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# Overview of gluconeogenesis and its necessity Gluconeogenesis is the vital metabolic pathway responsible for synthesizing glucose from non-carbohydrate precursors, particularly crucial when dietary intake or glycogen stores are insufficient to meet the body's energy demands [7](#page=7) [8](#page=8). ### 1.1 The critical need for glucose The human body requires approximately 160 grams of glucose per day. While glycogen reserves can supply around 190 grams, and body fluids contribute about 20 grams, these stores are not always sufficient. Certain organs, including the brain, central nervous system, red blood cells, and kidney medulla, rely on glucose as their primary energy source, with the brain alone needing about 120 grams daily. This dependence makes maintaining blood glucose levels paramount [4](#page=4) [5](#page=5) [7](#page=7). ### 1.2 When glucose production is essential Gluconeogenesis becomes indispensable during periods when carbohydrate availability is low, such as: * **Strenuous exercise:** Glycogen stores are significantly depleted during intense physical activity [5](#page=5). * **Fasting:** After more than one day of fasting, all available glycogen stores are typically exhausted, necessitating the synthesis of new glucose [5](#page=5). In these critical situations, gluconeogenesis ensures a continuous supply of glucose to these essential organs, preventing severe consequences, including death, that would result from a failure of this pathway. The process serves to restore depleted glycogen reserves and sustain normal bodily functions [5](#page=5) [7](#page=7). ### 1.3 The mechanism of gluconeogenesis Gluconeogenesis is defined as the process of producing glucose or glycogen from non-carbohydrate precursors. It essentially allows the body to "create new glucose from the products of its breakdown". While gluconeogenesis utilizes many of the same enzymes as glycolysis, it is not a simple reversal of the glycolytic pathway due to significant energy barriers [7](#page=7) [8](#page=8). --- # Substrates and enzymatic pathways of gluconeogenesis Gluconeogenesis is a metabolic pathway that synthesizes glucose from non-carbohydrate precursors, occurring primarily in the liver and kidney [9](#page=9). ### 2.1 Occurrence and location of gluconeogenesis Gluconeogenesis primarily takes place in the liver, accounting for about 90% of the process, with the kidney contributing approximately 10%. Both the liver and kidney possess the enzyme glucose-6-phosphatase, which is crucial for releasing free glucose into the bloodstream. While very little gluconeogenesis occurs in the brain and muscle, the glucose produced by the liver and kidney is essential for these tissues to maintain their metabolic demands. The enzymatic machinery for gluconeogenesis is located in both the cytoplasm and the mitochondria [9](#page=9). ### 2.2 Substrates for gluconeogenesis Various non-carbohydrate molecules can serve as substrates for gluconeogenesis. These include [10](#page=10): * **Glucogenic amino acids:** These amino acids can be converted into intermediates of the TCA cycle or pyruvate, which can then be used for glucose synthesis [10](#page=10) [13](#page=13). * **Glycerol:** Derived from the breakdown of triglycerides, glycerol can enter the gluconeogenic pathway [10](#page=10) [12](#page=12). * **Odd-chain fatty acids:** Specifically, propionate, a three-carbon fatty acid, can be converted into succinyl CoA, an intermediate of the TCA cycle, and subsequently used for gluconeogenesis [10](#page=10). * **Lactate:** Produced during anaerobic glycolysis, especially in red blood cells and exercising skeletal muscle, lactate can be converted to pyruvate, a key gluconeogenic precursor [10](#page=10) [11](#page=11). * **Pyruvate:** The end product of glycolysis, pyruvate, is a direct substrate for gluconeogenesis [10](#page=10). It is important to note that fats, except for the glycerol backbone and odd-chain fatty acid fragments like propionate, cannot be used for gluconeogenesis as they are converted to acetyl-CoA, which cannot be replenished from oxaloacetate in mammals [15](#page=15). #### 2.2.1 Lactate as a substrate Lactate produced during anaerobic glycolysis in exercising muscles diffuses into the bloodstream and is transported to the liver. In the liver, lactate