Muscle, purine metabolism

Uric acid is the end product of the purine metabolism. When uric acid excretion via the kidneys is disturbed, gout can develop (see p. 190). Creatinine is derived from the muscle metabolism, where it arises spontaneously and irreversibly by cyclization of creatine and creatine phosphate (see p. 336). Since the amount of creatinine an individual excretes per day is constant (it is directly proportional to muscle mass), creatinine as an endogenous substance can be used to measure the glomerular filtration rate. The amount of amino acids excreted in free form is strongly dependent on the diet and on the ef ciency of liver function. Amino acid derivatives are also found in the urine (e.g., hippu-rate, a detoxification product of benzoic acid). 

Muscle can metabolize AMP by using the purine nucleotide cycle. The initial step in this cycle, catalyzed by AMP deaminase, is the conversion of AMP into IMP. 

Role of purine nucleotides in muscle energy metabolism. The conversion of AMP to IMP prevents loss of adenosine from the cell. 

Occurrence In small amounts in muscles, liver, urinary calculi, beet juice, barley shoots, fly agarics, peanut kernels, potatoes, yeasts, coffee beans, tea leaves. X. is formed in the metabolism of higher animals by deamination of guanine (component of nucleic acid) or oxidation of hypoxanthine by xanthine oxidase present in muscles which then also oxidizes X. further to uric acid, the final product of the purine metabolism in humans. The nucleoside derived from X. is xanthosine. Although X. is chemically closely related to "caffein(e) and other methylxanthines, its activity is different. Stimulation of the central nervous system is less pronounced, the paralyzing effects dominate, and cardiac muscles are severely damaged. 

At previous meetings there have been pointers implicating purine metabolism in relation to normal cardiac and skeletal muscle function. During the present meeting much new data on both issues have been reported which indicate clear differences in the pathways of ATP metabolism. The widening of the field of interest is also illustrated by the recent work on infectious disease exploitation of the differences in purine metabolic pathways in certain parasites compared with those in human cells has resulted in new rationales for therapy being developed. 

Deficiency of the muscle-specific myoadenylate deaminase (MADA) is a frequent cause of exercise-related myopathy and is thought to be the most common cause of metabolic myopathy. MADA catalyzes the deamination of AMP to IMP in skeletal muscle and is critical in the purine nucleotide cycle. It is estimated that about 1-2% of all muscle biopsies submitted to medical centers for pathologic examination are deficient in AMP deaminase enzyme activity. MADA is 10 times higher in skeletal muscle than in any other tissue. Increase in plasma ammonia (relative to lactate) after ischemic exercise of the forearm may be low in this disorder, which is a useful clinical diagnostic test in patients with exercise-induced myalgia... 

The major bases found in nucleic acids are adenine and guanine (purines) and uracil, cytosine, and thymine (pyrimidines). Thymine is found primarily in DNA, uracil in RNA, and the others in both DNA and RNA. Their structures, along with their chemical parent compounds, purine and pyrimidine, are shown in Figure 10.1, which also indicates other biologically important purines that are not components of nucleic acids. Hypoxanthine, orotic acid, and xanthine are biosynthetic and/or degradation intermediates of purine and pyrimidine bases, whereas xanthine derivatives—caffeine, theophylline, and theobromine—are alkaloids from plant sources. Caffeine is a component of coffee beans and tea, and its effects on metabolism are mentioned in Chapter 16. Theophylline is found in tea and is used therapeutically in asthma, because it is a smooth muscle relaxant. Theobromine is found in chocolate. It is a diuretic, heart stimulant, and vasodilator. 

Hitchings interest in nucleic acids stemmed from his work at Harvard with Cyrus J. Fiske who had discovered ATP in muscle. The development of micro-analytical methods for the purine bases to follow the metabolism of ATP was the theme of Hitchings doctoral thesis. After completion of his PhD in 1933, during the depths of the depression, he experienced a nine-year period of impermanence both financial and intellectual with short appointments at Harvard s C. P. Huntington Laboratories in cancer... 

Reichmann, H. DeVivo, D.C. (1991) Comp. Biochem. Physiol. 98R 327-331. Coordinate enzymatic activity of beta-oxidation and purine nucleotide cycle in a diversity of muscle and other organs of rat. Melde, K., Jackson, S., Bartlett, K., Sherratt, H.S.A. Ghisla, S. 99 )Biochem. J. 274,395-400. Metabolic consequences of methylenecyclopropylglycine poisoning in rats. 

The regulation of mammalian adenylosuccinate synthetase is complicated. It is dependent on the isozyme content and levels in a given tissue as well as the effects of substrate and product levels. The two isozymes may have different metabolic roles either in AMP biosynthesis and interconversion, or in the functions of the purine nucleotide cycle. Most studies have considered kinetic parameters for the isolated enzyme and in only a few instances has regulation been studied in vivo. Sufficient information is available concerning the regulation of the basic isozyme in muscle to consider that enzyme in detail. Factors controlling the acidic isozyme are less clearly defined. 

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