Page last updated: 2024-10-24

futile creatine cycle

Definition

Target type: biologicalprocess

The phosphorylation and dephosphorylation of creatine in a futile cycle, which dissipates the high energy charge of phosphocreatine as heat without performing any mechanical or chemical work. The futile creatine cycle takes place in thermogenic fat cells and is part of adaptive thermogenesis. [PMID:33597756, PMID:33981039]

The futile creatine cycle, also known as the creatine kinase shuttle, is a metabolic pathway that involves the interconversion of creatine and phosphocreatine. This cycle plays a crucial role in energy homeostasis and muscle function. Here's a detailed breakdown of the process:

1. **Creatine Kinase Reaction:** The core of the futile creatine cycle is the reversible reaction catalyzed by creatine kinase (CK). CK exists in different isoforms, with CK-M (muscle) being the predominant form in skeletal muscle. The reaction involves the transfer of a phosphate group from phosphocreatine (PCr) to ADP, generating ATP and creatine (Cr).

2. **Energy Buffering:** PCr acts as a high-energy phosphate reservoir in muscle cells. During periods of high energy demand, such as intense exercise, the CK reaction rapidly produces ATP to fuel muscle contraction. This rapid ATP generation ensures sustained muscle activity by buffering the decline in ATP levels.

3. **Recharging PCr:** During rest or periods of low energy demand, the CK reaction proceeds in the reverse direction. ATP is used to phosphorylate creatine, regenerating PCr. This replenishes the PCr pool, preparing the muscle for subsequent bouts of activity.

4. **Futile Cycle:** The continuous interconversion of Cr and PCr by CK, although seemingly wasteful, plays an important role in regulating energy balance and cellular signaling. It is not truly futile because it serves several key functions:

- **Maintaining ATP homeostasis:** The CK reaction ensures a constant supply of ATP during periods of high energy demand, preventing ATP depletion and maintaining cellular function.
- **Thermogenesis:** The futile creatine cycle contributes to heat production in muscle tissue, particularly during cold stress.
- **Cellular signaling:** Changes in the Cr/PCr ratio can act as a signal for cellular responses, such as increased protein synthesis or glucose uptake.

5. **Implications:** Disruptions in the creatine cycle, often due to genetic mutations in CK or other related enzymes, can lead to various muscle disorders, including myopathies and muscular dystrophies.

The futile creatine cycle is a fascinating example of how seemingly simple metabolic pathways can play a vital role in maintaining cellular homeostasis and supporting complex physiological processes. '
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Proteins (2)

ProteinDefinitionTaxonomy
Alkaline phosphatase, tissue-nonspecific isozyme An alkaline phosphatase, tissue-nonspecific isozyme that is encoded in the genome of cow. [OMA:P09487, PRO:DNx]Bos taurus (cattle)
Alkaline phosphatase, tissue-nonspecific isozymeAn alkaline phosphatase, tissue-nonspecific isozyme that is encoded in the genome of human. [PRO:DNx, UniProtKB:P05186]Homo sapiens (human)

Compounds (14)

CompoundDefinitionClassesRoles
theophyllinedimethylxanthineadenosine receptor antagonist;
anti-asthmatic drug;
anti-inflammatory agent;
bronchodilator agent;
drug metabolite;
EC 3.1.4.* (phosphoric diester hydrolase) inhibitor;
fungal metabolite;
human blood serum metabolite;
immunomodulator;
muscle relaxant;
vasodilator agent
adenosine monophosphateAdenosine Monophosphate: Adenine nucleotide containing one phosphate group esterified to the sugar moiety in the 2'-, 3'-, or 5'-position.adenosine 5'-phosphate;
purine ribonucleoside 5'-monophosphate
adenosine A1 receptor agonist;
cofactor;
EC 3.1.3.1 (alkaline phosphatase) inhibitor;
EC 3.1.3.11 (fructose-bisphosphatase) inhibitor;
fundamental metabolite;
micronutrient;
nutraceutical
leucineleucine : A branched-chain amino acid that consists of glycine in which one of the hydrogens attached to the alpha-carbon is substituted by an isobutyl group.