dehydrogenase converts lactate to pyruvate, a process that also produces NADH in the cytoplasm, which is important for the subsequent steps of gluconeogenesis [11](#page=11). #### 2.2.2 Glycerol as a substrate Glycerol, released from the hydrolysis of triglycerides, can be phosphorylated by glycerol kinase to glycerol-3-phosphate. This intermediate is then oxidized to dihydroxyacetone phosphate (DHAP), a molecule that can directly enter the gluconeogenic pathway [12](#page=12). #### 2.2.3 Amino acids as substrates Amino acids serve as gluconeogenic substrates through transamination reactions, where their amino group is transferred to $\alpha$-ketoglutarate, forming glutamate. The carbon skeletons of these amino acids are then converted into either pyruvate or intermediates of the TCA cycle. Different amino acids yield different products [13](#page=13): * Alanine, cysteine, glycine, serine, threonine yield pyruvate [15](#page=15). * Aspartate and asparagine yield oxaloacetate [15](#page=15). * Phenylalanine and tyrosine yield fumarate [15](#page=15). * Isoleucine, valine, and methionine yield succinyl CoA [15](#page=15). * Arginine, glutamate, glutamine, and histidine yield $\alpha$-ketoglutarate [15](#page=15). * Leucine, lysine, phenylalanine, tryptophan, and tyrosine yield acetoacetate and acetyl-CoA [15](#page=15). ### 2.3 Gluconeogenesis is not a simple reversal of glycolysis While gluconeogenesis converts pyruvate to glucose, it is not a direct reversal of glycolysis, which converts glucose to pyruvate. The overall free energy change ($\Delta G$) for glycolysis is highly negative (approximately -74 kJ/mol) indicating a strongly favorable process in the direction of glucose breakdown. The reverse reaction would have a positive $\Delta G$ (+74 kJ/mol), making it energetically unfavorable. To achieve a favorable $\Delta G$ for glucose synthesis, gluconeogenesis utilizes alternative enzymatic reactions to bypass three essentially irreversible steps of glycolysis [17](#page=17) [18](#page=18). These irreversible steps in glycolysis are: * Step 1: Glucose $\rightarrow$ Glucose-6-phosphate (catalyzed by hexokinase) * Step 3: Fructose-6-phosphate $\rightarrow$ Fructose-1,6-bisphosphate (catalyzed by phosphofructokinase) * Step 10: Phosphoenolpyruvate $\rightarrow$ Pyruvate (catalyzed by pyruvate kinase) Gluconeogenesis retains seven steps of glycolysis, specifically steps 2 and 4-9 [18](#page=18). ### 2.4 Bypass reactions in gluconeogenesis Gluconeogenesis circumvents the three irreversible steps of glycolysis by employing a distinct set of enzymes [19](#page=19) [20](#page=20). #### 2.4.1 Bypass of the pyruvate kinase step This bypass involves two sequential reactions: 1. **Pyruvate to oxaloacetate:** Pyruvate is first carboxylated to oxaloacetate. This reaction is catalyzed by **pyruvate carboxylase**, a mitochondrial enzyme that requires biotin as a cofactor [21](#page=21). $$ \text{pyruvate} + \text{ATP} + \text{CO}_2 + \text{H}_2\text{O} \rightarrow \text{oxaloacetate} + \text{ADP} + \text{Pi} + 2\text{H}^+ $$ Since oxaloacetate cannot be directly transported out of the mitochondria, it is reduced to malate by mitochondrial malate dehydrogenase, using NADH. Malate is then transported to the cytosol via the malate-aspartate shuttle, where it is re-oxidized to oxaloacetate by cytosolic NAD$^+$-linked malate dehydrogenase [22](#page=22). 2. **Oxaloacetate to phosphoenolpyruvate (PEP):** Oxaloacetate is then converted to PEP by **phosphoenolpyruvate carboxykinase (PEPCK)**. This reaction requires GTP (which is energetically equivalent to ATP) and involves decarboxylation, which helps to drive the reaction forward [28](#page=28). $$ \text{oxaloacetate} + \text{GTP} \rightarrow \text{Phosphoenolpyruvate} + \text{GDP} + \text{CO}_2 $$ #### 2.4.2 Bypass of the phosphofructokinase step The conversion of fructose-1,6-bisphosphate to fructose-6-phosphate is achieved through a simple hydrolytic reaction catalyzed by **fructose-1,6-bisphosphatase**. This enzyme is allosterically regulated, with citrate and ATP acting as activators, and fructose-2,6-bisphosphate and AMP as inhibitors [31](#page=31) [32](#page=32). $$ \text{fructose-1,6-bisP} + \text{H}_2\text{O} \rightarrow \text{fructose-6-P} + \text{Pi} $$ #### 2.4.3 Bypass of the hexokinase step The final bypass involves the dephosphorylation of glucose-6-phosphate