20241129_Carbs1

1. Glycoproteins: e.g. mucins
2. Proteoglycans: e.g. cartilage matrix proteoglycan, fibronectin

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

1. Glycolysis
2. Gluconeogenesis
3. The synthesis and breakdown of glycogen

1. Glucose - the energy fuel that has the highest concentration in the blood.
2. Lactate - the major precursor of glucose in the circulation.
3. Glycogen - the storage form of carbohydrate in the body.

The main forms in circulation are glucose and lactate.

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

The key cellular intermediates are glucose-6-phosphate and pyruvate.

The function of glucogenesis is to synthesize glucose or glucose-6-phosphate (G-6-P) from pyruvate, and it is not simply a direct reversal of glycolysis.

Glycogen serves as the storage of the body's glucose. In the liver, it supplies glucose to the brain, while in muscle, it is the substrate used to generate ATP during exercise.

1. Hydrolysis of complex molecules to their component building blocks
2. Conversion of building blocks to acetyl CoA (or other simple intermediates)
3. Oxidation of acetyl CoA; oxidative phosphorylation

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

The key enzymes involved are glycogen synthase for synthesis and glycogen phosphorylase for breakdown, both of which exert effective controls over their respective processes.

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

The primary function of glycolysis is the regeneration of ATP. It converts glucose to lactate in anaerobic conditions and forms pyruvate in aerobic conditions.

The main storage form of carbohydrates is glycogen.

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

Glycolysis uses two ATP molecules for phosphorylation at the hexose level and 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 intermediates to retain them inside cells, preventing their diffusion out of the cell.

Inorganic phosphate is added at the triose level during glycolysis, contributing to the energy yield of the pathway.

1. Glucose is converted to Hexose monophosphates (G6P and F6P) by GK using ATP, releasing Pi.

2. Hexose monophosphates are converted to F1,6P2 by PFK1 with the help of ATP, releasing Pi.

3. F1,6P2 is converted to PEP using ATP.

4. PEP is converted to Pyruvic acid by PK with the help of ATP.

1. PEP is converted to Oxaloacetate by PEPCK using ATP.

2. Alternatively, malate or aspartate is transferred into the mitochondrion and converted to Oxaloacetate by PC with the help of ATP.

ATP is used to phosphorylate glucose and fructose-1,6-bisphosphate, activating these molecules for further breakdown. This investment of 2 ATPs is crucial for the initial steps of glycolysis.

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

The final product of glycolysis is pyruvate, which can be further metabolized in aerobic or anaerobic conditions, playing a crucial role in cellular respiration and energy production.

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

The first step in glycolysis is the formation of Glucose-6-Phosphate from Glucose, ATP, ADP, and Pi. This reaction is catalyzed by hexokinases (Types I to III) and glucokinases (Type IV).

The formation of Glucose-6-Phosphate is catalyzed by hexokinases (Types I to III) in most tissues and glucokinases (Type IV) mainly in the liver.

The reaction forming Glucose-6-Phosphate is considered essentially irreversible because the Vmax and Km of the enzymes favor the forward reaction over the reverse reaction, and it is sensitive to inhibition by G-6-P under physiological conditions.

The phosphorylation of glucose is a unidirectional process under physiological conditions, meaning it primarily proceeds forward to form Glucose-6-Phosphate, which is crucial for the regulation of glycolysis and energy metabolism.

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

G-6-P exerts absolute control over the rate of entry of glucose into glycolysis in tissues where hexokinase Type I is present, ensuring a constant input of G-6-P regardless of blood glucose levels.

Glucokinase is an inducible enzyme, and its amount is under the control of insulin, which regulates its expression in the liver.

Hexokinase functions at or near Vmax under physiological conditions due to its low Km, meaning its velocity is largely independent of glucose concentration once saturated.

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

ATP acts as an inhibitor of PFK1, decreasing the reaction velocity at higher concentrations, while AMP serves as an activator, increasing the reaction velocity. This creates a synergistic effect that enhances the sensitivity of control over PFK1 activity.

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 may be particularly important in muscle tissue.

A high concentration of H+ is a strong inhibitor of PFK1, which may help protect muscles from excess accumulation of H+ during anaerobic glycolysis.

Pyruvate kinase (PK) 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.

The synthesis of liver pyruvate kinase can be induced by a high carbohydrate diet.

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.

Phosphorylation of pyruvate kinase makes it less active, while dephosphorylation increases its activity.

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 is first converted to acetaldehyde by pyruvate decarboxylase, and then to ethanol by alcohol dehydrogenase, also reoxidizing NADH to NAD+. This process requires thiamine pyrophosphate (vit. B1).

Under aerobic conditions, pyruvate is converted to AcetylCoA through the reaction:

Pyruvate + NAD+ + CoA → AcetylCoA + NADH + CO2.

