Share 4.9.2025 - Introduction to metabolism; Carbohydrate metabolism I

Approximately 70% of weight differences between people is attributed to genetic factors.

The risk of obesity for a child with no obese parents is 10%.

The risk of obesity for a child with one obese parent increases to up to 40%.

The risk of obesity for a child with both obese parents can be as high as up to 80%.

Glucogenesis is largely controlled by the supply of precursors to the liver and kidney cortex, with hepatocytes containing important controls for this process.

Phosphoglucoisomerase facilitates the conversion of glucose-6-phosphate (an aldose) to fructose-6-phosphate (a ketose), enabling the interconversion between these two forms.

The phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate, catalyzed by phosphofructokinase (PFK1), is the first unique step in glycolysis and is essentially irreversible in vivo, making it a key regulatory point in the pathway.

Phosphofructokinase (PFK1) is the primary site for regulation of the flow of substrates through glycolysis, catalyzing the ATP-dependent phosphorylation of fructose-6-phosphate, which is crucial for controlling the glycolytic pathway.

ATP acts as an inhibitor of PFK1, slowing down the enzyme's activity when present in high concentrations. Conversely, AMP serves as an activator, stimulating PFK1 and glycolysis when energy levels are low. This creates a synergistic effect that enhances the sensitivity of control over PFK1.

Citrate acts as an inhibitor of PFK1 in vitro, potentially providing a control mechanism related to the supply of fatty acids or ketoacids. This regulation by citrate may be particularly important in muscle tissue.

A high concentration of H+ is a strong inhibitor of PFK1, which may help protect muscles from excessive accumulation of H+ during anaerobic glycolysis. This inhibition is crucial for maintaining muscle function under anaerobic conditions.

Glyceraldehyde-3-phosphate dehydrogenase catalyzes the conversion of D-glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate, generating a high-energy intermediate and reducing equivalents (NADH). It is inhibited by iodoacetate and heavy metals like mercury, and arsenate competes with inorganic phosphate in this process.

The conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate releases energy that is used to form ATP from ADP, catalyzed by the enzyme phosphoglycerate kinase. However, the net yield of ATP at this stage is zero.

Pyruvate kinase catalyzes the transfer of a high-energy phosphate from phosphoenolpyruvate (PEP) to ADP, producing pyruvate and ATP. It is the second substrate-level phosphorylation reaction and the third rate-limiting step in glycolysis.

Fructose 1,6-bisphosphate acts as a positive effector for pyruvate kinase in the liver, adipose tissue, kidney, and red blood cells, but it does not affect the muscle enzyme.

Pyruvate kinase activity is inhibited by ATP, Ca++, and alanine.

Glucogenesis synthesizes glucose or G6P from pyruvate, and it is not simply a reversal of glycolysis.

The hexose monophosphate shunt, also known as the pentose phosphate pathway, is crucial for generating NADPH and ribose-5-phosphate. NADPH is essential for anabolic reactions, including fatty acid synthesis and maintaining reduced glutathione levels, while ribose-5-phosphate is vital for nucleotide synthesis.

The urea cycle is responsible for removing excess nitrogen from the body by converting ammonia, which is toxic, into urea for excretion. This process involves several key enzymes and intermediates, including ornithine, citrulline, and arginine, facilitating the safe disposal of nitrogen from amino acid catabolism.

Chronic diseases influenced by diet include:

1. Heart disease
2. Stroke
3. Hypertension
4. Diabetes
5. Obesity
6. Some forms of cancer
7. Type 2 diabetes

Short-term effects include initial weight loss due to glycogen depletion and reduced water retention. However, long-term effects can be dangerous, such as the risk of ketoacidosis due to a significant decrease in ketone levels, which can lead to serious health issues.

Drinking lots of water is crucial on the Atkins diet to help remove ketones from the body. This helps prevent the buildup of ketones, which can lead to ketoacidosis, a dangerous condition.

4 kcal/g

4 kcal/g

9 kcal/g

Glucose is the primary fuel that can penetrate the blood-brain barrier and is utilized by the brain for energy production.

The GLUT-3 transporter in the brain is insulin-insensitive and facilitates the uptake of glucose into brain cells.

