Futile cycle

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A futile cycle, also known as a substrate cycle, occurs when two metabolic pathways run simultaneously in opposite directions and have no overall effect other than to dissipate energy in the form of heat. [1] The reason this cycle was called "futile" cycle was because it appeared that this cycle operated with no net utility for the organism. As such, it was thought of being a quirk of the metabolism and thus named a futile cycle. After further investigation it was seen that futile cycles are very important for regulating the concentrations of metabolites. [2] For example, if glycolysis and gluconeogenesis were to be active at the same time, glucose would be converted to pyruvate by glycolysis and then converted back to glucose by gluconeogenesis, with an overall consumption of ATP. [3] Futile cycles may have a role in metabolic regulation, where a futile cycle would be a system oscillating between two states and very sensitive to small changes in the activity of any of the enzymes involved. [4] The cycle does generate heat, and may be used to maintain thermal homeostasis, for example in the brown adipose tissue of young mammals, or to generate heat rapidly, for example in insect flight muscles and in hibernating animals during periodical arousal from torpor. It has been reported that the glucose metabolism substrate cycle is not a futile cycle but a regulatory process. For example, when energy is suddenly needed, ATP is replaced by AMP, a much more reactive adenine.

Contents

Example

The simultaneous carrying out of glycolysis and gluconeogenesis is an example of a futile cycle, represented by the following equation:

ATP + H2O ADP + Pi + H

For example, during glycolysis, fructose-6-phosphate is converted to fructose-1,6-bisphosphate in a reaction catalysed by the enzyme phosphofructokinase 1 (PFK-1).

ATP + fructose-6-phosphate → Fructose-1,6-bisphosphate + ADP

But during gluconeogenesis (i.e. synthesis of glucose from pyruvate and other compounds) the reverse reaction takes place, being catalyzed by fructose-1,6-bisphosphatase (FBPase-1).

Fructose-1,6-bisphosphate + H2O → fructose-6-phosphate + Pi

Giving an overall reaction of:

ATP + H2O → ADP + Pi + Heat

That is, hydrolysis of ATP without any useful metabolic work being done. Clearly, if these two reactions were allowed to proceed simultaneously at a high rate in the same cell, a large amount of chemical energy would be dissipated as heat. This uneconomical process has therefore been called a futile cycle. [5]

Futile Cycle's role in Obesity and Homeostasis

There are not many drugs that can effectively treat or reverse obesity. Obesity can increase ones risk of diseases primarily linked to health problems such as diabetes, hypertension, cardiovascular disease and even certain types of cancers. A study revolving around treatment and prevention of obesity using transgenic mice to experiment on reports positive feedback that proposes miR-378 may sure be a promising agent for preventing and treating obesity in humans. The study findings demonstrate that activation of the pyruvate-PEP futile cycle in skeletal muscle through miR-378 is the primary cause of elevated lipolysis in adipose tissues of miR-378 transgenic mice, and it helps orchestrate the crosstalk between muscle and fat to control energy homeostasis in mice. [6]

Our general understanding of futile cycle is a substrate cycle, occurring when two overlapping metabolic pathways run in opposite directions, that when left without regulation will continue to go on uncontrolled without any actual production until all the cells energy is depleted. However, the idea behind the study indicates miR-378-activated pyruvate-phosphoenolpyruvate futile cycle plays a regulatory benefit. [6] Not only does miR-378 result in lower body fat mass due to enhanced lipolysis it is also speculated that futile cycles regulate metabolism to maintain energy homeostasis. miR-378 has a unique function in regulating metabolic communication between the muscle and adipose tissues to control energy homeostasis at whole-body levels. [6]

Examples of futile cycle operating in different species

To understand how presence of a futile cycle helps maintain low levels of ATP and generation heat in some species we look at metabolic pathways dealing with reciprocal regulation of glycolysis and gluconeogenesis.

The swim bladder of many fish; such as zebrafish for example - is an organ internally filled with gas that helps contribute to their buoyancy. These gas gland cell are found to be located where the capillaries and nerves are found. Analyses of metabolic enzymes demonstrated that a gluconeogenesis enzyme fructose-1,6- bisphosphatase (Fbp1) and a glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (Gapdh) are highly expressed in gas gland cells. [7] The study signified that the characterization of the zebrafish swim bladder should not contain any expression fructose-1,6-bisphosphatase gene. The tissue of the swim bladder is known to be very high in glycogenic activity and lacking in gluconeogenesis, yet a predominant amount of Fbp was found to be expressed. This finding suggests that in the gas gland cell, Fbp forms an ATP-dependent metabolic futile cycle. Generation of heat is critically important for the gas gland cells to synthesize lactic acid because the process is strongly inhibited if ATP is accumulated.

Another example suggest that heat generation in fugu swim bladder will be transported out of the site of generation, however it may still be constantly recovered back through the rete mirabile so as to maintain the temperature of the gas gland higher than other areas of the body.