to glucose, catalyzed by **glucose-6-phosphatase**. This enzyme requires Mg$^{2+}$ as a cofactor [33](#page=33). $$ \text{Glucose-6-P} + \text{H}_2\text{O} \rightarrow \text{glucose} + \text{Pi} $$ Glucose-6-phosphatase is primarily located in the endoplasmic reticulum (ER) of hepatocytes and kidney cells. This localization is crucial for the liver to release free glucose into the bloodstream. The system involves the transport of glucose-6-phosphate into the ER by transporter T1, its hydrolysis into glucose by the phosphatase, and the export of glucose and Pi to the cytosol by transporters T2 and T3, respectively. Glucose is then exported into circulation via GLUT2 transporters. Muscle cells, lacking glucose-6-phosphatase, direct glucose-6-phosphate towards glycogen synthesis [34](#page=34) [35](#page=35) [36](#page=36). > **Tip:** The reciprocal regulation of glycolysis and gluconeogenesis is essential for maintaining blood glucose homeostasis. When one pathway is active, the other is suppressed. --- # Metabolic cycles involving gluconeogenesis and its regulation This section explores the interconnectedness of gluconeogenesis with other metabolic pathways, specifically the Cori and Alanine cycles, and details the intricate regulatory mechanisms that govern its activity, emphasizing its reciprocal control with glycolysis. ### 3.1 Metabolic cycles involving gluconeogenesis Integrated metabolic pathways play a crucial role in maintaining glucose homeostasis, especially during periods of high energy demand or fasting. These cycles often involve the interconversion of glucose and its derivatives between different tissues, with the liver serving as a central hub for glucose production and recycling. #### 3.1.1 The Cori cycle The Cori cycle, also known as the lactate cycle, describes the metabolic pathway where lactate produced by anaerobic glycolysis in muscles is transported to the liver and converted back into glucose. This newly synthesized glucose is then released into the bloodstream to be utilized by the muscles and red blood cells [38](#page=38). * **Process:** * During vigorous exercise, muscles can experience oxygen shortage, leading to increased glycolysis and the subsequent production of lactate and NADH [37](#page=37). * NADH is re-oxidized by reducing pyruvate to lactate [37](#page=37). * Lactate is then transported from the muscles to the liver [37](#page=37). * In the liver, lactate is re-oxidized to pyruvate by lactate dehydrogenase (LDH) [37](#page=37). * This pyruvate then enters the gluconeogenic pathway in the liver to form glucose [37](#page=37) [38](#page=38). * The liver then supplies this glucose back to the muscles for continued energy production [37](#page=37). * **Significance:** The Cori cycle allows for the recycling of lactate, preventing its accumulation in muscles and ensuring a continuous supply of glucose for active tissues. It highlights the liver's role in supporting muscle function during exercise [37](#page=37) [38](#page=38). #### 3.1.2 The Alanine cycle (Cahill cycle) The Alanine cycle, also referred to as the Cahill cycle or the glucose-alanine cycle, involves the transport of amino groups and carbon skeletons from muscles to the liver. This cycle is less energetically efficient than the Cori cycle due to the involvement of urea synthesis [39](#page=39). * **Process:** * In muscles, amino groups are transferred from amino acids to pyruvate, forming L-alanine, catalyzed by alanine transaminase (ALT) [39](#page=39). * L-alanine is then transported to the liver [39](#page=39). * In the liver, the amino group of alanine enters the urea cycle for excretion [39](#page=39). * The remaining carbon skeleton is converted back to pyruvate, which can then be used for gluconeogenesis to produce glucose [39](#page=39). * **Significance:** The Alanine cycle provides a mechanism for the liver to obtain carbon skeletons for glucose synthesis from amino acids, particularly during fasting or starvation when protein breakdown in muscles increases. However, the energy cost associated with urea removal makes it less productive than the Cori cycle in terms of net ATP production [39](#page=39). ### 3.2 Regulation of gluconeogenesis The regulation of gluconeogenesis is critically important to maintain blood glucose levels and ensure a continuous supply of glucose for essential tissues