Biochemistry Unit 16 Review: Carbohydrate Metabolism

Introduction to Carbohydrates

• Carbohydrates are organic molecules composed of carbon, hydrogen, and oxygen atoms, typically with a 1:2:1 ratio, respectively
• Classified into three main categories based on their structure and complexity: monosaccharides (simple sugars), disaccharides (two monosaccharides linked together), and polysaccharides (long chains of monosaccharides)
  • Monosaccharides include glucose, fructose, and galactose
  • Disaccharides include sucrose (table sugar), lactose (milk sugar), and maltose (malt sugar)
  • Polysaccharides include starch, glycogen, and cellulose
• Serve as the primary energy source for living organisms, providing 4 kilocalories (kcal) of energy per gram
• Play crucial roles in various biological processes, such as cell signaling, cell-cell recognition, and immune function
• Can be found in a wide variety of foods, including fruits, vegetables, grains, and dairy products
• Excess carbohydrates not immediately used for energy are stored as glycogen in the liver and muscles or converted to fat for long-term storage

Glycolysis: Breaking Down Glucose

• Glycolysis is a central metabolic pathway that breaks down glucose into two molecules of pyruvate, releasing energy in the form of ATP and NADH
• Occurs in the cytoplasm of cells and does not require oxygen (anaerobic process)
• Consists of ten enzymatic reactions divided into two phases: the preparatory phase (requires energy investment) and the payoff phase (yields net energy gain)
  • Preparatory phase: Glucose is phosphorylated twice, consuming 2 ATP molecules, and then split into two three-carbon molecules (glyceraldehyde 3-phosphate)
  • Payoff phase: Glyceraldehyde 3-phosphate is oxidized and phosphorylated, generating 2 NADH and 4 ATP molecules per glucose molecule
• Net yield of glycolysis is 2 ATP, 2 NADH, and 2 pyruvate molecules per glucose molecule
• Pyruvate can be further metabolized in the presence of oxygen (aerobic conditions) via the citric acid cycle and electron transport chain or converted to lactate under anaerobic conditions
• Glycolysis is a highly regulated process, with key enzymes such as hexokinase, phosphofructokinase, and pyruvate kinase being subject to allosteric regulation and covalent modification

The Citric Acid Cycle

• The citric acid cycle, also known as the Krebs cycle or tricarboxylic acid (TCA) cycle, is a central metabolic pathway that oxidizes acetyl-CoA derived from carbohydrates, fats, and proteins to generate energy in the form of ATP, NADH, and FADH2
• Occurs in the mitochondrial matrix and requires oxygen (aerobic process)
• Begins with the condensation of acetyl-CoA and oxaloacetate to form citrate, followed by a series of oxidation-reduction reactions that regenerate oxaloacetate and release CO2
• Key steps in the cycle include the oxidative decarboxylation of isocitrate and α-ketoglutarate, catalyzed by NAD+-dependent dehydrogenases, and the substrate-level phosphorylation of GDP to GTP by succinyl-CoA synthetase
• Each turn of the cycle yields 3 NADH, 1 FADH2, and 1 GTP (or ATP) per acetyl-CoA molecule
• NADH and FADH2 generated in the citric acid cycle are used to drive ATP synthesis through the electron transport chain and oxidative phosphorylation
• The citric acid cycle is highly regulated, with key enzymes such as citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase being subject to allosteric regulation by ATP, NADH, and calcium ions

