Creatine and Creatinine Metabolism - Physiological Reviews

More documents

Recommendations

Info

1118 MARKUS WYSS AND RIMA KADDURAH-DAOUK Volume 80 replenished. The observed or suspected effects of an elevated serum [Cr], namely, to downregulate the expression and/or activity of AGAT and possibly also the Cr transporter, would therefore help to spare precursors of Cr (Arg, Gly, Met) and to maintain normal, steady levels of Cr and PCr in CK-containing tissues. As a consequence, the rate of Cr biosynthesis is highest in young, healthy, fast-growing vertebrates under anabolic conditions on a balanced, Cr-free diet (1077). VI. PHOSPHOCREATINE AND CREATINE AS PURPORTED ALLOSTERIC EFFECTORS In some recent articles (e.g., Refs. 92, 641, 1068), the opinion has still been expressed that Cr and PCr may act as allosteric regulators of cellular processes. As a matter of fact, a number of studies, mainly performed in the 1970s, seemed to demonstrate that physiological concentrations of PCr inhibit glycogen phosphorylase a, phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase, lactate dehydrogenase, AMP deaminase, and 5�-nucleotidase from a variety of species. Similarly, PCr was claimed to activate fructose-1,6diphosphatase from rabbit skeletal muscle, while phosphorylarginine was suggested to inhibit phosphofructokinase from oyster adductor muscle (for references see Refs. 207, 247, 580, 666, 834, 951, 1012, 1099). Subsequent studies, however, proved that inhibition of at least phosphofructokinase, pyruvate kinase, lactate dehydrogenase, AMP deaminase, and 5�-nucleotidase, but probably also of all other enzymes listed above, is not afforded by PCr itself; rather, these effects were due to contaminants present in the commercial preparations of PCr which, at that time, were no more than 62–75% pure (1099). The contaminating inhibitors were identified as inorganic pyrophosphate for AMP deaminase (1099) and oxalate for lactate dehydrogenase and pyruvate kinase (1012). When added to the bathing medium of differentiating skeletal and heart muscle cells in tissue culture, Cr increased rather specifically the rate of synthesis as well as the specific activity of myosin heavy chain (406, 1153). In slices of the rat neostriatum, Cr inhibited the GABAsynthesizing enzyme glutamate decarboxylase as well as the veratridine-induced release of GABA, but significant effects were only observed at an unphysiologically high Cr concentration of 25 mM (864). In rat basophilic leukemia cells, PCr was seen to stimulate phospholipase C activity (196). Finally, in cell-free extracts of white gastrocnemius, soleus, heart muscle, and liver of the rat, PCr affected the extent of phosphorylation of various proteins, in particular of phosphoglycerate mutase and of a 18-kDa protein (742). Again, these findings are unlikely to be due to direct allosteric effects of Cr and PCr but are probably mediated indirectly, e.g., via alterations of the energy status of particular microcompartments or whole cells (195, 563, 742, 1153). In the unicellular alga Gonyaulax polyedra, several functions show circadian rhythmicity, for example, cell division, photosynthesis, bioluminescence, motility, and pattern formation. If cultures of Gonyaulax are first grown under a 12:12-h light-dark cycle, and if the conditions are then changed to constant dim light, the circadian rhythmicity persists for several weeks. This condition is called free-running circadian rhythmicity, with its period � depending on the color and intensity of the constant dim light. Extracts of several eukaryotic organisms, including bovine and rat brain and muscle, shorten the period of the free-running circadian rhythms in Gonyaulax. The substance responsible for this effect was identified as Cr. In the micromolar range (2–20 �M), Cr accelerates the circadian clock by as much as 4 h/day (Fig. 6A) (816). The Cr effect on � is very pronounced in constant dim blue light, whereas it is virtually absent in constant dim red light (Fig. 6B) (817). This finding, together with other lines of evidence, suggests that Cr interferes with light transduction pathways and in particular with the pathway(s) coupled to blue-sensitive photoreceptors. In addition to its effect on �, Cr also affects light-induced phase changes of the circadian rhythmicity (817). A period-shortening substance with properties similar to Cr is present in extracts of Gonyaulax itself (816) and has been identified as gonyauline (S-methyl-cis-2-[methylthio]cyclopropanecarboxylic acid) (815). Its rather close structural similarity to Cr (Fig. 6C), the complete lack of Cr in extracts of Gonyaulax (815), as well as the indication that Cr is not active