The major metabolic pathways in the brain during the absorptive state include the conversion of glucose to pyruvate, which is then transformed into acetyl CoA and enters the TCA cycle for energy production.

The three main types of complex molecules are Proteins, Carbohydrates, and Fats.

The building blocks produced are:

1. Proteins → Amino acids
2. Carbohydrates → Monosaccharides
3. Fats → Glycerol and fatty acids

Acetyl CoA serves as a key intermediate that enters the TCA cycle for further oxidation, leading to the production of ATP and CO₂.

The three stages of catabolism are:

1. Hydrolysis of complex molecules to building blocks
2. Conversion of building blocks to Acetyl CoA (or other simple intermediates)
3. Oxidation of Acetyl CoA and oxidative phosphorylation

Beta-oxidation is the metabolic process by which fatty acids are broken down in the mitochondria to generate acetyl-CoA, which can enter the citric acid cycle for energy production. This process is crucial for utilizing fat stores as an energy source, especially during fasting or prolonged exercise.

Glycolysis produces several key products:

1. Pyruvate - can be further oxidized in the citric acid cycle or converted to lactate.
2. NADH - used in oxidative phosphorylation to generate ATP.
3. ATP - provides immediate energy for cellular processes.
4. Glyceraldehyde 3-phosphate - can be used for gluconeogenesis or lipid synthesis.

Glycolysis converts glucose into pyruvate, which can then enter the citric acid cycle (TCA cycle) after being converted to acetyl-CoA. This connection allows for the efficient extraction of energy from carbohydrates, as the products of glycolysis feed directly into the TCA cycle for further oxidation and ATP production.

The main energy-yielding nutrients are Carbohydrates, Fats, and Proteins.

The end products of catabolism are CO2, H2O, and NH3.

ATP and NADH are key molecules that store and transfer energy during metabolic processes.

The precursor molecules involved in anabolic pathways include some amino acids, sugars, fatty acids, and nitrogenous bases.

Catabolic pathways release energy by breaking down complex molecules into simpler ones, while anabolic pathways require energy to build complex molecules from simpler precursors.

During starvation, the liver plays a crucial role in several metabolic pathways:

1. Glycogenolysis: Breakdown of glycogen to produce Glucose-6-P.
2. Glycolysis: Conversion of Glucose-6-P to Pyruvate.
3. Pyruvate Oxidation: Conversion of Pyruvate to Acetyl CoA.
4. Ketogenesis: Formation of Ketone bodies from Acetyl CoA for energy.
5. Fatty Acid Release: Release of Fatty acids into the bloodstream.
6. Amino Acid Metabolism: Utilization of Amino acids, Glycerol, and Lactate for gluconeogenesis and energy production.

During starvation, the brain primarily utilizes two metabolic pathways:

1. Glucose Metabolism:

   • Glucose enters the brain from the blood.
   • It is converted to Glucose 6-P, then to Pyruvate, and subsequently to Acetyl CoA.
   • Acetyl CoA enters the TCA cycle for energy production.

2. Ketone Body Utilization:

   • Ketone bodies can also enter the brain, providing an alternative energy source.
   • However, the brain cannot rely on ketones for long-term energy needs unless sufficient water is available to remove them.

During starvation, the brain primarily utilizes two metabolic pathways:

1. Glucose Metabolism:

   • Glucose enters the brain from the blood.
   • It is converted to Glucose 6-P, then to Pyruvate, and subsequently to Acetyl CoA.
   • Acetyl CoA enters the TCA cycle for energy production.

2. Ketone Body Utilization:

   • Ketone bodies can also enter the brain, providing an alternative energy source.
   • However, the brain cannot rely on ketones for long-term energy needs unless sufficient water is available to remove them.

During starvation, adipose tissue primarily engages in the following metabolic pathways:

1. Lipolysis: Breakdown of triacylglycerol into fatty acids and glycerol, which are released into the bloodstream.
2. Beta-oxidation: Fatty acids are transported to the mitochondria where they undergo beta-oxidation to produce Acetyl CoA.
3. TCA Cycle: Acetyl CoA enters the TCA cycle for energy production.