like the brain and red blood cells. Its regulation is tightly coupled with glycolysis, ensuring that these opposing pathways are not active simultaneously, preventing a futile cycle of glucose synthesis and breakdown [38](#page=38) [41](#page=41). #### 3.2.1 Reciprocal control with glycolysis A fundamental principle of metabolic regulation is the reciprocal control between glycolysis and gluconeogenesis. This means that when glycolysis is stimulated, gluconeogenesis should be inhibited, and vice versa. This prevents the wasteful consumption of ATP and other high-energy molecules. The key regulated enzymes in glycolysis are often the same enzymes that are regulated in the reverse direction by gluconeogenesis [41](#page=41). * **High energy status:** When the cell's energy charge is high, indicated by high ATP and citrate levels, glycolysis is turned off, and intermediates are directed towards synthesis and storage, favoring gluconeogenesis [48](#page=48). * **Low energy status:** Conversely, when the energy charge is low, signaled by high AMP levels, glucose is rapidly degraded through glycolysis to generate ATP [48](#page=48). #### 3.2.2 Regulatory mechanisms The regulation of gluconeogenesis occurs through several interconnected mechanisms: ##### 3.2.2.1 Hormonal control Hormones play a pivotal role in regulating gluconeogenesis in response to the body's metabolic needs, particularly blood glucose levels [53](#page=53). * **Insulin:** Insulin levels rise after a meal when blood glucose is high. It promotes glucose uptake and utilization, and generally inhibits gluconeogenesis by suppressing the expression of key gluconeogenic enzymes. It also stimulates the expression of enzymes involved in glycolysis, such as phosphofructokinase [45](#page=45). * **Glucagon:** Glucagon levels rise during fasting or starvation when blood glucose is low. It stimulates gluconeogenesis in the liver by inhibiting the expression of glycolytic enzymes and promoting the synthesis of key gluconeogenic enzymes like phosphoenolpyruvate carboxykinase and fructose 1,6-bisphosphatase. Glucagon also increases the concentration of cyclic AMP (cAMP) [45](#page=45) [46](#page=46). * **Epinephrine:** Epinephrine, like glucagon, is released in response to low blood glucose. It also inhibits glycolysis and stimulates gluconeogenesis in the liver, partly by increasing cAMP levels [46](#page=46). ##### 3.2.2.2 Transcriptional control (Induction & Repression) This is a slower regulatory mechanism, taking hours to days, and involves altering the synthesis rates of key enzymes [45](#page=45). * **Insulin:** Stimulates the expression of enzymes like phosphofructokinase and pyruvate kinase [45](#page=45). * **Glucagon:** Inhibits the expression of glycolytic enzymes and stimulates the production of gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase and fructose 1,6-bisphosphatase [45](#page=45). ##### 3.2.2.3 Covalent modification by reversible phosphorylation This is a rapid regulatory process that allows for quick adjustments in enzyme activity [46](#page=46). * **Mechanism:** Hormones like glucagon and epinephrine, acting through cAMP, activate cAMP-dependent protein kinase. This kinase phosphorylates and can inactivate enzymes like pyruvate kinase. It also influences the concentration of fructose 2,6-bisphosphate, thereby regulating both glycolysis and gluconeogenesis [46](#page=46). ##### 3.2.2.4 Allosteric modification This is an instantaneous process where regulatory molecules bind to enzymes at sites other than the active site, altering their conformation and activity [47](#page=47). * **Role of Acetyl-CoA:** Acetyl-CoA acts as an allosteric activator of pyruvate carboxylase, a key enzyme in gluconeogenesis. This ensures that when acetyl-CoA is abundant (e.g., from fatty acid oxidation), oxaloacetate is readily produced, facilitating gluconeogenesis. The activation of pyruvate carboxylase and reciprocal inhibition of pyruvate dehydrogenase by acetyl-CoA also explains how fatty acid oxidation spares pyruvate oxidation and stimulates gluconeogenesis [47](#page=47). * **Role of ATP and AMP:** * **Phosphofructokinase-1 (PFK-1):** This enzyme, a key regulator of glycolysis, is allosterically activated by AMP and inhibited by ATP and citrate. AMP signals low energy charge, promoting glycolysis, while high ATP and citrate indicate