Basic cognition of central metabolic pathways
1. Definition of central metabolic pathways
The central metabolic pathway is a series of interconnected chemical reactions within cells, occupying a core position in the field of cellular metabolism. It acts like a "central hub" for cellular metabolism, tightly linking numerous metabolic processes. Through this pathway, cells can efficiently process nutrients, generate and store energy, while providing the necessary material foundation for cell growth, repair, and reproduction. In the complex network of cellular metabolism, the central metabolic pathway plays a crucial regulatory role, ensuring that all metabolic stages proceed in an orderly manner, maintaining the stability of the intracellular environment, and safeguarding normal physiological functions and vital activities of the cell.
2. Key position and dual use characteristics
The central metabolic pathway lies at the heart of cellular catabolism and anabolism, as it not only participates in the breakdown of nutrients to release energy but also provides the necessary raw materials and energy for anabolism. In catabolism, it can gradually degrade large molecular nutrients, releasing energy stored in forms such as ATP to meet cellular energy needs. In anabolism, its intermediate products serve as the basic building blocks for constructing various biomacromolecules within cells. As a dual pathway, it is specifically manifested in two aspects: on one hand, through processes like glycolysis and the citric acid cycle, glucose and other substances are thoroughly oxidized and broken down, generating substantial amounts of energy; on the other hand, multiple intermediate products produced during these processes, such as pyruvate and acetyl-CoA, can be used to synthesize amino acids, fats, nucleic acids, and other biomacromolecules, thus achieving an organic unity between catabolism
Main components of central metabolic pathways
The central metabolic pathways comprise glycolysis (the Embden-Meyerhof-Parnas pathway or EMP pathway), the tricarboxylic acid cycle (TCA cycle), and the pentose phosphate pathway. Detailed descriptions of these pathways are provided below:
Glycolysis (EMP Pathway)
Glycolysis is the process of converting glucose to pyruvate within the cytoplasm of cells. This process is divided into two distinct stages: the energy-consuming stage and the energy-producing stage.
(1) Energy-Consuming Stage:
Phosphorylation of Glucose: Glucose is phosphorylated to form glucose-6-phosphate, facilitated by hexokinase, with the consumption of one ATP molecule. This step increases the reactivity of glucose and restricts its diffusion out of the cell by adding a phosphate group.
Isomerization: Glucose-6-phosphate is isomerized to fructose-6-phosphate by phosphohexose isomerase.
Second Phosphorylation: Fructose-6-phosphate is phosphorylated to yield fructose-1,6-bisphosphate, catalyzed by phosphofructokinase-1, consuming an additional ATP molecule.
Cleavage: Fructose-1,6-bisphosphate is cleaved into two three-carbon sugars, dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, by aldolase.
Isomerization: Dihydroxyacetone phosphate is rapidly converted to glyceraldehyde-3-phosphate by triose phosphate isomerase.
(2) Energy-Producing Stage:
Oxidation: Glyceraldehyde-3-phosphate is oxidized to 1,3-bisphosphoglycerate, catalyzed by glyceraldehyde-3-phosphate dehydrogenase, generating one molecule of NADH + H⁺ per conversion.
ATP Generation: 1,3-bisphosphoglycerate is dephosphorylated to form 3-phosphoglycerate, catalyzed by phosphoglycerate kinase, resulting in the production of one ATP molecule.
Conversion: 3-phosphoglycerate is converted to 2-phosphoglycerate by phosphoglycerate mutase.
Dehydration: 2-phosphoglycerate is dehydrated to form phosphoenolpyruvate, catalyzed by enolase.
Formation of Pyruvate: Phosphoenolpyruvate is converted to pyruvate by pyruvate kinase, producing a second molecule of ATP.
The glycolysis pathway yields a net production of two ATP molecules and two NADH molecules per glucose molecule metabolized, resulting in the generation of two pyruvate molecules. Glucose entry into the cell is mediated by glucose transporters present on the cell membrane, utilizing facilitated diffusion or active transport.