These processes help provide energy to the body when glucose levels are low.

The risk indicators for Metabolic Syndrome include:

1. High blood pressure: 130/85 mmHg or higher
2. Low HDL cholesterol:
   • Men: HDL level less than 40 mg/dl
   • Women: HDL level less than 50 mg/dL
3. Elevated glucose: Fasting level of 100 mg/dL or higher
4. Elevated triglycerides: 150 mg/dL or higher
5. Abdominal obesity:
   • Men: Waist circumference greater than 42 inches
   • Women: Waist circumference greater than 35 inches

The medical conditions related to Metabolic Syndrome include:

1. Type 2 diabetes: Insulin resistance can increase blood glucose levels, leading to type 2 diabetes.
2. Coronary artery disease: Elevated blood pressure and cholesterol levels can cause plaque buildup in coronary arteries, potentially leading to a heart attack.
3. Stroke: Plaque buildup can lead to blood clots that obstruct blood flow to the brain, causing damage to brain tissue.

The increase in obesity rates is largely attributed to the consumption of fatty foods, chips, sugary foods and drinks, and meat.

Adult obesity in females is significantly rooted in childhood obesity, indicating that early life factors play a crucial role in the development of obesity later in life.

Obesity in men tends to start around age 30, while in females, it is more closely linked to childhood obesity.

The content highlights a primary role of nurture in the development of obesity, suggesting that environmental and lifestyle factors are significant contributors.

In short-term experiments, people eating a low-calorie, high-fat diet lost weight more quickly than those on a low-calorie, high-carbohydrate diet.

Low-calorie, high-fat diets lead to more weight loss over time than low-calorie, high-carbohydrate diets.

At the end of the study, weight loss did not differ significantly between the two groups.

The hypothesis was not accepted, indicating that further studies are needed to investigate other aspects of the hypothesis.

Again, weight loss in the low-calorie, high-fat diet group and the low-calorie, high-carbohydrate diet group did not differ significantly after one year.

The study was peer-reviewed, conducted in an unbiased, scientific manner, and the results appeared valid.

a-Amylase initiates the breakdown of starch into smaller carbohydrate units such as starch dextrins, isomaltose, maltose, and maltotriose in the mouth.

In the mouth, carbohydrates such as starch, lactose, sucrose, and cellulose begin to be broken down by enzymes like a-amylase.

In the stomach, the low pH stops the action of salivary amylase, halting the breakdown of carbohydrates until they reach the small intestine.

In the small intestine, mucosal cell membrane-bound enzymes such as isomaltase, maltase, lactase, sucrase, and trehalase further break down carbohydrates into simple sugars like glucose, fructose, and galactose.

The final outcome of carbohydrate digestion is the production of simple sugars: glucose, fructose, and galactose, which are then absorbed into the bloodstream.

Any tissue proteins that are degraded during the postabsorptive period are resynthesized.

The main forms of carbohydrates in circulation are glucose and lactate.

The primary storage form of carbohydrates in the body is glycogen.

The key intracellular intermediates in carbohydrate metabolism are glucose-6-phosphate and pyruvate.

The main function of carbohydrates in the body is to serve as the primary source of fuel for the brain.

1. Converts glucose to lactate (anaerobic)
2. Forms pyruvate (aerobic)

Glycolysis is controlled by product inhibition by ATP and related compounds, which serves as a very effective control mechanism.

The function of glycogen synthesis and breakdown is to store the body's glucose:

1. In the liver, glycogen supplies glucose to the brain.
2. In muscle, glycogen is the substrate used to regenerate ATP during exercise.

Effective controls are exerted over both synthesis (via glycogen synthase) and breakdown (via glycogen phosphorylase).

The glycolytic pathway converts a 6-carbon molecule (hexose) into two 3-carbon molecules (pyruvate or lactate).

Two ATP molecules are used for the phosphorylation of the hexose, and glycolysis generates a net yield of two ATP molecules per molecule of glucose.

Each triose yields one NADH upon conversion to pyruvate, which is reoxidized either when lactate is formed or when transported into the mitochondria for ATP synthesis or fatty acid synthesis.

