BIOQUI - 19/05/2023

Anabolic Pathways and Their Importance

Overview of Anabolic Processes

• The previous class covered anabolic pathways, focusing on the synthesis of non-essential amino acids from various intermediates like pyruvate and oxaloacetate.

• The synthesis of fatty acids primarily originates from glucose consumption, with amino acids contributing minimally. This is crucial for weight loss diets that prioritize carbohydrate reduction.

Fatty Acid Synthesis Mechanism

• Pyruvate converts to acetyl-CoA in mitochondria, which then combines with oxaloacetate to form citrate. Excess energy inhibits the conversion of isocitrate to alpha-ketoglutarate.

• Citrate accumulates and exits the mitochondria, where it is converted back into acetyl-CoA by citrate lyase, serving as a building block for fatty acid synthesis.

Gluconeogenesis: A Critical Anabolic Process

• Gluconeogenesis synthesizes glucose from non-carbohydrate sources, vital during food scarcity or intense exercise when glycogen stores are depleted.

• Certain organs require glucose exclusively; severe hypoglycemia can damage the brain and other tissues reliant on glucose.

Key Organs Involved in Gluconeogenesis

• The liver is the primary organ for gluconeogenesis, with minor contributions from kidneys and other tissues. Glycolysis provides essential substrates like pyruvate for this process.

• Other organs such as muscles and kidneys also have significant glucose requirements; erythrocytes constantly produce lactate due to lack of mitochondria.

Barriers in Glycolysis and Their Implications

• Glycolysis has three energetic barriers that must be overcome through alternative mechanisms. Lactate production occurs especially in erythrocytes under aerobic conditions.

• The Krebs cycle plays a limited role but provides alternate pathways to bypass energetic barriers necessary for gluconeogenesis.

Substrates for Gluconeogenesis

• Key gluconeogenic substrates include lactate (from glycolysis), glycerol (from triglyceride hydrolysis), and certain amino acids released during protein degradation.

• These compounds enter gluconeogenic pathways at different stages, facilitating glucose production when needed.

Visual Representation of Glycolysis

• A diagram illustrates glycolysis from glucose to pyruvate while highlighting three key energetic barriers that must be navigated during this metabolic pathway.

Gluconeogenesis and Its Pathways

Conversion of Pyruvate to Oxaloacetate

• Pyruvate enters the mitochondria during hypoglycemia to convert into oxaloacetate, which then transforms into malate. This process is a reversal of the normal pathway where malate converts back to oxaloacetate.

Role of Malate in Gluconeogenesis

• Malate exits the mitochondria and, through the enzyme pyruvate carboxylase, converts back into oxaloacetate. Subsequently, phosphoenolpyruvate carboxykinase facilitates its conversion into phosphoenolpyruvate.

Importance of NADH in Glycolysis Reversal

• The conversion from dihydroxyacetone phosphate (DHAP) to fructose 1,6-bisphosphate requires NADH. Excessive alcohol consumption can block gluconeogenesis due to insufficient NAD+ levels, risking severe hypoglycemia.

Glycerol's Contribution to Gluconeogenesis

• Glycerol derived from triglycerides converts into DHAP via an essential step that also requires oxidized NAD+. This highlights glycerol as a significant substrate for gluconeogenesis alongside lactate and amino acids.

Amino Acids in Energy Production

• Not all glucogenic amino acids can convert directly into acetyl-CoA; some will enter gluconeogenesis by forming malate or other intermediates. This emphasizes the interconnectedness of metabolic pathways.

Overcoming Energetic Barriers in Gluconeogenesis

Enzymatic Steps in Fructose Conversion

• The transition from glycerol 3-phosphate and DHAP forms fructose 1,6-bisphosphate through reversible reactions facilitated by specific enzymes like fructose 1,6-bisphosphatase.

Phosphatases' Role in Metabolic Pathways

• Fructose 1,6-bisphosphatase removes a phosphate group from carbon one of fructose 1,6-bisphosphate converting it to fructose 6-phosphate. This is crucial for further conversion processes leading towards glucose production.

