Metabolism amino acid, enzyme deficiency

Phenylketonuria. Many enzyme deficiency diseases have been discovered that affect the pathways of amino acid metabolism. These deficiency diseases have helped researchers to elucidate the pathways in humans, in whom experimental manipulation is, at best, unethical. These spontaneous mutations ( experiments of nature), although devastating to patients, have resulted in an understanding of these diseases that now permit treatment of inborn errors of metabolism that were once considered to be untreatable. 

Pyridoxal phosphate is a coenzyme for many enzymes involved in amino acid metabolism, especially in transamination and decarboxylation. It is also the cofactor of glycogen phosphorylase, where the phosphate group is catalytically important. In addition, vitamin Bg is important in steroid hormone action where it removes the hormone-receptor complex from DNA binding, terminating the action of the hormones. In vitamin Bg deficiency, this results in increased sensitivity to the actions of low concentrations of estrogens, androgens, cortisol, and vitamin D. 

Other leukodystrophies are associated with the lysosomal and peroxisomal disorders in which specific lipids or other substances accumulate due to a deficiency in a catabolic enzyme - for example Krabbe s disease, meta-chromatic leukodystrophy (MLD) and adrenoleuko-dystrophy (ALD) [1,2]. (These are discussed in detail in Ch. 40.) Similarly, disorders of amino acid metabolism can lead to hypomyelination - for example phenylketonuria and Canavan s disease (spongy degeneration) [1, 2, 25] (Ch. 40). The composition of myelin in the genetically... 

The study of genetic defects in the oxidation of fat fuels is a relatively new field compared with the study of such defects in carbohydrate and amino acid metabolism. The first genetic defect was reported in 1970 and the first enzyme deficiency in 1973. The probable reasons for the late discovery of these defects are of some interest ... 

The terminology vitamin Bg covers a number of structurally related compounds, including pyridoxal and pyridoxamine and their 5 -phosphates. Pyridoxal 5 -phosphate (PLP), in particular, acts as a coenzyme for a large number of important enzymic reactions, especially those involved in amino acid metabolism. We shall meet some of these in more detail later, e.g. transamination (see Section 15.6) and amino acid decarboxylation (see Section 15.7), but it is worth noting at this point that the biological role of PLP is absolutely dependent upon imine formation and hydrolysis. Vitamin Bg deficiency may lead to anaemia, weakness, eye, mouth, and nose lesions, and neurological changes. 

The active form of vitamin Be, pyridoxai phosphate, is the most important coenzyme in the amino acid metabolism (see p. 106). Almost all conversion reactions involving amino acids require pyridoxal phosphate, including transaminations, decarboxylations, dehydrogenations, etc. Glycogen phosphory-lase, the enzyme for glycogen degradation, also contains pyridoxal phosphate as a cofactor. Vitamin Be deficiency is rare. 

Vitamin B6 (pyridoxine, pyridoxamine, and pyridoxal) has the active form, pyridoxal phosphate. It functions as a cofactor for enzymes, particularly in amino acid metabolism. Deficiency of this vitamin is rare, but causes glossitis and neuropathy. The deficiency can be induced by isoniazid, which causes sensory neuropathy at high doses. 

Amino acid metabolism in vertebrates contrasts sharply with amino acid metabolism in plants and microorganisms. Most striking is the fact that plants and microorganisms can synthesize all twenty amino acids required for protein synthesis whereas vertebrates can only synthesize about half this number. This leads to complex nutritional needs for vertebrates, which are discussed in chapter 22, Amino Acid Metabolism in Vertebrates. Vertebrate amino acid degradation pathways are also discussed in chapter 22 along with the existence of many pathological states that result from enzyme deficiencies in the degradative pathways. 

Four of the amino acids, alanine, aspartate, glutamate, and serine, are formed by the transamination of their corresponding oxoacids. The other nonessential amino acids are then derived from these four amino acids. The syntheses of serine and tyrosine are described below because of either their importance in aspects of metabolism or their clinical significance the synthesis of serine is essential for folic acid metabolism, while deficiencies in the enzymes synthesizing tyrosine can lead to phenylketonuria. 

