Creatine and Creatinine Metabolism - Physiological Reviews

1110 MARKUS WYSS AND RIMA KADDURAH-DAOUK Volume 80
system in endurance-type tissues (524, 837, 964). Therefore,
the buffer and transport models for CK function
should be regarded neither as strictly true nor as static
views that can be applied directly to any one tissue;
rather, the CK system displays a high degree of flexibility
and is able to adapt to the peculiar physiological requirements
of a given tissue. In skeletal muscle, for example,
an adaptation of the CK system from a more buffer to a
more transport type can be induced by endurance training
or by chronic electrical stimulation (26, 861).
PCr and Cr, relative to ATP and ADP, are smaller and
less negatively charged molecules and can build up to
much higher concentrations in most CK-containing cells
and tissues, thereby allowing for a higher intracellular
flux of high-energy phosphates. Furthermore, the change
in free energy (�G°�) (pH 7.0) for the hydrolysis of PCr is
�45.0 kJ/mol compared with �31.8 kJ/mol for ATP, implying
that in tissues with an active CK system, the cytosolic
phosphorylation potential can be buffered at a
higher level than in tissues devoid of the CK system. This
factor may, again, be essential for the proper functioning
of at least some cellular ATPases, e.g., the Ca 2� -ATPase of
the SR (see Ref. 646). Finally, by keeping [ADP] low, the
CK/PCr/Cr system may also protect the cell from a net
loss of adenine nucleotides via adenylate kinase, AMP
deaminase, and 5�-nucleotidase.
IV. CREATINE METABOLISM IN VERTEBRATES
Although the pathways of Cr metabolism in vertebrates
seem simple (Fig. 2), the situation is complicated
FIG. 2. Schematic representation of the reactions
and enzymes involved in vertebrate creatine
and creatinine metabolism. The respective enzymes
are denoted by numbers: 1) L-arginine:glycine
amidinotransferase (AGAT; EC 2.1.4.1); 2) S-adenosyl-L-methionine:N-guanidinoacetatemethyltransferase
(GAMT; EC 2.1.1.2); 3) creatine kinase (CK;
EC 2.7.3.2); 4) arginase (L-arginine amidinohydrolase;
EC 3.5.3.1); 5) ornithine carbamoyltransferase
(EC 2.1.3.3); 6) argininosuccinate synthase (EC
6.3.4.5); 7) argininosuccinate lyase (EC 4.3.2.1); 8)
L-ornithine:2-oxo-acid aminotransferase (OAT; EC
2.6.1.13); N) nonenzymatic reaction.