Phosphate groups are added to retain intermediates inside cells and to facilitate the conversion of the 6-carbon molecule into two 3-carbon molecules.

The three stages of glycolysis are: 1. Activation, 2. Oxidation, 3. ATP production.

UDP-Gal is formed from Galactose-1-P and is essential for the conversion of galactose into glucose derivatives, facilitating its entry into glycolysis.

The conversion of glucose-1-P to G6P is a crucial step that allows glucose to enter glycolysis, where it can be further metabolized for energy production.

The conversion of fructose to glyceraldehyde is important as it allows fructose to be integrated into the glycolytic pathway, contributing to energy production.

The end products of glycolysis from simple sugars are 2 molecules of pyruvate, which can be further utilized in cellular respiration or fermentation.

Aldolase catalyzes the cleavage of fructose-1,6-bisphosphate into glyceraldehyde and dihydroxyacetone phosphate (DHAP), which are key intermediates in glycolysis.

PFK1 (Phosphofructokinase 1) is a key regulatory enzyme in glycolysis that catalyzes the conversion of fructose-6-phosphate (F6P) to fructose-1,6-bisphosphate (F1,6P2), using ATP as a phosphate donor. This step is crucial for controlling the flow of glucose through the glycolytic pathway.

Pyruvic acid, produced at the end of glycolysis, can enter the mitochondria where it is converted into acetyl-CoA, which then enters the Krebs cycle. This process is essential for ATP production as it links glycolysis to aerobic respiration, allowing for further energy extraction from glucose.

NADH is a crucial electron carrier that is produced during glycolysis and the Krebs cycle. However, it is impermeable to the mitochondrial membrane and must be shuttled into the mitochondria via specific shuttle systems, such as the malate-aspartate shuttle, to contribute to ATP production through oxidative phosphorylation.

ATP is used to phosphorylate glucose, activating it for further reactions. Specifically, 2 ATP molecules are invested to convert glucose into fructose-1,6-bisphosphate, facilitating the breakdown of glucose into two three-carbon molecules.

The energy generation phase of glycolysis produces 2 NADH and 4 ATP molecules through substrate-level phosphorylation, resulting in a net gain of 2 ATP after accounting for the 2 ATPs invested in the energy investment phase.

The six-carbon sugar phosphate is cleaved into two three-carbon sugar phosphates, specifically glyceraldehyde-3-phosphate and dihydroxyacetone phosphate, during reactions 4 and 5 of glycolysis.

1,3-bisphosphoglycerate is a super-high-energy compound generated during glycolysis, which is crucial for the subsequent production of ATP and NADH, enhancing the energy yield of the pathway.

Pyruvate is formed at the end of glycolysis through a series of reactions that involve the conversion of phosphoenolpyruvate, resulting in the generation of 2 ATP molecules via substrate-level phosphorylation.

Dietary lipids break down into glycerol and fatty acids.

Polysaccharides break down into glucose, which undergoes glycolysis to form pyruvate. This process is crucial for energy production.

Acetyl CoA serves as a key intermediate that enters the citric acid cycle (TCA cycle), leading to the production of CO2, NADH, and ultimately ATP through oxidative phosphorylation.

Proteins break down into amino acids, which can be utilized for energy production or other metabolic processes.

The citric acid cycle is essential for converting Acetyl CoA into energy, producing CO2, NADH, and feeding into the oxidative phosphorylation pathway to generate ATP, H2O, and O2.

The two distinct phases of glycolysis are:

1. Energy Investment Phase:

   • Input: 2 ADP
   • Output: 2 ATP

2. Energy Generation Phase:

   • Input: 4 ADP
   • Output: 4 ATP
   • Input: 2 NAD+
   • Output: 2 NADH

Overall, glycolysis converts glucose into 2 pyruvate, yielding a net of 2 ATP and 2 NADH.

Lactate dehydrogenase catalyzes the conversion of pyruvate to lactate by facilitating the transfer of electrons from NADH + H+ to NAD+, thus playing a crucial role in anaerobic metabolism.