Tricarboxylic Acid Cycle (TCA Cycle)
The TCA cycle occurs within mitochondria, initiating with the condensation of the acetyl group of acetyl-CoA with oxaloacetate to form citrate and culminates in the regeneration of oxaloacetate. The process encompasses the following stages:
(1) Conversion of Pyruvate and Initiation of the Cycle:
Before entering the TCA cycle, pyruvate undergoes oxidative decarboxylation mediated by the pyruvate dehydrogenase complex, releasing carbon dioxide and producing acetyl-CoA and NADH. Acetyl-CoA condenses with oxaloacetate, catalyzed by citrate synthase, to form citrate, thus initiating the TCA cycle.
(2) Redox Reactions and Energy Production in the Cycle:
Isomerization: Citrate is converted to isocitrate via aconitase.
Decarboxylation and Oxidation: Isocitrate undergoes oxidative decarboxylation, catalyzed by isocitrate dehydrogenase, producing α-ketoglutarate, NADH, and releasing CO₂.
Further Decarboxylation: α-ketoglutarate undergoes oxidative decarboxylation catalyzed by the α-ketoglutarate dehydrogenase complex, forming succinyl-CoA, another NADH molecule, and CO₂.
GTP Formation: Succinyl-CoA is converted to succinate by succinyl-CoA synthetase, producing GTP (convertible to ATP).
Dehydrogenation: Succinate is oxidized to fumarate by succinate dehydrogenase, producing FADH₂.
Hydration: Fumarate is hydrated to malate by fumarase.
Final Oxidation: Malate is oxidized to regenerate oxaloacetate, catalyzed by malate dehydrogenase, yielding another NADH molecule.
A single cycle of the TCA pathway produces one GTP, three NADH, and one FADH₂, and generates critical intermediates such as citrate, α-ketoglutarate, and succinyl-CoA, which serve as precursors for various biosynthetic pathways.
Pentose Phosphate Pathway
Conducted in the cytoplasm, the pentose phosphate pathway divides into oxidative and non-oxidative phases:
(1) Oxidative Phase:
Initial Dehydrogenation: Glucose-6-phosphate is dehydrogenated to form 6-phosphoglucono-δ-lactone via glucose-6-phosphate dehydrogenase, producing NADPH.
Hydrolysis: 6-phosphoglucono-δ-lactone is hydrolyzed to 6-phosphogluconate by lactonase.
Secondary Dehydrogenation: 6-phosphogluconate is oxidatively decarboxylated to ribose-5-phosphate by 6-phosphogluconate dehydrogenase, yielding additional NADPH and CO₂.
(2) Non-Oxidative Phase:
Isomerization and Conversion: Ribose-5-phosphate is isomerized to ribulose-5-phosphate with the help of pentose phosphate isomerase.
Transketolase and Transaldolase Reactions: Ribulose-5-phosphate is converted through a series of transketolase and transaldolase reactions, leading to the generation of fructose-6-phosphate and glyceraldehyde-3-phosphate.
This pathway provides reducing equivalents in the form of NADPH for biosynthetic reactions and ribose-5-phosphate for nucleotide synthesis.
Schematic representation of the pentose phosphate pathway (PPP, left) and glycolysis (canonical topology of the Embden-Meyerhof-Parnas pathway) (right).
Services You May Be Interested In:
Additional Resources:
Regulation mechanism of central metabolic pathway
1. Fine regulation of enzyme activity
(1) allosteric regulation
Allosteric regulation plays a crucial role in the rate control of central metabolic pathways. Effectors, as signaling molecules, can specifically bind to allosteric sites on enzymes. When an effector binds to an allosteric site, the spatial conformation of the enzyme undergoes subtle yet critical changes. These conformational changes affect the active site structure of the enzyme, thereby altering its affinity for substrates and the rate of catalytic reactions. For example, in the EMP pathway, phosphofructokinase-1 is a key allosteric enzyme. ATP acts as an allosteric effector; when ATP levels are high within the cell, it binds to the allosteric site of phosphofructokinase-1, causing a conformational change that reduces its affinity for the substrate fructose-6-phosphate, thus slowing down the reaction rate of the EMP pathway and preventing excessive energy production. Conversely, when energy demand increases and ATP levels decrease, the allosteric effect is reversed, enzyme activity is restored, ensuring smooth metabolism.