Electron Transport Chain and ATP Synthesis

• The electron transport chain (ETC) is a series of protein complexes embedded in the inner mitochondrial membrane that transfer electrons from NADH and FADH2 to oxygen, generating a proton gradient that drives ATP synthesis
• Consists of four main protein complexes (I, II, III, and IV) and two mobile electron carriers (ubiquinone and cytochrome c)
  • Complex I (NADH dehydrogenase) oxidizes NADH and transfers electrons to ubiquinone, pumping protons from the mitochondrial matrix to the intermembrane space
  • Complex II (succinate dehydrogenase) oxidizes FADH2 and transfers electrons to ubiquinone without pumping protons
  • Complex III (cytochrome bc1 complex) transfers electrons from ubiquinone to cytochrome c, pumping protons in the process
  • Complex IV (cytochrome c oxidase) transfers electrons from cytochrome c to oxygen, forming water and pumping protons
• The proton gradient generated by the ETC is used by ATP synthase (sometimes referred to as Complex V) to synthesize ATP from ADP and inorganic phosphate (Pi) through the process of oxidative phosphorylation
• The overall yield of oxidative phosphorylation is approximately 2.5 ATP per NADH and 1.5 ATP per FADH2
• The electron transport chain and ATP synthesis are tightly coupled processes, with the rate of electron transport being regulated by the availability of ADP and Pi (respiratory control)
• Uncoupling proteins (UCPs) can dissipate the proton gradient without ATP synthesis, generating heat instead, which is important for thermogenesis in brown adipose tissue

Gluconeogenesis: Making Glucose

• Gluconeogenesis is the process of synthesizing glucose from non-carbohydrate precursors, such as lactate, amino acids, and glycerol
• Occurs primarily in the liver and, to a lesser extent, in the kidneys
• Shares several enzymes with glycolysis but requires four unique enzymes to bypass the irreversible steps of glycolysis: pyruvate carboxylase, phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase, and glucose-6-phosphatase
• Pyruvate carboxylase catalyzes the carboxylation of pyruvate to oxaloacetate, which is then converted to phosphoenolpyruvate (PEP) by PEPCK
• Fructose-1,6-bisphosphatase catalyzes the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate, bypassing the irreversible phosphofructokinase step in glycolysis
• Glucose-6-phosphatase catalyzes the final step of gluconeogenesis, hydrolyzing glucose-6-phosphate to glucose, which can be released into the bloodstream
• Gluconeogenesis is an energy-intensive process, requiring 6 ATP equivalents per glucose molecule synthesized
• Gluconeogenesis is highly regulated, with key enzymes such as PEPCK and fructose-1,6-bisphosphatase being subject to hormonal control by glucagon, cortisol, and insulin

Glycogen Metabolism

• Glycogen is a branched polysaccharide of glucose that serves as a storage form of energy in animals, primarily found in the liver and skeletal muscle
• Glycogen synthesis (glycogenesis) occurs when glucose is abundant, such as after a meal, and is stimulated by the hormone insulin
  • Glucose is first phosphorylated to glucose-6-phosphate by hexokinase or glucokinase, then converted to glucose-1-phosphate by phosphoglucomutase
  • Glucose-1-phosphate is activated to UDP-glucose by UDP-glucose pyrophosphorylase, which then serves as the substrate for glycogen synthase to elongate the glycogen chain
  • Branching enzyme introduces branch points in the glycogen molecule by transferring a segment of 6-7 glucose residues from the end of a chain to the C6 hydroxyl of a glucose residue within the same or another chain
• Glycogen breakdown (glycogenolysis) occurs when energy is needed, such as during fasting or exercise, and is stimulated by the hormones glucagon and epinephrine
  • Glycogen phosphorylase catalyzes the phosphorolytic cleavage of glycogen, releasing glucose-1-phosphate from the non-reducing ends of the glycogen molecule
  • Debranching enzyme removes the branch points by transferring a segment of 3-4 glucose residues to the end of another chain and hydrolyzing the remaining α-1,6-glycosidic bond
  • Glucose-1-phosphate is converted to glucose-6-phosphate by phosphoglucomutase, which can then enter glycolysis or be hydrolyzed to glucose by glucose-6-phosphatase in the liver
• Glycogen metabolism is highly regulated, with glycogen synthase and glycogen phosphorylase being subject to allosteric regulation and covalent modification by phosphorylation/dephosphorylation in response to hormonal and metabolic signals

