Biochemistry of Amino Acids - A. Majster 1961

Disorders of Amino Acid Metabolism in Certain Pathological Conditions
Aminoaciduria

Although the source of urinary Amino Acids is plasma amino acids, there is no direct correlation between the concentrations of various amino acids in the Blood and the urine. For instance, the amino acids excreted in the largest quantities in the urine are not necessarily those whose plasma levels are highest (see Table 3). Furthermore, human blood amino acid concentrations remain relatively constant, whereas urinary excretion fluctuates significantly. These Qualitative and quantitative differences in amino acid excretion are driven by several factors, including diet and heredity. Under normal conditions, amino acids account for less than 3% of urinary nitrogen in humans, meaning an average daily excretion of roughly 80 to 300 mg of Amino Acid Nitrogen. There are notable Species Differences in amino acid excretion [43]; interestingly, cats excrete felinine, an amino acid absent from the urine of other animal species (p. 52). In humans, genetic factors influence the excretion rate of ß-aminoisobutyric acid (which likely originates from thymine degradation, see p. 309). Approximately 10% of people excrete about 200 mg of ß-aminoisobutyric acid daily, whereas the majority excrete only about one-tenth of this amount. This elevated excretion of ß-aminoisobutyric acid is presumably linked to renal function, as there is no evidence of elevated blood levels of this amino acid in individuals who excrete it in high amounts [44–46].

Amino acid excretion is heavily influenced by the extent of their reabsorption in the renal tubules [47–54, 235]. Normally, substantial amounts of amino acids undergo tubular reabsorption—the higher the blood amino acid level, the greater the reabsorption. Experimental studies on renal reabsorption have been conducted primarily in dogs, with many experiments utilizing racemic amino acids. The data indicate that Arginine, Lysine, and glutamic acid are reabsorbed with greater difficulty than Glycine, Alanine, isoleucine, valine, Threonine, Tryptophan, phenylalanine, and Methionine. Competitive interactions during reabsorption have been observed between creatine and Certain amino acids (such as glycine or alanine), whereas glucose does not compete with amino acids. While it has been suggested that a single mechanism mediates amino acid reabsorption, findings related to cystinuria (see below) point to a specialized mechanism dedicated to the reabsorption of arginine, Ornithine, lysine, and cystine. Instances of competition among amino acids themselves during reabsorption are also known; if such competition occurs between L- and D-amino acids, it would significantly compromise the validity of experiments performed using racemic amino acids.

Generally, elevated amino acid excretion occurs either when blood amino acid levels are substantially increased or when renal reabsorption is impaired.

An example of the first type (exceeding the renal threshold [54, 55]) is The excretion of phenylalanine in Phenylpyruvic Oligophrenia (p. 474). Liver damage typically elevates the overall plasma amino acid level, resulting in generalized aminoaciduria [17, 55–60]. This is hardly surprising, given that AMINO ACID DEAMINATION occurs primarily in the liver. Dent and Walshe [56] observed increased urinary excretion of cystine, taurine, ß-aminoisobutyric acid, methylhistidine, ethanolamine, and methionine in patients with mild liver disease. In more severe hepatic impairment, the excretion of all amino acids increases markedly, mirroring The amino acid excretion profile seen in animals following hepatectomy [61].

Generalized aminoaciduria [65] is also observed in other pathological conditions associated with elevated plasma amino acid levels, such as cachexia, muscular atrophy [62, 63], hyperthyroidism, and trauma [64]. Renal diseases characterized by impaired tubular reabsorption can likewise present with generalized aminoaciduria, glucosuria, and proteinuria.

Cystinuria is characterized by a specific impairment in the renal reabsorption of cystine, as well as ornithine, arginine, and lysine [66–71]. Aside from The formation of cystine calculi, patients with this condition typically exhibit no other metabolic abnormalities. It is noteworthy that cystine—one of the first amino acids to be isolated from natural sources—was discovered by Wollaston [72] in 1810 in a Urinary Bladder stone. Dent and co-workers [69–71] concluded that the sole anomaly in cystinuria is a dysfunction of the renal tubules. Interestingly, arginine, ornithine, and lysine are also excreted in this condition; Dent et al. [71] suggested that a common transport mechanism is involved in the reabsorption of all these amino acids.