as such but has to be metabolized to exert its effects on the circadian rhythmicity (see Ref. 817) all suggest that, at least in algae, Cr itself is not a physiological component or modulator of the circadian clock. To conclude, the data suggesting that Cr and PCr act as direct (allosteric) regulators of cellular processes (other than the repression by Cr of AGAT and possibly also of the Cr transporter) must be treated with skepticism, at least until new, convincing data are presented. There may be four notable exceptions that deserve further attention: 1) PCr stimulates glutamate uptake into synaptic vesicles (1127; see also sect. IXG). A series of control experiments showed that the effect of PCr is not mediated indirectly via CK and ATP. Remarkably, PCr-stimulated glutamate uptake was even higher than that stimulated maximally by ATP. 2) PCr at relatively high concentrations of 10–60 mM was found to promote efficient endonucleolytic cleavage of mammalian precursor RNA in vitro (364), which is a prerequisite for subsequent poly(A) addition. Neither
July 2000 CREATINE AND CREATININE METABOLISM 1119 CK nor ATP was required for this effect, and ATP could in fact inhibit 3�-end cleavage. PCr was not hydrolyzed, suggesting that it may act as an allosteric regulator. Phosphorylarginine (PArg) had a similar effect, whereas Cr was ineffective. 3) AMP-activated protein kinase (AMPK) from rabbit skeletal muscle is inhibited by PCr, whereby it is not yet completely clear whether this effect is CK independent or not (774). In turn, AMPK inhibits CK by phosphorylation in vitro and in differentiated muscle cells, and it also activates fatty acid oxidation. These findings suggest that CK, AMPK, and fatty acid oxidation form an intricate regulatory network for meeting energy supply with energy demands. In transgenic mice lacking both M-CK and sarcomeric Mi-CK, due to permanently high levels of PCr even during exercise, AMPK most likely remains inactive and, thus, cannot switch on fatty acid oxidation (774). In fact, these mice are defective in lipid metabolism and show signs of impaired capacity to utilize fatty acids (938). 4) Cr has been identified as an essential cofactor of thiamine-diphosphate (TDP) kinase from pig skeletal muscle, with half-maximal stimulation of enzymatic activity being observed at a [Cr] of 0.2 mM FIG. 6. Effects of creatine and gonyauline on the period of free-running circadian rhythms in the unicellular marine alga Gonyaulax polyedra. A: effects of authentic natural gonyauline, synthetic gonyauline, and Cr on the bioluminescent glow rhythm of Gonyaulax. [Modified from Roenneberg et al. (815).] B: relationship between Cr concentration and period length �, under conditions of constant dim red or constant dim blue light. [Modified from Roenneberg and Taylor (817).] C: chemical structures of Cr and gonyauline. For further information see text. (881). In contrast, PCr, Crn, Arg, guanidinoacetic acid, and GPA had no effect on TDP kinase activity. VII. MICROBIAL CREATINE AND CREATININE DEGRADATION PATHWAYS In contrast to the nonenzymatic conversion of Cr and PCr to Crn in vertebrates, a growing number of microorganisms are being discovered to express specific enzymes for the degradation of Cr and Crn. Several lines of evidence suggest an involvement of microbial Cr and Crn degradation in vertebrate physiology and pathology. Bacteria and fungi capable of degrading Cr and Crn have been identified in chicken and pigeon droppings (278, 772), human urine (499) and feces (204, 992, 1029), as well as the bacterial flora of the human colon (204, 439). The latter bacteria may be particularly relevant to renal disease (see sect. IXH). In uremic patients in whom [Crn] in the serum is highly increased (163), Crn was suggested to diffuse into the intestinal tract where it induces bacterial creatininase, creatinase, and Crn deaminase activity, resulting ultimately in the breakdown of part of the body’s Crn pool (439, 438) as well as in partial recycling of Cr (652).
Page 1 and 2: PHYSIOLOGICAL REVIEWS Vol. 80, No.
Page 3 and 4: July 2000 CREATINE AND CREATININE M
Page 11: July 2000 CREATINE AND CREATININE M
Page 63 and 64:
July 2000 CREATINE AND CREATININE M
Page 65 and 66:
Page 67 and 68:
Page 69 and 70:
Page 71 and 72:
Page 73 and 74:
Page 75 and 76:
Page 77 and 78:
Page 79 and 80:
Page 81 and 82:
Page 83 and 84:
Page 85 and 86:
Page 87 and 88:
Page 89 and 90:
Page 91 and 92:
Page 93 and 94:
Page 95 and 96:
Page 97 and 98:
Page 99 and 100:
Page 101 and 102:
Page 103 and 104:
Page 105 and 106:
Page 107:
show all

Creatine and Creatinine Metabolism - Physiological Reviews

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?