Regulation of Carbohydrate Metabolism

• Carbohydrate metabolism is tightly regulated to maintain blood glucose levels within a narrow range (70-110 mg/dL) and to meet the energy demands of various tissues
• Hormonal regulation plays a central role in coordinating carbohydrate metabolism, with insulin and glucagon being the primary hormones involved
  • Insulin is released by the pancreatic β-cells in response to high blood glucose levels and promotes glucose uptake, glycolysis, glycogenesis, and lipogenesis while inhibiting gluconeogenesis and glycogenolysis
  • Glucagon is released by the pancreatic α-cells in response to low blood glucose levels and stimulates glycogenolysis, gluconeogenesis, and lipolysis while inhibiting glycolysis and glycogenesis
• Other hormones, such as cortisol, growth hormone, and thyroid hormones, also influence carbohydrate metabolism by modulating insulin sensitivity, glucose production, and energy expenditure
• Allosteric regulation of key enzymes in glycolysis, gluconeogenesis, and glycogen metabolism allows for rapid responses to changes in metabolic state
  • Phosphofructokinase, the rate-limiting enzyme of glycolysis, is allosterically inhibited by ATP and activated by AMP and fructose-2,6-bisphosphate
  • Pyruvate kinase, another key glycolytic enzyme, is allosterically inhibited by ATP and alanine and activated by fructose-1,6-bisphosphate
  • Fructose-1,6-bisphosphatase, a key enzyme in gluconeogenesis, is allosterically inhibited by AMP and fructose-2,6-bisphosphate
• Covalent modification of enzymes by phosphorylation and dephosphorylation, catalyzed by protein kinases and phosphatases, respectively, allows for longer-term regulation of enzyme activity
  • Glycogen synthase is inactivated by phosphorylation by glycogen synthase kinase 3 (GSK3) and activated by dephosphorylation by protein phosphatase 1 (PP1)
  • Glycogen phosphorylase is activated by phosphorylation by phosphorylase kinase and inactivated by dephosphorylation by PP1

Clinical Relevance and Disorders

• Diabetes mellitus is a group of metabolic disorders characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both
  • Type 1 diabetes is caused by autoimmune destruction of pancreatic β-cells, leading to absolute insulin deficiency
  • Type 2 diabetes is caused by a combination of insulin resistance and impaired insulin secretion, often associated with obesity and sedentary lifestyle
  • Complications of diabetes include cardiovascular disease, nephropathy, retinopathy, and neuropathy
• Hypoglycemia is a condition characterized by abnormally low blood glucose levels (<70 mg/dL), which can cause symptoms such as sweating, tremors, confusion, and seizures
  • Causes include insulin overdose, insulin-secreting tumors (insulinomas), and inherited disorders of glucose metabolism (e.g., glycogen storage diseases)
• Glycogen storage diseases (GSDs) are a group of inherited disorders characterized by defects in enzymes involved in glycogen synthesis or breakdown, leading to abnormal accumulation of glycogen in tissues
  • GSD type I (von Gierke disease) is caused by a deficiency in glucose-6-phosphatase, resulting in hypoglycemia, hepatomegaly, and lactic acidosis
  • GSD type II (Pompe disease) is caused by a deficiency in lysosomal α-glucosidase, leading to glycogen accumulation in lysosomes and muscle weakness
  • Other types of GSDs affect the liver, muscle, or both, and present with various combinations of hypoglycemia, hepatomegaly, and muscle weakness
• Lactose intolerance is a common condition characterized by the inability to digest lactose, a disaccharide found in milk, due to a deficiency in the enzyme lactase
  • Symptoms include abdominal pain, bloating, diarrhea, and flatulence after consuming lactose-containing products
  • Management involves reducing lactose intake or using lactase enzyme supplements
• Fructose intolerance is a rare inherited disorder caused by a deficiency in the enzyme aldolase B, which is required for the metabolism of fructose
  • Ingestion of fructose or sucrose leads to hypoglycemia, lactic acidosis, and liver damage
  • Treatment involves strict avoidance of fructose and sucrose in the diet