Creatine and Creatinine Metabolism - Physiological Reviews

July 2000 CREATINE AND CREATININE METABOLISM 1109
sion and for references, see Refs. 837, 838, 1084, 1124). In
textbooks of biochemistry, the participation of the CK/
PCr/Cr system in energy metabolism is often neglected,
and it is tacitly assumed that high-energy phosphate transport
between sites of ATP production (mitochondria, glycolysis)
and ATP consumption (all sorts of cellular ATPases)
relies on diffusion of ATP and ADP alone. This
concept may reflect the situation in tissues devoid of CK
and PCr, like liver, but is clearly inadequate for CKcontaining
tissues with high and fluctuating energy demands
like skeletal or cardiac muscle, brain, retina, and
spermatozoa. In these latter tissues of mammals and
birds, four distinct types of CK subunits are expressed
species specifically, developmental stage specifically, and
tissue specifically. The cytosolic M-CK (M for muscle) and
B-CK (B for brain) subunits form dimeric molecules and
thus give rise to the MM-, MB-, and BB-CK isoenzymes.
The two mitochondrial CK isoforms, ubiquitous Mi-CK
and sarcomeric Mi-CK, are located in the mitochondrial
intermembrane space and form both homodimeric and
homooctameric molecules that are readily interconvertible.
All CK isoenzymes catalyze the reversible transfer of
the �-phosphate group of ATP to the guanidino group of
Cr to yield ADP and PCr (Fig. 1).
In fast-twitch skeletal muscles, a large pool of PCr is
available for immediate regeneration of ATP hydrolyzed
during short periods of intense work. Because of the high
cytosolic CK activity in these muscles, the CK reaction
remains in a near-equilibrium state, keeps [ADP] and
[ATP] almost constant (over several seconds), and thus
“buffers” the cytosolic phosphorylation potential that
seems to be crucial for the proper functioning of a variety
of cellular ATPases.
Heart, slow-twitch skeletal muscles, or spermatozoa,
on the other hand, depend on a more continuous delivery
of high-energy phosphates to the sites of ATP utilization.
According to the “transport” (“shuttle”) hypothesis for the
CK system, distinct CK isoenzymes are associated with
sites of ATP production (e.g., Mi-CK in the mitochondrial
intermembrane space) and ATP consumption [e.g., cytosolic
CK bound to the myofibrillar M line, the sarcoplasmic
reticulum (SR), or the plasma membrane] and fulfill
the function of a “transport device” for high-energy phosphates.
The �-phosphate group of ATP, synthesized
within the mitochondrial matrix, is transferred by Mi-CK
in the mitochondrial intermembrane space to Cr to yield
ADP plus PCr. ADP liberated by the Mi-CK reaction may
directly be transported back to the matrix where it is
rephosphorylated to ATP. PCr leaves the mitochondria
and diffuses through the cytosol to the sites of ATP
consumption. There cytosolic CK isoenzymes locally regenerate
ATP and thus warrant a high phosphorylation
potential in the intimate vicinity of the respective ATPases.
Cr thus liberated diffuses back to the mitochondria,
thereby closing the cycle. According to this hypothesis,
transport of high-energy phosphates between sites of ATP
production and ATP consumption is achieved mainly (but
not exclusively) by PCr and Cr. Whereas for the buffer
function, no Mi-CK isoenzyme is required, Mi-CK may be
a prerequisite for efficient transport of high-energy phosphates,
especially if diffusion of adenine nucleotides
across the outer mitochondrial membrane were limited
(see sect. IVB). In accordance with these ideas, the proportion
of Mi-CK seems to correlate with the oxidative
capacity of striated muscles. It is by far higher in heart (up
to 35% of total CK activity) than in fast-twitch skeletal
muscles (0.5–2%).
Although the shuttle hypothesis seems logical and
intelligible on first sight, there is an ongoing debate on
whether it accurately describes the function of the CK
FIG. 1. The creatine kinase (CK) reaction. PCr,
phosphorylcreatine; Cr, creatine.