abundant energy, inhibiting glycolysis [48](#page=48). * **Fructose 1,6-bisphosphatase:** This enzyme, key to gluconeogenesis, is inhibited by AMP and activated by citrate. High AMP inhibits gluconeogenesis, while high ATP and citrate promote it [48](#page=48). * **Pyruvate kinase:** High levels of ATP and alanine, signaling high energy charge, inhibit pyruvate kinase in the liver. ADP also inhibits phosphoenolpyruvate carboxykinase [49](#page=49). * **Overall:** Gluconeogenesis is favored when the cell is rich in biosynthetic precursors and ATP [49](#page=49). * **Role of Fructose 2,6-Bisphosphate (F2,6BP):** This molecule is a potent allosteric regulator that plays a central role in coordinating glycolysis and gluconeogenesis in the liver [50](#page=50). * **Activation:** F2,6BP is the most potent positive allosteric activator of phosphofructokinase-1 (PFK-1) and a strong inhibitor of fructose 1,6-bisphosphatase. It relieves ATP inhibition of PFK-1 and increases its affinity for fructose 6-phosphate. It inhibits fructose 1,6-bisphosphatase by increasing its $K_m$ for fructose 1,6-bisphosphate [50](#page=50). * **Synthesis and Breakdown:** F2,6BP is formed from fructose 6-phosphate by phosphofructokinase-2 (PFK-2) and degraded by fructose 2,6-bisphosphatase activity; both activities reside on the same bifunctional enzyme. Fructose 6-phosphate allosterically stimulates the kinase and inhibits the phosphatase [51](#page=51). * **Hormonal Regulation of F2,6BP:** * When glucose is abundant, F2,6BP concentration increases, stimulating glycolysis via PFK-1 and inhibiting fructose 1,6-bisphosphatase [52](#page=52). * During fasting, glucagon stimulates cAMP production, activating cAMP-dependent protein kinase. This kinase phosphorylates and inactivates PFK-2 while activating fructose 2,6-bisphosphatase [52](#page=52). * Consequently, F2,6BP levels decrease, which inactivates PFK-1 and relieves the inhibition of fructose 1,6-bisphosphatase, thus stimulating gluconeogenesis [52](#page=52). #### 3.2.3 The energetic cost of gluconeogenesis Gluconeogenesis is an energetically expensive process compared to glycolysis. While glycolysis generates 2 ATP and 2 NADH per glucose molecule, gluconeogenesis requires the consumption of 6 ATP (4 ATP + 2 GTP) and 2 NADH to synthesize one glucose molecule from two pyruvate molecules. This significant energy investment is necessary to ensure the overall thermodynamic favorability and irreversibility of the gluconeogenic pathway. This cost is primarily borne by hepatocytes [54](#page=54) [55](#page=55). ### 3.3 Glucogenic precursors It is a common misconception that fats cannot be converted to glucose. While even-chain fatty acids are not glucogenic, as their carbons are lost as CO2 during the TCA cycle and acetyl-CoA cannot be converted back to pyruvate, other components of fats can be converted to glucose [43](#page=43). * **Odd-chain fatty acids:** Oxidation of odd-chain fatty acids produces propionyl-CoA, which can be converted to succinyl-CoA, a substrate for gluconeogenesis [44](#page=44). * **Glycerol:** The glycerol component of triglycerides, upon hydrolysis, can be converted to dihydroxyacetone phosphate, a direct intermediate in gluconeogenesis [44](#page=44). Therefore, the statement "It is incorrect to say that fats can not be converted to glucose" is justified, as glycerol and odd-chain fatty acids are indeed glucogenic. Even-chain fatty acids, however, cannot be used for net glucose synthesis [43](#page=43) [44](#page=44). --- # Summary and key takeaways of gluconeogenesis This section summarizes the gluconeogenesis pathway, outlining its key enzymes, regulatory mechanisms, precursor molecules, and its critical relationship with glycolysis, particularly emphasizing the energetic considerations and the role of the liver. ### 4.1 Overview of the gluconeogenesis pathway Gluconeogenesis (GNG) is the metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates. It is an anabolic process that is distinct from, but shares some enzymes with, glycolysis. While glycolysis breaks down glucose, gluconeogenesis synthesizes it [58](#page=58). ### 4.2 Key enzymes and reactions in gluconeogenesis Gluconeogenesis involves a series of enzymatic reactions, with specific enzymes bypassing the irreversible steps of glycolysis. The following are some of the key enzymes and reactions