Final Steps Leading to Glucose Release

• A second phosphatase acts on glucose 6-phosphate removing its phosphate group and yielding free glucose ready for release into the bloodstream.

Hormonal Regulation of Blood Sugar Levels

Hormones Involved in Glycemic Control

• Glucagon and adrenaline play critical roles in maintaining blood sugar levels during fasting or low carbohydrate intake by activating lipases that mobilize energy stores.

Mechanism Behind Hormonal Action

• Glucagon is released when blood sugar drops below approximately 90 mg/dL while adrenaline responds during severe hypoglycemia or stress situations. Both hormones stimulate lipid breakdown for energy production.

Metabolism and Hypoglycemia: Key Insights

Fructose-1,6-bisphosphate Formation

• The formation of fructose-1,6-bisphosphate occurs without oxidation or production of byproducts. This step is crucial in the metabolic pathway.

Glucose Metabolism and Glycogen Storage

• The relationship between glucose-6-phosphate and glucose highlights issues related to glycogen storage, particularly during hypoglycemic conditions.

Lipolysis and Glycerol Conversion

• Lipases hydrolyze triglycerides into three fatty acids and glycerol. Glycerol is phosphorylated to glycerol-3-phosphate, which is then oxidized to dihydroxyacetone phosphate.

Pathways of Gluconeogenesis

• Three gluconeogenic pathways are identified: from lactate, glucogenic amino acids, and glycerol.

Lactate to Pyruvate Conversion

• Amino acids enter the cycle alongside lactate converting into pyruvate through pyruvate carboxylase, leading to further metabolic processes.

Alcohol Consumption and Hypoglycemia Risks

Impact of Alcohol on Glycogen Stores

• Excessive alcohol consumption (especially after fasting for over 18 hours) can lead to severe hypoglycemia due to depleted hepatic glycogen stores.

Ethanol Metabolism Process

• Ethanol is metabolized by alcohol dehydrogenase into acetaldehyde, which is further converted into acetate by aldehyde dehydrogenase. Both enzymes require NAD+ as a cofactor.

Importance of NAD+ in Glycolysis

• NAD+ plays a critical role in glycolysis; its absence due to ethanol metabolism can halt essential steps in energy production.

Consequences of NAD+ Depletion

Effects on Pyruvate Production

• Without sufficient NAD+, the conversion from glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate cannot proceed effectively, impacting overall glycolytic function.

Implications for Gluconeogenesis

• The lack of NAD+ also affects gluconeogenesis pathways that convert pyruvate back into glucose under low carbohydrate availability conditions.

Hormonal Regulation During Hypoglycemia

Role of Glucagon

• Glucagon stimulates glycogenolysis (glycogen breakdown), gluconeogenesis (glucose synthesis), and lipolysis (fat breakdown), primarily affecting liver metabolism.

Adrenaline's Influence

• Adrenaline promotes glycogenolysis in muscles while also stimulating gluconeogenesis and lipolysis across tissues—contrasting with glucagon's liver-specific effects.

Cortisol's Contribution

Understanding Diabetes: Types and Hormonal Influence

Overview of Diabetes Types

• The discussion begins with the distinction between Type 1 and Type 2 diabetes. Type 1 is characterized as juvenile, insulin-dependent diabetes caused by the immune-mediated destruction of pancreatic beta cells.

• In contrast, Type 2 diabetes, often referred to as adult-onset diabetes, is linked to stress factors that stimulate hormone production.

Hormonal Response to Stress

• Stress triggers the release of hormones such as adrenaline and cortisol. Adrenaline is particularly associated with acute stress responses while cortisol relates more to chronic stress situations.

• Excessive production of these hormones can lead to unnecessary glucose production in the liver through gluconeogenesis, which is not warranted in many stressful scenarios.

Impact on Glucose Metabolism

• In Type 2 diabetes, chronic stress proves detrimental as it promotes glucose release from glycogen stores in the liver alongside lipid mobilization for gluconeogenesis.

Treatment Options: Metformin

• One of the primary medications prescribed for managing Type 2 diabetes is metformin. Its main action involves inhibiting hepatic glucose synthesis (gluconeogenesis).