Phase I and Phase II metabolic reactions require amino acids for enzyme synthesis. A diet that is deficient in amino acid sources (proteins) can result in the individual not synthesizing significant enough enzyme quantities to... 

Concentrations of various carboxylic acids in human body fluids reflect some of the major metabolic processes of the body. These metabolites apparently originate from lipid and amino acid metabolism the major metabolic defects are frequently associated with unbalanced concentrations of these acidic substances. One of the most widely occurring conditions of this kind is ketoacidosis in diabetic disease high concentrations of the so-called ketone bodies (3-hydroxybutyric acids, acetoacetic acid and others) are the traditional hallmarks of ketoacidosis. Many additional acidurias were discovered (particularly during the last 15 years) in major part due to the availability of GC and GC/MS techniques. Acidurias are among the serious medical conditions that are usually a result of genetic aberration (enzyme deficiencies), but environmental factors or nutritional deficiency could occasionally be involved. These conditions are characterized by either (a) drastically enhanced excretion of normal metabolic intermediates, or (b) excretion of unusual metabolites that are produced from the accumulated intermediates via alternate biochemical pathways. Many acidemic conditions have now been documented in the literature, and the role of GC in such medical discoveries has been adequately stressed in the recent reviews of Jellum [15] and Tanaka and Hine [373]. 

Because of the numerous enzymes requiring pyridoxal phosphate, a large variety of biochemical lesions are associated with vitamin B5 deficiency. These lesions are concerned primarily with amino acid metabolism, and a deficiency affects the animal s growth rate. Convulsions may also occur, possibly because a reduction in the activity of glutamic acid decarboxylase results in an accumulation of glutamic acid. In addition, pigs reduce their food intake and may develop anaemia. Chicks on a deficient diet show jerky movements in adult birds, hatchability and egg production are adversely affected. In practice, vitamin B5 deficiency is unlikely to occur in farm animals because of the vitamin s wide distribution. 

An aminoaciduria usually results from the congenital absence of an enzyme needed for metabolism of an amino acid. Aminoacidopathies typically involve an inherited deficiency of an enzyme that is important for the metabolism of a particular amino acid (Table 40-1). The concentration of that amino acid and its metabolites consequently rise sharply in blood, urine and body tissues, including the brain. When the enzymatic deficiency is nearly complete, the onset of disease tends to occur in infancy, even in the neonatal period. Partial enzyme deficiencies may not become apparent until later in life [1,2]. 

Cultured fibroblasts or amniocytes can be probed with FAO substrates and carnitine. Cell cultures deficient of an FAO enzyme will accumulate specific acylcarni-tine species when incubated with substrates such as palmitate, allowing for the diagnosis of FAO disorders [28-37]. Modifications of this assay system have also been developed for the diagnosis of defects affecting the metabolism of branched-chain amino acids [20, 31, 34]. Recently, this approach was also adapted for the study of peripheral blood mononuclear cells [38]. 

Diet. The constituents and amount of food (deficiency/starvation) may influence disposition and hence toxicity of chemicals. Food constituents may be enzyme inducers or inhibitors. Lack of food or specific constituents (e.g., protein or vitamins) may decrease metabolic capability, for example, a protein-deficient diet decreases cytochrome P-450 activity. Lack of sulfur amino acids decreases glutathione level. The effect on toxicity will depend on the role of metabolism. 

Maple syrup urine disease (MSUD) is a recessive disorder in which there is a partial or complete deficiency in branched-chain o-ketoacid dehydrogenase, an enzyme that decarboxylates leucine, isoleucine, and valine (see Figure 20.10). These amino acids and their corre sponding a-keto acids accumulate in the blood, causing a toxic effect that interferes with brain functions. The disease is characterized by feeding problems, vomiting, dehydration, severe metabolic acidosis, and a characteristic maple syrup odor to the urine. If untreated, the disease leads to mental retardation, physical disabilities, and death. 

Disturbances in the metabolism of amino acids occur mainly with the aromatic amino acids, such as phenylalanine and tyrosine. The error may be caused by the deficiency of a specific enzyme, a defect in the enzyme itself, or by the absence of factors necessary for the proper function of the enzyme. 

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