Alanine blood concentration

The major role of skeletal muscle is movement, which is described and discussed in Chapter 13). Nevertheless, since muscle comprises 40% of the body it is large enough to play a part in control of the blood concentrations of the major fuels glucose, fatty acids, triacylglycerol and some amino acids. Skeletal muscle contains the largest quantity of protein in the body, which is used as a source of amino acids under various conditions (e.g. starvation, trauma, cancer see above). It plays an important part in the metabolism, in particular, of branched-chain amino acids, glutamine and alanine, which are important in the overall metabolism of amino acids in the body (discussed below). 

PDH deficiency results in raised blood concentrations of pyruvate, lactate and alanine. Some patients respond to supplementation with lipoic acid or thiamin (coenzymes for PDH). Treatment with a low carbohydrate, ketogenic diet has been advocated but with limited success. (The ketone bodies readily cross the blood-brain barrier and their catabolism produces acetyl CoA independently of PDH.)... 

Most patients with pyruvate-carboxylase deficiency present with failure to thrive, developmental delay, recurrent seizures and metabolic acidosis. Lactate, pyruvate, alanine, [3-hydroxybutyrate and acetoacetate concentrations are elevated in blood and urine. Hypoglycemia is not a consistent finding despite the fact that pyruvate carboxylase is the first rate-limiting step in gluconeogenesis. 

Muscle protein catabolism generates amino acids some of which may be oxidized within the muscle. Alanine released from muscle protein or which has been synthesized from pyruvate via transamination, passes into the blood stream and is delivered to the liver. Transamination in the liver converts alanine back into pyruvate which is in turn used to synthesise glucose the glucose is exported to tissues via the blood. This is the glucose-alanine cycle (Figure 7.11). In effect, muscle protein is sacrificed in order to maintain blood adequate glucose concentrations to sustain metabolism of red cells and the central nervous system. 

Amino groups released by deamination reactions form ammonium ion (NH " ), which must not escape into the peripheral blood. An elevated concentration of ammonium ion in the blood, hyperammonemia, has toxic effects in the brain (cerebral edema, convulsions, coma, and death). Most tissues add excess nitrogen to the blood as glutamine. Muscle sends nitrogen to the liver as alanine and smaller quantities of other amino acids, in addition to glutamine. Figure I-17-1 summarizes the flow of nitrogen from tissues to either the liver or kidney for excretion. The reactions catalyzed by four major enzymes or classes of enzymes involved in this process are summarized in Table T17-1. 

Alanine and Glutamine in the Blood Normal human blood plasma contains all the amino acids required for the synthesis of body proteins, but not in equal concentrations. Alanine and glutamine are present in much higher concentrations than any other amino acids. Suggest why. 

Pyruvate kinase catalyzes the third irreversible step in glycolysis. It is activated by fructose 1,6-bisphosphate. ATP and the amino acid alanine allosterically inhibit the enzyme so that glycolysis slows when supplies of ATP and biosynthetic precursors (indicated by the levels of Ala) are already sufficiently high. In addition, in a control similar to that for PFK (see above), when the blood glucose concentration is low, glucagon is released and stimulates phosphorylation of the enzyme via a cAMP cascade (see Topic J7). This covalent modification inhibits the enzyme so that glycolysis slows down in times of low blood glucose levels. 

High Blood Alanine Level Associated with Defects in Oxidative Phosphorylation Most individuals with genetic defects in oxidative phosphorylation are found to have relatively high concentrations of alanine in their blood. Explain this in biochemical terms. 

Answer In these individuals, the usual route for pyruvate metabolism—conversion to acetyl-CoA and entry into the citric acid cycle—is slowed by the decreased capacity for carrying electrons from NADH to oxygen. Accumulation of pyruvate in the tissues shifts the equilibrium for pyruvate-alanine transaminase, resulting in elevated concentrations of alanine in tissues and blood. 

A 23-year-old Asian butcher developed diffuse abdominal pain, vomiting, and diarrhea, followed by constipation (4). He had a sinus tachycardia and generalized abdominal tenderness without peritonism. His serum bilirubin concentration and alanine transaminase activity were raised, but alkaline phosphatase activity, albumin concentration, and prothrombin time were normal. He had a blood lead concentration of 767 ng/ml and a raised zinc protoporphyrin concentration, diagnostic of lead poisoning. He had taken an herbal medicine, purchased in India, for vague aU-ments. He stopped taking it, and 3 months later was asymptomatic, with normal liver function tests and marked falls in blood lead (387 ng/ml) and zinc protoporphyrin. 

Plasma A77 1726 concentrations can be measured by high-performance liquid chromatography (99,100). Monitoring of platelets, white blood cells, hemoglobin, and alanine transaminase activity is advised at baseline, monthly for 6 months, and every 6-8 weeks thereafter. Leflunomide should be withdrawn if pulmonary symptoms such as cough and dyspnea start or worsen (80). 

The breakdown of fat leads to a transient increase in body water. Normally, however, an osmotic diuresis soon reduces the blood volume even though glomerular filtration may be impaired, as demonstrated by increased serum creatinine concentration and reduced creatinine clearance. Hepatic blood supply may also be reduced. BSP retention is increased, and the serum bilirubin rises the unconjugated bilirubin more than doubles within 48 hours. Increased serum activities of aspartate and alanine aminotransferase and of lactate dehydrogenase are observed. The enzyme changes may be linked more to focal necrosis of the liver than to general circulatory impairment. 

Within a few minutes of an infant s birth, fluid passes from the blood vessels into the extravascular spaces. This fluid is similar to plasma except that the fluid lost from the intravascular space contains no protein. Consequently the plasma protein concentration increases. The serum activities of several eu2ymes, including CK, GGT, and AST, are high at birth, but the increase of alanine aminotransferase (ALT) activity is less than that of other enzymes. 

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