reactions; arginase is a notable exception, as its activity remains largely unaffected. The consequences of these disruptions include the accumulation of substantial amounts of amino acids in the blood, The excretion of free amino acids in the urine (up to 10–20 g/day; normal is about 1 g/day), and a dramatic drop in the production and urinary excretion of urea.

In protein deficiency, alongside general disturbances in amino acid metabolism, specific alterations in the Metabolism of individual Amino acids are observed. For instance, disruptions in Tryptophan Metabolism manifest both as a decline in nicotinamide synthesis and as the accumulation within the body of

3-hydroxyanthranilic and xanthurenic acids. The latter, according to some data, exerts a toxic effect on pancreatic islet ß-Cells, thereby acting as one of the pathogenetic factors in diabetes. Disturbances in Histidine Metabolism boil down to reduced activity of histidase (histidine ammonia-lyase) and histaminase, coupled with an increased activity of histidine decarboxylase. All of this promotes the accumulation of histamine in tissues with all the resulting negative consequences. In protein deficiency, Methionine Metabolism remains virtually undisturbed. Collectively, these findings point to a severe dyscoordination of enzymatic systems involved in amino acid amino acid metabolism, greatly complicating therapeutic strategies aimed at reversing the effects of protein deficiency.

Aminoaciduria. The Qualitative and quantitative composition of amino acids in human urine is primarily of diagnostic value, since certain human diseases arise from primary defects in the metabolism of a single amino acid or a group of amino acids. Moreover, a range of organic lesions affecting human organs and tissues, as well as metabolic anomalies, feature characteristic urinary amino acid profiles. Because of this, and due to the ready accessibility of urine as a research sample, amino acid urinalysis holds immense clinical significance. Amino acid excretion is heavily influenced by age, diet, sex, Hormones, and other factors. It has been established that infants excrete more amino acids in their urine than adults. Generally, elevated and reduced amino acid excretion are distinguished. Hyperaminoaciduria, in turn, is subdivided into renal—associated with acquired or congenital defects in renal amino acid reabsorption—and extrarenal, caused by elevated concentrations of all or specific amino acids in the blood (see Chapter 18).

As is well known, the tubular reabsorption of amino acids in the kidneys occurs against a concentration gradient. Fundamentally, this process is most likely enzymatic in nature, although the precise details remain to be fully elucidated. In chronic nephritis, the urine frequently contains elevated amounts of lysine, arginine, Proline, and citrulline, even though their blood levels may remain within normal limits. In nephrosis, urine almost invariably shows increased excretion of ethanolamine, taurine, and ß-aminobutyric acid, and this type of hyperaminoaciduria is considered an unfavorable prognostic sign.

Much more common are hereditary defects in renal amino acid reabsorption. One of the best-characterized disorders is cystinosis, which is equated by several authors with the Abderhalden-Fanconi Syndrome in terms of both clinical and biochemical manifestations and the pattern of inheritance. The primary metabolic defect in both cases involves a congenital impairment in the reabsorption of nearly all amino acids (except cyclic ones) within the renal tubules. The consequences include a 5- to 10-fold increase in amino acid excretion, a 20- to 30-fold increase in cystine and cysteine excretion, and the selective deposition of cystine crystals in Bone Marrow reticular cells, the Spleen, the liver, and corneal cells. Interestingly, unlike another inherited metabolic disorder—cystinuria—cystinosis rarely leads to Kidney stone formation, whereas cystinuria is invariably characterized by cystine stones. The precise Nature of the tubular reabsorption defect in cystinosis remains unresolved.

Cystinuria is a fairly common inherited disorder. Its metabolic defect is manifested by the urinary excretion of four amino acids—cystine, lysine, arginine, and Ornithine—at levels up to 50 times the normal range. Blood cystine levels typically do not exceed normal limits. Individuals suffering from cystinuria are generally healthy, save for a strong tendency toward kidney stone formation. This congenital metabolic anomaly stems from a complete block in cystine reabsorption coupled with a partial impairment in the tubular reabsorption of the other Three amino acids; no disturbances in the Intermediary Metabolism of these amino acids are detected.

In another inherited metabolic disorder—hepatolenticular degeneration (Wilson's disease)—alongside generalized (global) hyperaminoaciduria, one observes a drop in the serum concentration of the copper-containing protein ceruloplasmin and the pathological deposition of copper in the brain, liver, and kidneys. The genetic defect is tied to impaired ceruloplasmin synthesis. It is possible that copper forms complexes with amino acids that cannot be reabsorbed by the renal tubules. Similar hyperaminoaciduria is observed in galactosemia, Lowe syndrome, and other Hereditary diseases. Decreased amino acid excretion has been described in kwashiorkor.