(2) Covalent modification regulation
Covalent modification regulation primarily involves phosphorylation and dephosphorylation to rapidly and reversibly modulate enzyme activity, profoundly impacting the progression of central metabolic pathways. Taking glycogen synthase as an example, its phosphorylated state determines its activity during glycogen synthesis. When intracellular signaling pathways activate protein kinases, these kinases transfer the phosphate group from ATP to glycogen synthase, causing it to become phosphorylated. The phosphorylated glycogen synthase has reduced activity, inhibiting glycogen synthesis. However, when the cell needs to synthesize glycogen, phosphatases catalyze the dephosphorylation of glycogen synthase, restoring its activity and promoting glycogen synthesis. This covalent modification regulation can quickly adjust enzyme activity in response to changes in the cellular environment, ensuring that central metabolic pathways operate accurately under various physiological conditions, meeting the cells needs for material and energy metabolism.
2. Feedback regulation of metabolite concentration
(3) product inhibition
The products of central metabolic pathways play a crucial role in maintaining the balance and stability of these pathways, with product inhibition being a common regulatory mechanism. When the products of metabolic pathways accumulate to a certain concentration within cells, they inhibit the activity or synthesis rate of related enzymes through feedback mechanisms. For example, in the TCA cycle, when ATP levels rise, it acts as a product to feed back and inhibit the activity of citrate synthase. Citrate synthase is the initial enzyme in the TCA cycle; its activity being inhibited slows down the condensation reaction between acetyl-CoA and oxaloacetate, reducing the rate of the TCA cycle and thus decreasing further energy production. This feedback inhibition mechanism prevents excessive accumulation of metabolic products, avoids waste of cellular resources, ensures that metabolic pathways proceed at an appropriate rate, and maintains the stability of the cellular environment.
(4) Substrate activation
Changes in substrate concentration also play a crucial role in regulating central metabolic pathways, with substrate activation being one such mechanism. When the concentration of substrates within cells increases, it activates relevant enzymes, promoting the progression of central metabolic pathways to meet the cells demand for energy and materials. In the EMP pathway, when the glucose concentration outside the cell rises, more glucose enters the cell. Glucose, as a substrate, activates hexokinase. With enhanced hexokinase activity, glucose can be more efficiently phosphorylated into 6-phosphogluconate, driving subsequent reactions in the EMP pathway and thus accelerating glucose metabolism, providing the cell with more energy. This substrate activation mechanism allows cells to flexibly adjust the rate of metabolic pathways based on substrate availability, ensuring normal physiological functions.
Physiological significance of central metabolic pathway
1. The key role of energy supply
The central metabolic pathway is the core channel for energy supply in cells and organisms. In daily cellular activities, whether its active transport of substances, the generation of bioelectricity, or muscle contraction, all rely on the energy produced by the central metabolic pathway. Under normal physiological conditions, cells primarily oxidize glucose aerobically through the EMP pathway, TCA cycle, and subsequent oxidative phosphorylation processes, efficiently breaking down glucose completely to produce large amounts of ATP, meeting the cells continuous demand for energy.
In some special physiological states, such as during intense exercise, muscle cells are in a relatively hypoxic environment, where anaerobic respiration plays a crucial role. Glucose is converted into pyruvate through the EMP pathway and then transformed into lactic acid under hypoxic conditions. Although this process produces relatively less energy, it can quickly provide energy to cells, maintaining muscle contraction activities. In a state of hunger, the body prioritizes using stored glycogen, converting it into energy through glycolysis and other pathways to sustain basic life activities. In summary, the central metabolic pathways can flexibly adjust their energy supply strategies according to different physiological states, ensuring the normal functioning of life activities.