Leucine: An essential branched-chain amino acid important for hemoglobin formation.
amino acid zwitterion;
L-alpha-amino acid;
leucine;
proteinogenic amino acid;
pyruvate family amino acid
algal metabolite;
Escherichia coli metabolite;
human metabolite;
mouse metabolite;
plant metabolite;
Saccharomyces cerevisiae metabolite
phenylalanineL-phenylalanine : The L-enantiomer of phenylalanine.

phenylalanine : An aromatic amino acid that is alanine in which one of the methyl hydrogens is substituted by a phenyl group.

Phenylalanine: An essential aromatic amino acid that is a precursor of MELANIN; DOPAMINE; noradrenalin (NOREPINEPHRINE), and THYROXINE.
amino acid zwitterion;
erythrose 4-phosphate/phosphoenolpyruvate family amino acid;
L-alpha-amino acid;
phenylalanine;
proteinogenic amino acid
algal metabolite;
EC 3.1.3.1 (alkaline phosphatase) inhibitor;
Escherichia coli metabolite;
human xenobiotic metabolite;
micronutrient;
mouse metabolite;
nutraceutical;
plant metabolite;
Saccharomyces cerevisiae metabolite
tryptophantryptophan : An alpha-amino acid that is alanine bearing an indol-3-yl substituent at position 3.

Tryptophan: An essential amino acid that is necessary for normal growth in infants and for NITROGEN balance in adults. It is a precursor of INDOLE ALKALOIDS in plants. It is a precursor of SEROTONIN (hence its use as an antidepressant and sleep aid). It can be a precursor to NIACIN, albeit inefficiently, in mammals.
erythrose 4-phosphate/phosphoenolpyruvate family amino acid;
L-alpha-amino acid;
L-alpha-amino acid zwitterion;
proteinogenic amino acid;
tryptophan;
tryptophan zwitterion
antidepressant;
Escherichia coli metabolite;
human metabolite;
micronutrient;
mouse metabolite;
nutraceutical;
plant metabolite;
Saccharomyces cerevisiae metabolite
homoarginineL-homoarginine : An L-lysine derivative that is the L-enantiomer of homoarginine.homoarginine;
L-lysine derivative;
non-proteinogenic L-alpha-amino acid
biomarker;
EC 3.1.3.1 (alkaline phosphatase) inhibitor;
human metabolite;
rat metabolite;
xenobiotic metabolite
levamisolelevamisole : A 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazole that has S configuration. It is used (generally as the monohydrochloride salt) to treat parasitic worm infections in pigs, sheep and cattle and was formerly used in humans as an adjuvant to chemotherapy for the treatment of various cancers. It is also widely used as an adulterant to coccaine.

Levamisole: An antihelminthic drug that has been tried experimentally in rheumatic disorders where it apparently restores the immune response by increasing macrophage chemotaxis and T-lymphocyte function. Paradoxically, this immune enhancement appears to be beneficial in rheumatoid arthritis where dermatitis, leukopenia, and thrombocytopenia, and nausea and vomiting have been reported as side effects. (From Smith and Reynard, Textbook of Pharmacology, 1991, p435-6)
6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b][1,3]thiazoleantinematodal drug;
antirheumatic drug;
EC 3.1.3.1 (alkaline phosphatase) inhibitor;
immunological adjuvant;
immunomodulator
levamisole hydrochlorideorganic molecular entity
1-(3,4-dihydroxyphenyl)-2-(1-imidazolyl)ethanonearomatic ketone
1-(3,4-dihydroxyphenyl)-2-[(4,6-dimethyl-2-pyrimidinyl)thio]ethanonearomatic ketone
2,5-dimethoxy-n-(quinolin-3-yl)benzenesulfonamide2,5-dimethoxy-N-(quinolin-3-yl)benzenesulfonamide: a tissue-nonspecific alkaline phosphatase inhibitor; structure in first sourcequinolines
3-nitrobenzaldehyde isonicotinoylhydrazone3-nitrobenzaldehyde isonicotinoylhydrazone: structure in first source
salinazidaromatic carboxylic acid;
pyridinemonocarboxylic acid
phthivazide