In an earlier study, putrescine and cadaverine were detected in the urine of a cystinuric patient [73]; these compounds likely originate from their respective amino acid precursors through the action of bacterial Decarboxylases present in the urine. Cystinuria apparently does not stem from a disruption in the intermediate METABOLISM of cystine; compelling evidence indicates that it belongs to the category of inborn errors of metabolism. Cystinuria also occurs in dogs, where the underlying Etiology of the syndrome is identical to that in humans [74].

Various types of aminoaciduria have also been observed in A number of other, relatively rare disorders that remain fully unelucidated to this day. Fanconi Syndrome [75–77] is a hereditary disease accompanied by generalized aminoaciduria along with the urinary excretion of Peptides, bicarbonate, and phosphate. This condition may be complicated by Osteomalacia, Rickets, and hepatic involvement [65, 78, 79]; cystinuria is sometimes observed as well, though this symptom is clearly distinct from uncomplicated cystinuria. Simple cystinuria must be differentiated from cystinosis, a significantly more severe and often fatal disease in early childhood. This disorder is characterized by generalized aminoaciduria coupled with systemic manifestations caused by the deposition of cystine crystals in Tissues, particularly within the reticuloendothelial system [80–86]. It has been suggested that cystinosis and Fanconi syndrome are closely related conditions [81]. In Fanconi syndrome, blood amino acid concentrations generally remain within normal limits, and accumulating evidence points to a primary renal tubular defect. In later stages, the clinical course may be further complicated by The Development of hepatic lesions.

In hepatolenticular degeneration (Wilson's disease), generalized aminoaciduria is observed, which is associated with liver damage [87—89]. However, aminoaciduria may appear before clinical signs of liver disease develop, and there is usually no significant increase in blood amino acid levels. There are also indications of peptide excretion in the urine in this condition [89]. Of particular interest is the evidence that copper metabolism is impaired in such patients [90—95]. Copper is deposited in the lentiform Nucleus of the Brain, the liver, and the cornea; unusually large amounts of copper are excreted in the urine as chelate complexes with dicarboxylic amino acid peptides. In normal blood serum, copper is bound to ceruloplasmin, an α-globulin. The concentration of this protein is decreased in Wilson's disease, yet the total copper content in blood serum remains normal or exceeds normal levels [93, 95]. There is a parallelism between amino acid excretion and copper excretion—for instance, enhanced amino acid output induced by a high-protein diet is accompanied by increased copper excretion [94]. The Nature of the primary lesion in this disease remains elusive. Interestingly, renal Damage caused by heavy metals (uranium, lead, cadmium, mercury) [96—98] and other agents [99, 100] also leads to aminoaciduria.

Another inherited metabolic disorder, galactosemia, is likewise associated with aminoaciduria, which, according to some reports, disappears when galactose is excluded from the diet [101—103]. There are indications that in this case, too, aminoaciduria is caused by impaired reabsorption in the renal tubules. In some patients with spontaneous idiopathic hypoglycemia, the administration of amino acids or protein lowers the fasting Blood Glucose Level [104].

The Study of amino acid excretion has already led to the discovery of several fascinating metabolic abnormalities in various pathological states, including certain relatively rare diseases; it is quite possible, however, that more subtle alterations in amino acid excretion accompany other conditions as well. Such phenomena can now be investigated thanks to advanced Methods for determining amino acids. At the same time, all conditions (especially diet) must be strictly controlled. The Regulation of Blood amino acid levels involves the participation of Hormones (p. 179); it is highly probable that their action also affects amino acid excretion. Thus, when cortisone was administered to patients with rheumatoid Arthritis, an increased excretion of amino acids was observed [105]. There is also evidence of relatively regular fluctuations in the excretion of certain amino acids in women associated with the Menstrual cycle. For instance, during Pregnancy, women exhibit increased excretion of Histidine, threonine, lysine, and tryptophan, whereas during Lactation, amino acid excretion is relatively decreased [106].