The overall net reaction of the futile cycle involves the consumption of ATP and generation of heat as follows:

ATP + H2O → ADP + Pi + Heat

Another example of futile cycle benefiting in generation of heat is found in bumblebees. The futile cycle involving Fbp and Pfk is used by bumble bees to produce heat in flight muscles and warm up their bodies considerably at low ambient temperatures. [7]

Related Research Articles

<span class="mw-page-title-main">Glycolysis</span> Series of interconnected biochemical reactions

Glycolysis is the metabolic pathway that converts glucose into pyruvate and, in most organisms, occurs in the liquid part of cells. The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.

<span class="mw-page-title-main">Metabolic pathway</span> Linked series of chemical reactions occurring within a cell

In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reactions catalyzed by enzymes. In most cases of a metabolic pathway, the product of one enzyme acts as the substrate for the next. However, side products are considered waste and removed from the cell.

<span class="mw-page-title-main">Cellular respiration</span> Process to convert glucose to ATP in cells

Cellular respiration is the process by which biological fuels are oxidized in the presence of an inorganic electron acceptor, such as oxygen, to drive the bulk production of adenosine triphosphate (ATP), which contains energy. Cellular respiration may be described as a set of metabolic reactions and processes that take place in the cells of organisms to convert chemical energy from nutrients into ATP, and then release waste products.

<span class="mw-page-title-main">Anabolism</span> Metabolic pathways to build molecules

Anabolism is the set of metabolic pathways that construct macromolecules like DNA or RNA from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breaking-down aspect. Anabolism is usually synonymous with biosynthesis.

Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

<span class="mw-page-title-main">Fructose 1,6-bisphosphatase</span> Class of enzymes

The enzyme fructose bisphosphatase (EC 3.1.3.11; systematic name D-fructose-1,6-bisphosphate 1-phosphohydrolase) catalyses the conversion of fructose-1,6-bisphosphate to fructose 6-phosphate in gluconeogenesis and the Calvin cycle, which are both anabolic pathways:

<span class="mw-page-title-main">Fructose bisphosphatase deficiency</span> Medical condition

In fructose bisphosphatase deficiency, there is not enough fructose bisphosphatase for gluconeogenesis to occur correctly. Glycolysis will still work, as it does not use this enzyme.

Carbohydrate metabolism is the whole of the biochemical processes responsible for the metabolic formation, breakdown, and interconversion of carbohydrates in living organisms.

<span class="mw-page-title-main">Phosphofructokinase 1</span> Class of enzymes

Phosphofructokinase-1 (PFK-1) is one of the most important regulatory enzymes of glycolysis. It is an allosteric enzyme made of 4 subunits and controlled by many activators and inhibitors. PFK-1 catalyzes the important "committed" step of glycolysis, the conversion of fructose 6-phosphate and ATP to fructose 1,6-bisphosphate and ADP. Glycolysis is the foundation for respiration, both anaerobic and aerobic. Because phosphofructokinase (PFK) catalyzes the ATP-dependent phosphorylation to convert fructose-6-phosphate into fructose 1,6-bisphosphate and ADP, it is one of the key regulatory steps of glycolysis. PFK is able to regulate glycolysis through allosteric inhibition, and in this way, the cell can increase or decrease the rate of glycolysis in response to the cell's energy requirements. For example, a high ratio of ATP to ADP will inhibit PFK and glycolysis. The key difference between the regulation of PFK in eukaryotes and prokaryotes is that in eukaryotes PFK is activated by fructose 2,6-bisphosphate. The purpose of fructose 2,6-bisphosphate is to supersede ATP inhibition, thus allowing eukaryotes to have greater sensitivity to regulation by hormones like glucagon and insulin.

<span class="mw-page-title-main">Pyruvate kinase</span> Class of enzymes

Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Pyruvate kinase was inappropriately named before it was recognized that it did not directly catalyze phosphorylation of pyruvate, which does not occur under physiological conditions. Pyruvate kinase is present in four distinct, tissue-specific isozymes in animals, each consisting of particular kinetic properties necessary to accommodate the variations in metabolic requirements of diverse tissues.

<span class="mw-page-title-main">Glucose 6-phosphate</span> Chemical compound

Glucose 6-phosphate is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cells as the majority of glucose entering a cell will become phosphorylated in this way.

<span class="mw-page-title-main">Pyruvate carboxylase</span> Enzyme

Pyruvate carboxylase (PC) encoded by the gene PC is an enzyme of the ligase class that catalyzes the physiologically irreversible carboxylation of pyruvate to form oxaloacetate (OAA).

<span class="mw-page-title-main">Sugar phosphates</span>

Sugar phosphates are often used in biological systems to store or transfer energy. They also form the backbone for DNA and RNA. Sugar phosphate backbone geometry is altered in the vicinity of the modified nucleotides.

<span class="mw-page-title-main">Fructose 2,6-bisphosphate</span> Chemical compound

Fructose 2,6-bisphosphate, abbreviated Fru-2,6-P2, is a metabolite that allosterically affects the activity of the enzymes phosphofructokinase 1 (PFK-1) and fructose 1,6-bisphosphatase (FBPase-1) to regulate glycolysis and gluconeogenesis. Fru-2,6-P2 itself is synthesized and broken down in either direction by the integrated bifunctional enzyme phosphofructokinase 2 (PFK-2/FBPase-2), which also contains a phosphatase domain and is also known as fructose-2,6-bisphosphatase. Whether the kinase and phosphatase domains of PFK-2/FBPase-2 are active or inactive depends on the phosphorylation state of the enzyme.