involved [58](#page=58): * **Pyruvate Carboxylase:** Catalyzes the carboxylation of pyruvate to oxaloacetate, using bicarbonate and ATP. This reaction occurs in the mitochondria [56](#page=56). * The reaction is: Pyruvate + HCOUSD_{3}USDUSD^{-}$ + ATP $\rightarrowUSD Oxaloacetate + ADP + Pi [56](#page=56). * **PEP Carboxykinase (PEPCK):** Converts oxaloacetate to phosphoenolpyruvate (PEP). This step can occur in the mitochondria or cytosol, depending on the shuttle system used [56](#page=56). * The reaction in the mitochondria often uses GTP: Oxaloacetate + GTP $\rightarrow$ PEP + CO$_{2}$ + GDP [56](#page=56). * **Fructose-1,6-bisphosphatase:** Catalyzes the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate, releasing inorganic phosphate. This is a key regulatory step [57](#page=57). * **Glucose-6-phosphatase:** Converts glucose-6-phosphate to glucose, a reaction that primarily occurs in the liver and kidney, allowing for the release of free glucose into the bloodstream [57](#page=57). ### 4.3 Mitochondrial shuttle systems Some steps of gluconeogenesis require transport of intermediates from the mitochondria to the cytosol, necessitating mitochondrial shuttle systems. The malate shuttle is a common system employed for this purpose. In this shuttle, oxaloacetate is reduced to malate in the mitochondria, transported to the cytosol, and then re-oxidized to oxaloacetate, generating NADH in the cytosol [56](#page=56) [58](#page=58). ### 4.4 Precursors for gluconeogenesis Various non-carbohydrate precursors can be utilized for glucose synthesis through gluconeogenesis. These include [58](#page=58): * Lactate [58](#page=58). * Glycerol [58](#page=58). * Amino acids (specifically glucogenic amino acids) [58](#page=58). * Pyruvate [58](#page=58). ### 4.5 Relationship with glycolysis Gluconeogenesis and glycolysis are interconnected pathways that regulate glucose homeostasis. While they share several enzymes, the irreversible steps of glycolysis are bypassed by unique enzymes in gluconeogenesis [58](#page=58). * **Shared enzymes:** Phosphoglycerate kinase, enolase, phosphoglyceromutase, and triosephosphate isomerase are involved in both pathways [56](#page=56) [57](#page=57). * **Irreversible steps bypassed:** The reactions catalyzed by hexokinase/glucokinase, phosphofructokinase-1, and pyruvate kinase in glycolysis are overcome by glucose-6-phosphatase, fructose-1,6-bisphosphatase, and pyruvate carboxylase/PEP carboxykinase, respectively, in gluconeogenesis [56](#page=56) [57](#page=57). > **Tip:** Understanding which enzymes are shared and which are unique to each pathway is crucial for comprehending the regulation of glucose metabolism. The unique enzymes are the primary targets for regulation. ### 4.6 Energetic cost of gluconeogenesis Gluconeogenesis is an energetically expensive process, requiring the input of ATP and GTP. For example, the synthesis of one molecule of glucose from two molecules of pyruvate requires a net input of approximately six high-energy phosphate bonds (four ATP and two GTP). This highlights that gluconeogenesis is a pathway of synthesis, consuming energy, whereas glycolysis is a catabolic pathway that produces energy [56](#page=56) [58](#page=58). ### 4.7 Role of the liver and associated metabolic cycles The liver is the primary organ responsible for gluconeogenesis in mammals, playing a central role in maintaining blood glucose levels. The liver's capacity for gluconeogenesis is essential during fasting or periods of low glucose availability [58](#page=58). * **Cori Cycle:** This cycle involves the conversion of lactate produced by muscles and red blood cells during anaerobic glycolysis into glucose in the liver. The glucose is then returned to the muscles and red blood cells for energy [58](#page=58). * **Alanine Cycle:** Similar to the Cori cycle, the Alanine cycle facilitates the transport of amino groups from muscles to the liver. Alanine, derived from pyruvate, carries amino groups to the liver, where it is converted back to pyruvate and used for gluconeogenesis [58](#page=58). --- ## Common mistakes to avoid - Review all topics thoroughly before exams - Pay attention to formulas and key definitions - Practice with examples provided in each section - Don't memorize without understanding the underlying concepts