The chemical formula for pyruvate is:

• COO
• C=O
• CH3

The chemical formula for lactate is:

• COO
• HO-C-H
• CH3

The key intermediates produced during glycolysis include:

1. Glucose 6-Phosphate
2. Fructose 6-Phosphate
3. Fructose 1,6-bisphosphate
4. Glyceraldehyde 3-Phosphate
5. 1,3-bis-Phosphoglycerate
6. 3-Phosphoglycerate
7. 2-Phosphoglycerate
8. Phosphoenolpyruvate
9. Pyruvate

The end products of glycolysis differ between aerobic and anaerobic conditions:

• Aerobic Glycolysis: The end product is Pyruvate, which is further converted to Acetyl CoA for entry into the Krebs cycle.
• Anaerobic Glycolysis: The end product is Lactate, which is produced when oxygen is not available for further metabolism of pyruvate.

NAD+ and NADH are crucial coenzymes in glycolysis:

• NAD+ acts as an electron acceptor, facilitating the conversion of glyceraldehyde 3-phosphate to 1,3-bis-phosphoglycerate.
• NADH is produced during this reaction and carries electrons to the electron transport chain during oxidative phosphorylation, contributing to ATP production.

The first irreversible step in glycolysis is the phosphorylation of glucose to form glucose 6-phosphate (G-6-P), catalyzed by Hexokinase in the presence of ATP and Magnesium ions (Mg++).

Glucose 6-phosphate cannot diffuse back out of the cell because the cell membrane is impermeable to it, thus trapping it inside for further metabolic processes.

Glucose 6-phosphate (G-6-P) can be converted into several metabolites:

1. Glucose 1-phosphate leading to Glycogen
2. Fructose 6-phosphate leading to Glycolysis
3. Glucosamine 6-phosphate via the Pentose pathway
4. Glucuronate

Glucokinase acts as a 'glucostat', metabolizing or storing glucose when blood glucose is high and remobilizing it when blood glucose is low.

Glucokinase has a high Km of 20mM, while hexokinase has a much lower Km of 0.01mM, making hexokinase saturated with glucose under normal physiological conditions.

Insulin controls the amount of glucokinase, which is an inducible enzyme, promoting its activity when blood glucose levels are high.

G-6-P exerts absolute control over the rate of entry of glucose into glycolysis in tissues where hexokinase is present, acting as a product inhibitor that decreases the velocity of the reaction.

The low Km of hexokinase (0.01mM) ensures that it is saturated with glucose, providing a constant supply of glucose-6-phosphate for energy production in the brain.

Synthesis of liver pyruvate kinase can be induced by a high carbohydrate diet. Its activity is regulated by phosphorylation (which decreases activity) and dephosphorylation (which increases activity), and is under hormonal control influenced by blood glucose levels.

When blood glucose levels are low, insulin decreases and glucagon rises, leading to an increase in liver cAMP, which results in the phosphorylation and inactivation of pyruvate kinase, favoring the conversion of amino acids to glucose.

1. Formation of Lactic Acid: In animal tissues and certain bacteria, pyruvate is converted to lactic acid by lactate dehydrogenase, reoxidizing NADH to NAD+.

2. Formation of Alcohol: In yeast and certain microorganisms, pyruvate undergoes decarboxylation to form acetaldehyde, which is then converted to ethanol with the help of alcohol dehydrogenase, also reoxidizing NADH to NAD+. This process requires thiamine pyrophosphate (vit. B₁).

Under aerobic conditions, pyruvate is converted to AcetylCoA through a reaction catalyzed by pyruvate dehydrogenase. This reaction also produces NADH and CO2, linking the glycolytic pathway with the TCA cycle. AcetylCoA serves as an important intermediate in lipid metabolism, cholesterol biosynthesis, and acetylation reactions.

The key enzymes involved in glycolysis include:

1. Hexokinase: Converts Glucose to Glucose-6-Phosphate (uses - ATP).
2. PFK-1: Converts Fructose-6-Phosphate to Fructose-1,6-Bisphosphate.
3. Pyruvate Kinase: Converts Phosphoenol-pyruvate (PEP) to Pyruvate (produces + 2 ATP).

In glycolysis, ATP and NADH are produced during the energy-acquiring phases:

• ATP: A total of + 2 ATP is produced during the conversion of 2 Phosphoenol-pyruvate (PEP) to 2 Pyruvate.
• NADH: A total of + 2 NADH is produced during the conversion of Glyceraldehyde-3-Phosphate to 1,3-Bisphosphoglycerate.