<span class="mw-page-title-main">Fructose-bisphosphate aldolase</span>

Fructose-bisphosphate aldolase, often just aldolase, is an enzyme catalyzing a reversible reaction that splits the aldol, fructose 1,6-bisphosphate, into the triose phosphates dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (G3P). Aldolase can also produce DHAP from other (3S,4R)-ketose 1-phosphates such as fructose 1-phosphate and sedoheptulose 1,7-bisphosphate. Gluconeogenesis and the Calvin cycle, which are anabolic pathways, use the reverse reaction. Glycolysis, a catabolic pathway, uses the forward reaction. Aldolase is divided into two classes by mechanism.

Glucose-1,6-bisphosphate synthase is a type of enzyme called a phosphotransferase and is involved in mammalian starch and sucrose metabolism. It catalyzes the transfer of a phosphate group from 1,3-bisphosphoglycerate to glucose-1-phosphate, yielding 3-phosphoglycerate and glucose-1,6-bisphosphate.

<span class="mw-page-title-main">Inborn errors of carbohydrate metabolism</span> Medical condition

Inborn errors of carbohydrate metabolism are inborn error of metabolism that affect the catabolism and anabolism of carbohydrates.

Bisphosphate may refer to:

Glyceroneogenesis is a metabolic pathway which synthesizes glycerol 3-phosphate from precursors other than glucose. Usually, glycerol 3-phosphate is generated from glucose by glycolysis, in the liquid of the cell's cytoplasm. Glyceroneogenesis is used when the concentrations of glucose in the cytosol are low, and typically uses pyruvate as the precursor, but can also use alanine, glutamine, or any substances from the TCA cycle. The main regulator enzyme for this pathway is an enzyme called phosphoenolpyruvate carboxykinase (PEPC-K), which catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. Glyceroneogenesis is observed mainly in adipose tissue, and in the liver. A significant biochemical pathway regulates cytosolic lipid levels. Intense suppression of glyceroneogenesis may lead to metabolic disorders such as type 2 diabetes.

<span class="mw-page-title-main">TP53-inducible glycolysis and apoptosis regulator</span> Protein-coding gene in the species Homo sapiens

The TP53-inducible glycolysis and apoptosis regulator (TIGAR) also known as fructose-2,6-bisphosphatase TIGAR is an enzyme that in humans is encoded by the C12orf5 gene.

References

  1. ↑ Schwender J, Ohlrogge J, Shachar-Hill Y (2004). "Understanding flux in plant metabolic networks". Curr Opin Plant Biol. 7 (3): 309–17. doi:10.1016/j.pbi.2004.03.016. PMID   15134752.
  2. ↑ H., Garrett, Reginald (2016-02-11). Biochemistry. Grisham, Charles M. (Sixth ed.). Boston, MA. p. 767. ISBN   9781305577206. OCLC   914290655.{{cite book}}: CS1 maint: location missing publisher (link) CS1 maint: multiple names: authors list (link)
  3. ↑ Boiteux A, Hess B (1981). "Design of glycolysis". Philos Trans R Soc Lond B Biol Sci. 293 (1063): 5–22. Bibcode:1981RSPTB.293....5B. doi:10.1098/rstb.1981.0056. PMID   6115423.
  4. ↑ Samoilov M, Plyasunov S, Arkin A (2005). "Stochastic amplification and signaling in enzymatic futile cycles through noise-induced bistability with oscillations". Proc Natl Acad Sci USA. 102 (7): 2310–5. Bibcode:2005PNAS..102.2310S. doi: 10.1073/pnas.0406841102 . PMC   548975 . PMID   15701703.
  5. ↑ Nelson, D. L., Lehninger, A. L., & Cox, M. M. (2008). Lehninger principles of biochemistry (5th ed., pp. 582-583). New York: W.H. Freeman.
  6. 1 2 3 Zhang, Yong; Li, Changyin; Li, Hu; Song, Yipeng; Zhao, Yixia; Zhai, Lili; Wang, Haixia; Zhong, Ran; Tang, Huiru; Zhu, Dahai (2016-03-01). "miR-378 Activates the Pyruvate-PEP Futile Cycle and Enhances Lipolysis to Ameliorate Obesity in Mice". eBioMedicine. 5: 93–104. doi: 10.1016/j.ebiom.2016.01.035 . ISSN   2352-3964. PMC   4816830 . PMID   27077116.
  7. 1 2 Munakata, Keijiro; Ookata, Kayoko; Doi, Hiroyuki; Baba, Otto; Terashima, Tatsuo; Hirose, Shigehisa; Kato, Akira (January 2012). "Histological demonstration of glucose transporters, fructose-1,6-bisphosphatase, and glycogen in gas gland cells of the swimbladder: Is a metabolic futile cycle operating?". Biochemical and Biophysical Research Communications. 417 (1): 564–569. doi:10.1016/j.bbrc.2011.12.006. ISSN   0006-291X. PMID   22177956.
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