| Term | Definition | |------|------------| | Gluconeogenesis (GNG) | The metabolic process by which glucose or glycogen is synthesized from non-carbohydrate precursors, playing a vital role in maintaining blood glucose levels. | | Glycolysis | A metabolic pathway that converts glucose into pyruvate, releasing energy in the form of ATP and NADH. | | Glucogenic amino acids | Amino acids that can be converted into glucose or glycogen through metabolic pathways, serving as precursors for gluconeogenesis. | | Lactate | A byproduct of anaerobic glycolysis, which can be transported to the liver and converted back into glucose through gluconeogenesis. | | Glycerol | A component of triglycerides that can be utilized as a substrate for gluconeogenesis after the breakdown of fats. | | Pyruvate | A key intermediate in glucose metabolism that can be converted to lactate or acetyl-CoA, and also serves as a precursor for gluconeogenesis. | | Oxaloacetate | An intermediate in the citric acid cycle and a crucial molecule in gluconeogenesis, formed from pyruvate and converted to phosphoenolpyruvate. | | Phosphoenolpyruvate (PEP) | A high-energy intermediate in both glycolysis and gluconeogenesis, formed from oxaloacetate during the bypass reactions. | | Cori Cycle | A metabolic pathway involving the interconversion of lactate and glucose between muscles and the liver, allowing for the recycling of lactate into glucose. | | Alanine Cycle (Cahill Cycle) | A metabolic pathway where amino groups and carbons from muscle are transported to the liver as alanine, which is then converted to pyruvate for glucose synthesis and enters the urea cycle. | | Bicarbonate (HCO3−) | An inorganic ion that acts as a substrate in the carboxylation reaction catalyzed by pyruvate carboxylase during gluconeogenesis. | | Biotin | A coenzyme required by pyruvate carboxylase, essential for the carboxylation reaction that converts pyruvate to oxaloacetate. | | GTP (Guanosine triphosphate) | An energy-carrying molecule used in the conversion of oxaloacetate to phosphoenolpyruvate during gluconeogenesis, equivalent to ATP in energy terms. | | GDP (Guanosine diphosphate) | The molecule formed after GTP is hydrolyzed to provide energy for the conversion of oxaloacetate to phosphoenolpyruvate. | | Malate Dehydrogenase | An enzyme involved in the malate transport system, which converts oxaloacetate to malate within the mitochondrion and malate back to oxaloacetate in the cytosol. | | Cytosol | The aqueous component of the cytoplasm of a cell, within which various organelles and particles are suspended. | | Mitochondrion | An organelle found in large numbers in most cells, in which the biochemical processes of respiration and energy production occur. | | ER (Endoplasmic Reticulum) | A network of membranes found throughout the cytoplasm of eukaryotic cells, involved in protein and lipid synthesis and transport. | | G-6-Pase (Glucose-6-phosphatase) | An enzyme located in the ER of liver and kidney cells that catalyzes the final step of gluconeogenesis, releasing free glucose into the bloodstream. | | Phosphofructokinase-1 (PFK-1) | A key regulatory enzyme in glycolysis that catalyzes the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate. | | Fructose-1,6-bisphosphatase | A key regulatory enzyme in gluconeogenesis that catalyzes the dephosphorylation of fructose-1,6-bisphosphate to fructose-6-phosphate, bypassing the PFK-1 step. | | Pyruvate Kinase | A key regulatory enzyme in glycolysis that catalyzes the final step, converting phosphoenolpyruvate to pyruvate. | | Pyruvate Carboxylase | A mitochondrial enzyme that catalyzes the carboxylation of pyruvate to oxaloacetate, the first bypass reaction in gluconeogenesis. | | Phosphoenolpyruvate carboxykinase (PEPCK) | An enzyme that catalyzes the conversion of oxaloacetate to phosphoenolpyruvate, a key step in the gluconeogenesis bypass pathway. | | Allosteric regulation | A type of enzyme regulation where the binding of an effector molecule at a site other than the active site alters the enzyme's activity. | | Covalent modification | A rapid process of enzyme regulation involving the addition or removal of chemical groups, such as phosphate groups, to or from the enzyme. | | Induction & Repression | Processes where hormones influence the synthesis (induction) or degradation (repression) of key metabolic enzymes, affecting pathway activity over longer time scales. |