This reaction is catalyzed by pyruvate dehydrogenase, a complex involving three enzymes and five coenzymes, linking glycolysis to the TCA cycle. AcetylCoA is also crucial for lipid metabolism and cholesterol biosynthesis.

AcetylCoA serves as a central intermediate in several metabolic pathways, including:

• Lipid Metabolism: Involved in the synthesis and breakdown of fatty acids.
• Cholesterol Biosynthesis: Precursor for cholesterol production.
• Acetylation Reactions: Participates in various biochemical reactions requiring acetyl groups.

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

The overall reaction of glycolysis is:

Glucose + 2ADP + 2Pi + 2 NAD⁺ → 2 pyruvate + 2ATP + 2NADH + 2H⁺ + 2H₂O

The three non-equilibrium reactions in glycolysis are:

1. Hexokinase (HK) - catalyzes the conversion of glucose to glucose-6-phosphate (G6P), controlling the entry of glucose into the glycolytic pathway.

2. Phosphofructokinase-1 (PFK1) - converts fructose-6-phosphate (F6P) to fructose-1,6-bisphosphate (F1,6P2), serving as a key regulatory step in glycolysis.

3. Pyruvate Kinase (PK) - converts phosphoenolpyruvate (PEP) to pyruvate, primarily regulating glycolysis and influencing gluconeogenesis and the synthesis of 2,3-diphosphoglycerate in red blood cells.

The TCA cycle plays a central role in energy metabolism by generating reducing equivalents in the form of NADH and FADH, which are used in the electron transport pathway for energy production.

All reactions of the TCA cycle take place in the mitochondrial matrix.

Acetyl CoA enters the TCA cycle by condensing with oxaloacetate to form a six-carbon compound, which then undergoes a series of reactions to regenerate oxaloacetate.

Acetyl CoA can be formed from pyruvate (through decarboxylation), fatty acids (via β-oxidation), or amino acids.

Most of the oxidative reactions in the TCA cycle are dehydrogenations, involving the removal of two hydrogens to an acceptor molecule, which is typically NAD or FAD.

The major function of the TCA cycle is to provide reducing equivalents (NADH and FADH) to the electron transport pathway for energy production.

The TCA cycle proceeds in two phases:

1. Addition of a two-carbon moiety (acetyl CoA) to a four-carbon compound (oxaloacetate) to form a six-carbon organic anion, citrate, followed by the loss of two carbons as CO2 (steps 1-4).
2. Regeneration of oxaloacetate (steps 5-8).

The TCA cycle is influenced by the energy and redox states of the cell through allosteric interactions and substrate concentrations. High ratios of ATP/ADP, acetyl CoA/CoA, and NADH/NAD+ inhibit the cycle, while increased ADP concentrations stimulate isocitrate dehydrogenase, enhancing cycle activity.

Isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase are key sites for allosteric regulation in the TCA cycle. They facilitate the conversion of substrates and are inhibited by NADH, which directly affects the cycle's operation.

Pyruvate dehydrogenase regulates the TCA cycle by controlling the conversion of pyruvate to acetyl CoA. It is inhibited by ATP, NADH, and acetyl CoA, while activated by AMP, thus responding to the cell's energy needs.

One turn of the TCA cycle yields a total of 12 ATPs, which includes ATP produced from various steps: 3 ATP from isocitrate to alpha-ketoglutarate, 3 ATP from alpha-ketoglutarate to succinyl CoA, 1 GTP (ATP) from succinyl CoA to fumarate, 2 ATP from succinate to fumarate, and 3 ATP from malate to oxaloacetate.

TCA cycle intermediates are involved in amino acid metabolism through transamination reactions:

1. Glutamate is converted to α-ketoglutarate.
2. Aspartate is converted to oxaloacetate.
3. Alanine is converted to pyruvate.

In lipid metabolism, TCA cycle intermediates play key roles:

• AcetylCoA and citrate are starting points for the biosynthesis of fatty acids.
• AcetylCoA is also produced from the breakdown of fatty acids and is the starting point for steroid synthesis.

SuccinylCoA, along with glycine, is essential for the biosynthesis of porphyrins, which are crucial for the production of hemoglobins, cytochromes, and other hemoproteins.

In nitrogen metabolism, aspartate serves as a nitrogen source in biosynthetic pathways, such as the production of argininosuccinate and purines. The end product of these processes is fumarate, which then re-enters the TCA cycle.

The products of glycolysis are:

• 2 pyruvate
• 2 NADH
• 2 H+
• 2 ATP
• 2 H2O

Assuming that two molecules of ATP are formed, the oxidation of two NADH generates 4 ATP.

NADH is produced during glycolysis and is essential for the oxidation process, contributing to ATP generation when oxidized in the mitochondria.

The products of the TCA cycle are:

• 6 CO2
• 30 ATP
• 34 H2O