These molecules are crucial for energy transfer and storage in cellular metabolism.

Glycolysis illustrates energy consumption and acquisition through:

• Energy Consumption: The initial steps (e.g., Hexokinase and PFK-1) consume ATP to convert glucose into intermediates.
• Energy Acquisition: Subsequent steps produce ATP and NADH, particularly during the conversion of 1,3-Bisphosphoglycerate to 3-Phosphoglycerate and from PEP to Pyruvate, resulting in a net gain of energy.

The net ATP production from glycolysis per glucose molecule is +2 ATP.

The overall reaction of glycolysis is:

Reactants:
Glucose + 2ADP + 2Pi + 2 NAD+

Products:
2 pyruvate + 2ATP + 2NADH + 2H+ + 2H2O

In the mitochondria, 2 NADH contribute to the production of 6 ATP through oxidative phosphorylation when combined with oxygen and other substrates.

The addition of NADH and ADP in the overall reaction leads to the conversion of glucose into 2 pyruvate, producing 8 ATP and 10 H2O in total.

The initial substrate is Glucose, which is converted to Glucose 6-phosphate.

The conversion of 2 PEP results in the production of 2 Pyruvate and 2 ATP.

The net synthesis during glycolysis is 2 moles of ATP.

NAD+ is converted to NADH during the conversion of Pyruvate to Lactate in the mitochondria.

Fructose 1,6-bisphosphate is converted to 3-Phosphoglyceraldehyde and DHAP (dihydroxyacetone phosphate).

Hexokinase catalyzes the conversion of Glucose to Glucose-6-Phosphate, utilizing 1 ATP in the process.

The energy acquiring phase of glycolysis results in the production of 2 Pyruvate and 2 ATP from Fructose-1,6-Bisphosphate through several enzymatic steps.

In the energy consumption phase of glycolysis, 2 ATP molecules are used: one during the conversion of Glucose to Glucose-6-Phosphate and another during the conversion of Fructose-6-Phosphate to Fructose-1,6-Bisphosphate.

The conversion of Dihydroxyacetone to Glyceraldehyde-3-Phosphate produces 2 NADH molecules.

PFK-1 (Phosphofructokinase-1) is a key regulatory enzyme in glycolysis that catalyzes the conversion of Fructose-6-Phosphate to Fructose-1,6-Bisphosphate, using 1 ATP and playing a crucial role in controlling the glycolytic pathway.

ATP is used to phosphorylate glucose, converting it to glucose 6-phosphate, and in the process, ADP is produced.

Fructose 1,6-bisphosphate is converted into 3-Phosphoglyceraldehyde and Dihydroxyacetone phosphate.

Under anaerobic conditions, a net synthesis of two molecules of ATP occurs for every molecule of glucose that enters the glycolytic pathway.

Phosphoenolpyruvate is converted to Pyruvate, producing ATP in the process.

NAD is reduced to NADH during glycolysis, which is crucial for the continuation of the pathway and for energy production under anaerobic conditions.

The main categories of essential nutrients from the diet include:

1. Energy sources:

   • Carbohydrates
   • Fats
   • Protein
   • Ethanol

2. Essential fatty acids

3. Essential amino acids

4. Vitamins

5. Minerals

In a well-fed state, nearly 100% of the brain's energy needs are met by glucose. In a starved state, the brain uses a combination of:

1. Glucose - ~30%
2. 3-Hydroxybutyrate - major part
3. Acetoacetate - smaller portion
4. Amino acids - small portion

This shift indicates the brain's adaptation to using ketone bodies during starvation.

Obesity, often referred to as Globesity, affects approximately 67% of the U.S. population, leading to various health issues such as cardiovascular disease (CVD) and diabetes mellitus (DM).

The Atkins diet is a low carbohydrate, high fat and protein diet that aims to reduce insulin release. A high carbohydrate diet elevates insulin levels, leading to glucose storage and potential obesity. By depleting glucose through a low carb intake, the body burns fat for energy instead of relying on glucose.