Carbohydrate metabolic pathways
Carbohydrate metabolism includes several key pathways that a medical student needs to know at the level of substrates, enzymes, and regulation: aerobic glycolysis (EMP pathway, dichotomous oxidation of glucose), anaerobic glycolysis, synthesis and degradation of glycogen, gluconeogenesis, and the pentose phosphate pathway (HMP shunt). All of them are connected by common metabolites and regulatory mechanisms, allowing the body to flexibly switch between energy storage and expenditure.
The names of the same process differ across textbooks: the EMP pathway, dichotomous oxidation, and aerobic glycolysis are synonyms; the pentose phosphate pathway and hexose monophosphate pathway are also the same thing.
Glycolysis: aerobic and anaerobic pathways
Glycolysis is the breakdown of a glucose molecule (C6) into two molecules of pyruvate (C3). The process takes place in the cytoplasm and involves 10 reactions divided into two stages:
- The preparatory phase consumes 2 ATP molecules; two phosphotrioses are formed: dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GAP). They are isomers and readily interconvertible.
- The ATP synthesis phase — glyceraldehyde-3-phosphate (×2) is converted into pyruvate with the generation of ATP and NADH.
During aerobic glycolysis, pyruvate enters the mitochondrion, where oxidative decarboxylation and the Krebs cycle produce acetyl-CoA; reduced coenzymes NADH and FADH₂ transfer electrons to the ETC, providing a net yield of approximately 38 ATP.
During anaerobic glycolysis, oxygen is insufficient or mitochondria are absent. NADH cannot be oxidized in the ETC, so it transfers hydrogens to pyruvate, forming lactate through the action of lactate dehydrogenase. Anaerobic glycolysis is typical for erythrocytes and the lens of the eye (lack of mitochondria), the myocardium during ischemia (infarction), rapidly growing tumors, and intensively working skeletal muscles.
Gluconeogenesis and glycogen metabolism
Gluconeogenesis is the synthesis of glucose from non-carbohydrate precursors: lactate, glycerol, amino acids. Its main function is to maintain blood glucose levels (normal range 3.3–5.5 mmol/L) during fasting. Glycolysis and gluconeogenesis are reciprocal processes; they differ in their regulatory enzymes, which catalyze irreversible reactions (3 enzymes in glycolysis, 4 in gluconeogenesis). Reversible reactions are shared by both pathways.
Glycogen is the reserve carbohydrate in animals, stored in the liver and muscles. Glycogen synthase is responsible for its synthesis (active after a meal), while glycogen phosphorylase is responsible for its breakdown (active during fasting).
Pentose phosphate pathway
The pentose phosphate pathway is an alternative oxidation pathway of glucose that actively occurs in the liver, adipose tissue, adrenal cortex, erythrocytes, lactating mammary gland, and testes. It includes oxidative and non-oxidative phases.
In the oxidative phase, glucose-6-phosphate is converted into ribulose-5-phosphate by the action of glucose-6-phosphate dehydrogenase (the key regulatory enzyme) and 6-phosphogluconate dehydrogenase, generating two molecules of NADPH and releasing CO₂.
Biological significance of the products:
- Ribose-5-phosphate is a substrate for nucleotide synthesis.
- NADPH is a hydrogen donor in anabolic reactions: synthesis of cholesterol, bile acids, fatty acids, and steroid hormones; protection of the cell against reactive oxygen species via the glutathione system.
The non-oxidative phase involves epimerases, isomerases, transketolase (cofactor TPP, a vitamin B₁ derivative), and transaldolase; carbon skeletons are rearranged with a return to hexoses.
Interconnection of carbohydrate and lipid metabolism
The connection between the two metabolic pathways is realized at the level of shared metabolites:
- Dihydroxyacetone phosphate is a key linking compound. It is reduced to glycerol-3-phosphate (enzyme glycerol-3-phosphate dehydrogenase, cofactor NADH), which serves as the backbone for the synthesis of triacylglycerols (fats).
- Acetyl-CoA, formed during the oxidative decarboxylation of pyruvate, is the starting substrate for fatty acid synthesis.
- NADPH from the pentose phosphate pathway is required as a reducing agent in fatty acid and cholesterol synthesis reactions.
- ATP from glycolysis provides energy for biosynthetic processes.
Triacylglycerol synthesis in the adipocyte: glycerol-3-phosphate is successively acylated (fatty acid residues—acyls—are attached) to form phosphatidic acid; then a phosphatase removes the phosphate group, and a third acyl residue attaches to the free OH group.
Hormonal regulation: absorptive and postabsorptive periods
In the absorptive period (after a meal), when blood glucose rises, insulin is secreted. Its effects include:
- Insertion of the GLUT-4 transporter into the membrane of adipocytes and myocytes, facilitating glucose entry into insulin-dependent tissues.
- Activation of glycolysis enzymes (hexokinase, phosphofructokinase, pyruvate kinase).
- Activation of glycogen synthase, leading to glycogen synthesis.
- Induction of glucose-6-phosphate dehydrogenase, enhancing the pentose phosphate pathway and NADPH production.
- Activation of enzymes involved in fatty acid and triacylglycerol synthesis.
In the postabsorptive period (fasting), counter-regulatory hormones—glucagon, adrenaline, cortisol—predominate. They activate glycogen phosphorylase (glycogen breakdown), gluconeogenesis, and lipolysis, ensuring the maintenance of blood glucose levels and the mobilization of energy substrates.
Key points
- Glycolysis involves 10 reactions in the cytoplasm; glucose (C6) is split into 2 molecules of pyruvate (C3).
- Anaerobic glycolysis ends with the formation of lactate involving lactate dehydrogenase; it is characteristic of erythrocytes, the lens, the ischemic myocardium, and tumors.
- Dihydroxyacetone phosphate is the main link between carbohydrate and lipid metabolism: it forms glycerol-3-phosphate for triacylglycerol synthesis.
- Acetyl-CoA from glycolysis is a substrate for fatty acid synthesis; NADPH from the pentose phosphate pathway is the hydrogen donor for this synthesis.
- Glucose-6-phosphate dehydrogenase is the key regulatory enzyme of the pentose phosphate pathway; its products are NADPH and ribose-5-phosphate.
- Gluconeogenesis uses the same substrates as glycolysis, but 4 unique regulatory enzymes catalyze irreversible reactions in the reverse direction.
- Insulin activates synthesis pathways (glycogen, fats, proteins) and glucose utilization; glucagon and adrenaline promote the mobilization of energy reserves.
- Normal blood glucose is 3.3–5.5 mmol/L; its maintenance is ensured by the balance of glycogenolysis, gluconeogenesis, and dietary glucose intake.