The TCA cycle is a signaling hub.
2. An important basis for material synthesis
The intermediate products of central metabolic pathways serve as crucial raw materials for the synthesis of numerous substances within cells. In amino acid synthesis, α-ketoglutarate produced by the TCA cycle can be converted into glutamate through transamination, which in turn participates in the synthesis of various other amino acids. These amino acids are fundamental building blocks of proteins and are essential for cellular structure, enzyme catalytic functions, and signal transmission processes.
In fat synthesis, acetyl-CoA is a key raw material. It can synthesize fatty acids under the action of a series of enzymes, and these fatty acids then combine with glycerol to form fats. Acetyl-CoA primarily comes from the oxidation and breakdown of sugars, continuously produced through central metabolic pathways, providing an ample material foundation for fat synthesis. Nucleic acid synthesis is also closely related to central metabolic pathways. The pentose phosphate pathway, as part of the central metabolic pathway, provides ribose for nucleic acid synthesis, while the NADPH generated also participates in the synthesis of nucleotides. Additionally, some intermediate products of the TCA cycle can be involved in the synthesis of purines and pyrimidines. The synthesis of these substances is essential for processes such as genetic information transmission and gene expression regulation, fully demonstrating the crucial supporting role of central metabolic pathways in material synthesis.
3. Association with other metabolic pathways
The central metabolic pathway is closely linked and coordinated with other metabolic pathways such as the pentose phosphate pathway and gluconeogenesis. The pentose phosphate pathway complements the central metabolic pathway by utilizing 6-phosphogluconate produced from glucose metabolism to generate NADPH and ribose phosphate through a series of reactions. NADPH provides reducing power for anabolic processes in cells, such as the synthesis of fatty acids and cholesterol; ribose phosphate serves as a crucial raw material for nucleic acid synthesis. Additionally, intermediates from the pentose phosphate pathway can be converted into those of the EMP pathway, maintaining the balance of sugar metabolism within the cell.
The gluconeogenesis pathway and the central metabolic pathway work together under different physiological conditions. During starvation or when sugar supply is insufficient, the gluconeogenesis pathway utilizes non-sugar substances such as lactic acid, glycerol, and gluconeogenic amino acids to produce glucose through a series of reactions, thereby replenishing blood glucose levels. Most of these non-sugar substances come from intermediate products or metabolic branches of the central metabolic pathway. This interconnection allows cells to flexibly regulate sugar metabolism under various nutritional conditions, maintaining stable blood glucose concentrations. The coordinated interaction between these metabolic pathways ensures dynamic equilibrium in material and energy metabolism within cells, sustaining cellular metabolic homeostasis and ensuring normal physiological functions of both cells and organisms.
References
- Stincone A, Prigione A, Cramer T, Wamelink MM, Campbell K, Cheung E, Olin-Sandoval V, Grüning NM, Krüger A, Tauqeer Alam M, Keller MA, Breitenbach M, Brindle KM, Rabinowitz JD, Ralser M. The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biol Rev Camb Philos Soc. 2015 Aug;90(3):927-63. doi: 10.1111/brv.12140. Epub 2014 Sep 22. PMID: 25243985; PMCID: PMC4470864.
- Ge, T., Yang, J., Zhou, S., Wang, Y., Li, Y., & Tong, X. (2020). The Role of the Pentose Phosphate Pathway in Diabetes and Cancer. Frontiers in Endocrinology, 11, Article 365. https://doi.org/10.3389/fendo.2020.00365
- Martínez-Reyes, I., Chandel, N.S. Mitochondrial TCA cycle metabolites control physiology and disease. Nat Commun 11, 102 (2020). https://doi.org/10.1038/s41467-019-13668-3