Congenital disorders of individual amino acid metabolism. Intense scientific interest surrounds certain inherited human diseases that result from primary defects in the metabolism of specific amino acids. The onset and progression of specific pathological syndromes in these disorders are driven by the complete or partial loss of activity of particular enzymes: the organism either loses The ability to synthesize the enzyme in question, produces it in insufficient quantities, or synthesizes an aberrant enzyme with an altered structure compared to the native protein. The consequence of such a congenital metabolic defect is the accumulation within tissues of normal intermediary or side (non-specific) metabolic products that exert toxic effects on the body, most notably on the Central Nervous system. This likely explains why these conditions predominantly manifest in early childhood, subsequently leading to specific cognitive and psychiatric disorders. It is also highly probable that Certain amino acids and their metabolites, at optimal concentrations, are essential for normal brain function. Therefore, the task of biochemists, physiologists, and clinicians is to unravel the relationship between The Development of pathological syndromes in congenital "errors" of metabolism and specific disruptions in Amino Acid Pathways. Below are Examples of such disorders.

Phenylketonuria (Phenylpyruvic Oligophrenia) develops as a consequence of the body's loss of ability to synthesize phenylalanine 4-monooxygenase, the enzyme that catalyzes The conversion of phenylalanine to tyrosine. Characteristic Features of the disease include a drastic deceleration of mental development in the child, alongside the urinary excretion of large quantities of phenylpyruvic acid (up to 1–2 g/day) and phenylacetylglutamine (up to 2–3 g/day). Definitive proof of the metabolic block in phenylketonuria comes from data showing the massive accumulation of phenylalanine in tissues. For instance, its blood level can reach 600 mg/L (normal is 15 mg/L), and in cerebrospinal fluid, it can reach 80 mg/L (normal is 1.5 mg/L). The onset of the disease can be prevented by drastically restricting dietary phenylalanine intake from early infancy.

Alcaptonuria is characterized by the urinary excretion of large quantities (up to 0.5 g/day) of homogentisic acid, The oxidation of which by atmospheric oxygen imparts a dark color to the urine. In advanced cases, ochronosis develops, accompanied by pigment deposition in tissues and darkening of the Nose, ears, and sclera. This disease has been known since antiquity; however, it was not until 1962 that definitive evidence proved the metabolic defect in alcaptonuria is tied to a Congenital absence of homogentisic acid oxidase in the liver and kidneys.

Albinism is the congenital absence of pigments in the Skin, Hair, and retina. The metabolic defect is linked to the loss of melanocytes' ability to synthesize tyrosinase—the enzyme that catalyzes the oxidation of tyrosine to dihydroxyphenylalanine (DOPA) and DOPAquinone, which serve as precursors for melanin. The hypothesis that the melanin polymerization process is blocked in albinism was ultimately disproven.

Hartnup disease is characterized by specific disturbances in tryptophan metabolism. The primary manifestations of the disorder, alongside pellagra-like skin lesions, psychiatric symptoms, and ataxia, include hyperaminoaciduria. Because urine contains elevated levels of indolylacetate, indolylacetylglutamine, and indican, but normal amounts of indolyllactic acid, the metabolic block evidently occurs at the very first step of the normal tryptophan degradation pathway, forcing metabolism predominantly down alternative decarboxylation routes. In another inherited disorder of branched-chain amino acids—maple syrup urine disease—as well as in phenylketonuria, indolylacetate is also excreted, but in these cases, its source is indolylpyruvate, since large quantities of indolyllactic acid (which can only be formed from phenylpyruvate) are concomitantly excreted in the urine. According to recent data, the metabolic defect in Hartnup disease involves a congenital impairment of intestinal tryptophan absorption alongside defective tubular reabsorption of tryptophan and its metabolites in the kidneys. It follows that analyzing The chemical composition of urinary and blood indole derivatives allows clinicians to deduce The Nature of the underlying pathology (such as carcinoid tumors or phenylketonuria) and the specific mechanism of altered tryptophan metabolism, which is critical for accurate Diagnosis and effective Treatment.

In a number of instances, the blockade of a specific enzymatic reaction leads to severe mental retardation. The question of what precisely drives this cognitive impairment—whether it is the toxic action of abnormally high concentrations of amino acids or their metabolites on the brain, a disruption in the physiological balance of amino acids and subsequent protein biosynthesis, or secondary disturbances in energy and other Types of Metabolism—remains definitively unresolved. Thus, identifying the chemical reaction or enzyme system whose functional failure triggers a severe hereditary disease is not only of immense theoretical interest today, but in many cases plays a decisive role in the diagnosis and management of these conditions. It must always be borne in mind that when the normal metabolic pathway of a particular amino acid is blocked, the intermediate metabolites situated downstream of the block become essential nutrients for the patient.